Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C[O-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N+]([O-])=O)[CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ccnc1Sc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 52.8 %

Procedure:
To a solution of 10 g (87.7 mmoles) of 2-mercapto-1-methylimidazole in 300 ml of ethanol was added 10.4 g (193 mmoles) of sodium methoxide followed by 20.8 g (92.1 mmoles) of 1-chloro-3,4-dinitrobenzene. The mixture was stirred and refluxed for 8 hours. An additional 3 g of sodium methoxide was added and refluxing was continued for 5 more hours. The mixture was filtered hot and the filtrates concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organics were dried and concentrated. The residue was recrystallized from dichloromethane and methanol to give 12.5 g (53%) of the product as yellow prisms, mp 130°-131° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(OCC)(=O)C>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[CH2:8][CH2:7][CH:2]2[O:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(CCC1OCCCO1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
108 mL of (1,3-dioxan-2-ylethyl) magnesium bromide (0.5M) was added to a solution of 4-bromobenzaldehyde (10 g, 54.0 mmol) in THF (350 mL) at −78° C. under nitrogen and stirred for 2 hours before warming to 0° C. The reaction was quenched with sat NH4Cl soln, diluted with diethyl ether and washed with brine. The crude product was charged (CH2Cl2) to a 40M Biotage silica gel cartridge; Gradient elution 15-100% B over 750 mL (A=Hexanes; B=ethyl acetate) to give Example J1, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-ol (quantitative yield). 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.70-4.66 (m, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.12-4.19 (m, 2H), 3.76 (tt, J=11.9, 2.7 Hz, 2H), 2.87 (d, J=3.7 Hz, 1H), 2.12-2.03 (m, 1H), 1.86-1.87 (m, 2H), 1.74-1.68 (m, 2H), 1.36-1.32 (m, 1H). RT=1.8 minutes (condition 1); LRMS: No parent ion evident.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:17]=[CH:16][CH:15]=1.O.NN>C1COCC1>[NH2:3][O:12][CH2:13][C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cccc(N2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NOCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (50 g, 125 mmol) in THF (350 mL) was added dropwise hydrazine hydrate (61 mL, 1.25 mol) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. Purification of the residue on silica gel afforded 6-[(aminooxy)methyl]pyridin-2-amine as a colourless oil [10.0 g; 57% of theory; HPLC/MS: m/z=140 (M+H); log P(HCOOH)<−0.23].
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH:17]2[CH2:19][CH2:18]2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21].NN>C(O)C.CCCCCCC.Cl>[CH:17]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:6]=2[C:4](=[O:5])[N:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)[N:21]=3)[CH2:18][CH2:19]1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CCCCCCC
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Yield: 80.2 %

Procedure:
4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 0.0041 mols) and 4-hydrazino-benzoic acid (1.0 g, 0.0068 mols) were stirred in ethanol (30 ml) at reflux for 16 h. The bright yellow suspension was diluted with heptane, filtered, washed with cold t-butylmethyl ether and left to dry under suction to yield crude solid containing hydrazine. This solid was suspended in 1 M HCl, filtered, washed with water and then dried in vacuo to yield 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (1.135 g, 80%) as a yellow solid, LCMS m/z 346.20 [M+H]+ @ RT 1.05 min: 96% purity. δH (400 MHz, (CD3)2SO) 11.4 (1H, s), 8.43 (2H, d, J 8.1), 8.21 (1H, dd, J1 1.2, J2 8.1), 8.07 (2H, d, J 8.1), 7.92 (1H, d, J 8.1), 7.67 (1H, t, J 6.6), 7.52 (1H, t, J 6.5), 3.43 (1H, m), 1.59 (2H, m), 1.43 (2H, m). Step 4 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]-quinolin-2-yl)-benzoyl chloride
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1.ICCCCCCOCCC#CC1C=C(N2C(=O)CNC2=O)C=CC=1.[CH2:51]([NH:58][CH2:59][C@@H:60]([C:62]1[CH:73]=[CH:72][C:65]2[O:66][C:67]([CH3:71])([CH3:70])[O:68][CH2:69][C:64]=2[CH:63]=1)[OH:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(#N)C.C(N(C(C)C)CC)(C)C>[CH2:51]([N:58]([CH2:59][C@@H:60]([C:62]1[CH:73]=[CH:72][C:65]2[O:66][C:67]([CH3:70])([CH3:71])[O:68][CH2:69][C:64]=2[CH:63]=1)[OH:61])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Reactant: O=C1CNC(=O)N1c1cccc(C#CCCOCCCCCCBr)c1
Agent: O=C1CNC(=O)N1c1cccc(C#CCCOCCCCCCI)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCC#Cc3cccc(N4C(=O)CNC4=O)c3)Cc3ccccc3)ccc2O1
Temperature: 50 °C

Procedure:
A solution of 3-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione and 3-(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione (3:1, 23.98 g) in acetonitrile (240 ml) and diisopropylethylamine (20 ml) was treated with (1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (18.22 g) and the mixture was heated to 50° C. for 5 days. The solvent was removed under reduced pressure, the residue was diluted with EtOAc (250 ml) and washed with water. The aqueous phase was re-extracted with EtOAc (75 ml) and the combined organic solutions were washed with brine, dried (MgSO4), and evaporated. The residue was purified by chromatography on flash silica gel eluting with dichloromethane-EtOAc (1:1) to give the title compound (17.25 g) LCMS RT=2.80 min
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.[CH2:18]([O:25][C:26]1[CH:27]=[C:28](Br)[C:29]([C:32]#[N:33])=[N:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH2:18]([O:25][C:26]1[CH:31]=[N:30][C:29]2[C:28]([CH:27]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:32]=2[NH2:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: N#Cc1ncc(OCc2ccccc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Nc1nc2ccccc2c2cc(OCc3ccccc3)cnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 5-(benzyloxy)-3-bromopicolinonitrile (from step 3) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 50-100% ethyl acetate in hexane to give 2-(benzyloxy)benzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 8.36 (s, 1H), 7.86 (s, 1H), 7.59-7.56 (d, 2H), 7.46-7.42 (dd, 2H), 7.40-7.37 (d, 1H), 7.20-7.15 (dd, 1H), 7.12-7.09 (d, 1H), 6.88-6.86 (d, 1H), 6.77-6.73 (dd, 1H), 5.51 (s, 2H), 4.74 (br, 2H). LRMS [M+H]=302.3.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:8]2[N:9]=[CH:10][N:11]([C:43]=2[N:44]=[CH:45][N:46]=1)[C@:12]1(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:23][C@H:18]([CH2:19][O:20]OC)[C@@H:16]([OH:17])[C@H:13]1[O:14][CH3:15])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>N1C=CC=CC=1>[C:47]([O:17][C@@H:16]1[C@@H:18]([CH2:19][OH:20])[O:23][C@@H:12]([N:11]2[C:43]3[N:44]=[CH:45][N:46]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:8]=3[N:9]=[CH:10]2)[C@@H:13]1[O:14][CH3:15])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCCC(=O)Nc1ncnc2c1ncn2[C@]1(C(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H](COOC)[C@@H](O)[C@H]1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-Butyryl-5′-O-monomethoxytrityl-2′-O-methyladenosine 7 (100 mg, 0.16 mmol) was dried by evaporation of added dry pyridine (5 mL) under reduced pressure and finally by keeping on a vacuum pump for 30 min. Dry pyridine was added (2 mL) and the solution was put into ice-bath whereupon benzoyl chloride was added (1.2 eq, 0.19 mmol, 22.2 μL) and after 10 min the ice-bath was removed and the reaction was allowed to warm up and was then left stirring overnight at room temperature. A small amount of NaHCO3 (aq. sat.) was added and the solvent was evaporated under reduced pressure. Dichloromethane was added and the organic phase was washed with NaHCO3 (aq. sat. 2×). The organic phase was collected, dried (MgSO4), filtered and concentrated. Evaporation of added toluene (2×) and dichloromethane (2×) was done to remove traces of pyridine. The remaining crude material of compound 8 was dissolved in 80% acetic acid (10 mL) and allowed to react at room temperature for 4 h. after which deprotection of 5′-monomethoxytrityl was complete (TLC, mass). The solution was concentrated and added toluene (2×) and dichloromethane (2×) evaporated under reduced pressure to remove excess acetic acid. The compound was purified on silica gel column chromatography using a gradient of methanol in dichloromethane (0-5%). Yield 80% of compound 9. 1H NMR (CDCl3) δ 1.04 (3H, t, J=7.4 Hz), 1.80 (2H, m), 2.92 (2H, t, J=7.4 Hz), 3.31 (3H, s), 3.96 (2H, m), 4.51 (1H, s), 4.87 (1H, m), 5.90 (1H, d, J=4.9 Hz), 6.01 (1H, d, J=7.9 Hz), 6.32 (1H, d, J=9.9 Hz), 7.27 (2H, m), 7.51 (1H, m), 8.12 (2H, m), 8.18 (1H, s), 8.70 (1H, s), 9.27 (1H, s), 13C NMR δ 13.9, 18.4, 40.0, 59.3, 63.1, 72.7, 77.4, 81.4, 86.8, 89.9, 123.7, 128.1, 128.9, 129.8, 133.7, 143.5, 150.2, 152.1, 165.8, 173.5, MS (ES-TOF) m/z calculated: 455.18. found: 455.38.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.CCOC(C)=O>C1COCC1>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-thiol (1.14 g, 10 mmol) in THF (50 ml) under argon at 0° C. was treated with NaH (303 mg, 11.98 mmol). The mixture was warmed to rt. A solution of 2-chloro-1-fluoro-4-nitro-benzene (1.76 g, 10 mmol) in THF (50 ml) was added, and the mixture was stirred at 70° C. for 4 h, cooled to rt. Treated with EtOAc (100 ml), the mixture was washed with H2O (2×25 ml), 1N KOH (30 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave a yellow solid. Recrystalization of the solid in CH2Cl2/hexanes gave 426A (2.31 g, 86%) as a slight yellowish solid. It has a retention time of 3.99 min (standard LC1 method, 8 min run). MS Found: (M+H)+=270.1
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:31])[CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[ClH:32]>O.C(O)C>[ClH:32].[ClH:32].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:21]3=[O:31])[CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCN(c3ccccc3)C2=O)cn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(CC(C(=O)O)c2cn(C3CCN(c4ccccc4)C3=O)cn2)cn1

Procedure:
A solution of 23.1 mg (0.06 mmol) of the compound from example 9a in 0.5 ml of water and 0.5 ml of 37% strength hydrochloric acid was treated in a microwave at 180° C. for 3 min. The reaction solution was taken up in ethanol and concentrated under reduced pressure several times. Freeze-drying of the residue taken up in water afforded 19.0 mg of the desired compound in the form of an amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1>C(O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCNC1
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 3-pyridinylcarbamate (2.2 g) and 5% rhodium on carbon (200 mg) in ethanol (50 mL) at 25° C. in a paar apparatus was stirred under hydrogen at 60 pounds per square inch for 24 hours, filtered through diatomaceous earth (Celite®), and concentrated. 1H NMR (300 MHz, CDCl3) δ 5.86 (b, 1H), 3.59 (b, 1H), 3.07 (dd, 1H), 2.84 (m, 1H), 2.68 (m, 1H), 2.55 (m, 1H), 2.10 (s, 1H), 1.82 (m, 1H), 1.68 (m, 1H), 1.50 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Br)c1C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of 2-amino-6-bromo-benzoic acid (3.06 g, 14.2 mmol) in toluene (75 mL) cooled to 0° C. in an ice-bath was added pyridine (0.60 mL, 7.10 mmol) followed by a solution of chloroacetyl chloride (2.26 mL, 28.4 mmol) in toluene (75 mL) drop-wise over 1 hr. The reaction mixture was allowed to warm to RT, and was heated at 115° C. for 3 hr and then allowed to cool to RT. The solvent volume was reduced by half by evaporation in vacuo. Upon standing overnight, the product precipitated and was collected by filtration to afford 2-bromo-6-(2-chloroacetamido)benzoic acid (1a, X═Cl) (1.44 g) as a white solid: m/z 290/292 (M+H)+ (ES+). The filtrate was concentrated in vacuo and the residue triturated with ethanol/heptane to afford 2-bromo-6-(2-hydroxyacetamido) benzoic acid (1b X═OH) (1.02 g, combined yield, 59%): m/z 274/276 (M+H)+ (ES+). Both 1a and 1b can be used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH:16]([N-]C(C)C)([CH3:18])[CH3:17].[Li+].C(Br)C=C.Cl>O1CCCC1>[OH:1][C:2]1[CH:11]([CH2:18][CH:16]=[CH2:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1=C(O)CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1Cc2ccccc2C(C(=O)OC)=C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a stirred solution of 3,4-dihydro-2-hydroxynaphthalene carboxylic acid, methyl ester (36.2 g, 177 mmol) in dry tetrahydrofuran (440 ml) at -30° C. under argon was added dropwise lithium diisopropylamide (195 ml, 2M solution, 390 mmol). Allyl bromide (24.3 ml, 284 mmol) was then added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, then treated with hydrochloric acid (5M) to pH2-3. The resulting mixture was extracted with ethyl acetate (2×1000 ml) and the combined extracts were washed with brine (1000 ml), dried (Na2SO4) and evaporated in vacuo to give the title compound as a brown oil (46.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[S:27][C:26]([CH2:28]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:26]3[S:27][C:23]([Br:22])=[CH:24][CH:25]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Br)s1
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCc3ccc(Br)s3)cc2)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
3.5 g of 4-(6-chloro-2-pyridinyloxy)-phenol and 3.2 g of potassium carbonate are stirred for one hour at 60° C. in 100 ml of anhydrous dimethylformamide. Subsequently, 6.5 g of 5-bromo-2-chloromethylthiophene in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 6 hours at 80° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 200 ml of ice water. The crude product which precipitates out is filtered off and recrystallized from n-hexane/ethyl acetate (4/1). There is obtained 3.1 g of 2-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-5-bromothiophene of m.p.: 78°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:27]([O:33][CH2:34][O:14][C:13](=[O:15])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)COc1ccc(Cc2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.3 g (0.06 mol) of 4-(4'-chlorobenzyl)-phenoxy acetic acid in 50 ml of dimethylformamide are added 6.0 g (0.06 mol) of triethylamine, whereafter the mixture is stirred for 30 minutes at room temperature and, after adding 9.0 g (0.06 mol) of chloromethyl pivalate, is heated for 6 hours in an oil bath at 85°-90° C. The residue which is obtained by concentration by evaporation at reduced pressure in a Buchi rotary evaporator is washed with water and extracted with ether. The ethereal solution is once again washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation in the Buchi rotary evaporator, an oil being obtained which quickly solidifies. By recrystallisation from ether/n-hexane, 9.5 g of product are obtained in the form of white crystals with the melting point 54°-55° C.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.ClCCl>[N:21]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:20])([F:1])[CH2:3][CH2:4]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCC1CCC(F)(F)CC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of toluene-4-sulfonic acid 4,4-difluorocyclohexylmethyl ester (100 mg, 0.33 mmol)) in N,N-Dimethylformamide (0.5 mL) was added sodium azide (32 mg, 0.49 mmol). The reaction mixture was stirred at 90° C. for 90 min, cooled to room temperature and diluted with dichloromethane (5 mL). The organic layer was washed with water (2×5 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.CC(C)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1([CH3:22])[NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1cc(-c2ccncc2)sc1N
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)NC(=O)c2cc(-c3ccncc3)sc2N1
Yield: 18.1 %

Procedure:
A mixture of 2-amino-5-(pyridin-4-yl)thiophene-3-carboxamide (300 mg, 1.37 mmol), p-toluenesulfonic acid monohydrate (150 mg) and acetone (30 mL) in toluene (30 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the crude title compound (70 mg), which was further purified by preparative TLC to give the title compound (37 mg, yield 10%) as an orange solid:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O)(=O)[C:10](O)=[O:11].C=O>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:10]=[O:11])[OH:2]
Reactant: O=C(O)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: C=O
Solvent: O
Product: O=Cc1c(O)cccc1O
Reaction time: 1 h

Procedure:
In terms of weight, 110 parts of resorcinol, 0.62 part of oxalic acid, and 248 parts of water were charged into a flask, to which 50 parts of 37% formalin was dropwise added at 60° C. in one hour under stirring. Then, the stirring was further continued for 1 hour to obtain a resorcinol-formaldehyde condensate (B) containing excess resorcinol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: N#Cc1ccnc(-c2ccc(F)cc2)c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A mixture of 2-chloro-isonicotinonitrile (1.9 g), 4-fluorophenylboronic acid (2.9 g), sodium carbonate (4.3 g), tetrakis(triphenylphosphine)palladium (480 mg), 1,2-dimethoxyethane (40 mL), ethanol (20 mL) and water (20 mL) was stirred while heating at 100° C. for 2 hr. The solvent was distilled off under reduced pressure, and the resulting residue was then purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=94:6-50:50) to afford 2-(4-fluorophenyl)pyridine-4-carbonitrile (2.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.Cl.COC1C=C2C(C(CCCN3CCC(C(=O)C4C=CC(F)=CC=4)CC3)=C(C)N2)=CC=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([CH:22]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[OH:30])[CH2:18][CH2:17]3)=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(C)[nH]c2c1
Agent: Cl
Product: COc1ccc2c(CCCN3CCC(C(O)c4ccc(F)cc4)CC3)c(C)[nH]c2c1

Procedure:
A sample of 6-methoxy-2-methyl-3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indole, free base of Example 24, is reduced and treated by the method described in Example 2 to give 6-methoxy-2-methyl-3-{3-[4-(4-fluorophenylhydroxymethyl)piperidyl]propyl}indole.