Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:10][CH3:9])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1ccc(I)cn1
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)nc1

Procedure:
2-Amino-5-methoxypyridine is prepared by combining 55 g. of 2-amino-5-iodopyridine, 20 g. of sodium methoxide, 5 g. of copper powder, 500 ml. of methanol in a glass lined bomb and rocking at 150° C. for 12 hours. Upon concentration to dryness, an extraction with chloroform extracts are dried and evaporated to dryness in vacuo. The residue is chromatographed on 1200 g. of silica gel eluting with 50% ethylacetate and methylenechloride affording 2-amino-5-methoxy pyridine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)[CH:26]=[CH:25][N:24]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[CH:30]=3)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of acryloyl chloride (37 μL, 0.45 mmol) in CH2Cl2 (2.32 mL) was added dropwise over 5 minutes to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 143, 189 mg, 0.43 mmol) in CH2Cl2 (5.8 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (67 mg, 32%) as an pale yellow solid after trituration with diethyl ether; 1H NMR: 2.29 (3H, s), 2.36-2.41 (2H, m), 2.53-2.58 (2H, m), 2.98-3.02 (2H, m), 3.90 (3H, s), 3.91 (3H, s), 5.69-5.73 (2H, m), 6.22 (1H, dd), 6.52 (1H, dd), 6.86 (1H, s), 7.20-7.28 (3H, m), 7.52-7.55 (1H, m), 7.88 (1H, s), 8.33-8.37 (2H, m), 8.43 (1H, s), 8.45 (1H, s), 9.34 (1H, s); m/z: ES+ MH+ 495.70.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([C:29]6[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=6)=[CH:41][CH:40]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, off-white solid (54 mg, 53%), MS (ISP) m/z=510.5 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-pyridin-3-yl-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH:5]=[O:6]
Reactant: OCCc1ccccc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCc1ccccc1F
Yield: 99 %

Procedure:
A mixture of 2-fluorophenethyl alcohol (Intermediate C1) (commercially available from Aldrich) (2.8 g, 20 mmol) in CH2Cl2 at −10° C. was oxidized by action of pyridinium chlorochromate: PCC (5 g, 23 mmol) in the presence of Celite (10 g) for 1 h at −10° C. and a couple hours at rt. The mixture was filtered through silica gel and the solvent was removed under vacuum to give (2-fluoro-phenyl)-acetaldehyde (Intermediate C2) 2.8 g (99%).
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:9][C:10]1[C:11]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[C:12]([NH2:15])[NH:13][N:14]=1>C(O)(=O)C>[CH3:9][C:10]1[C:11]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[C:12]2[NH:15][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:13]2[N:14]=1
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2c(C)nn3c(=O)cc(C)[nH]c23)c(C)c1
Yield: 65.5 %

Procedure:
Methyl acetoacetate (0.38 ml) was added to a solution of 5-methyl-4-(2,4,6-trimethyl-phenyl)-2H-pyrazol-3-ylamine (641 mg, 2.98 mmol) in 4 ml of acetic acid. The reaction mixture was heated at reflux for overnight. The mixture was concentrated to dryness and the residue was purified through silica gel column chromatography using 5% methanol in chloroform as eluent to give 560 mg (65.5%) of the title compound as a white solid;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5](Br)=[CH:4][N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1Br
Product: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Yield: 71 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-bromopyrimidine-4-ylamino)butan-1-ol (18.17 g, 64.8 mmol) with thiophen-2-boronic acid (e. g.: Aldrich, Acros, Apin) (9.12 g, 128.0 mmol) according to procedure 3, the desired product is obtained in 71% yield (13.1 g) after chromatographic purification (silica gel, ethyl acetate/hexane (20%-50% ethyl acetate)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[CH:19]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=1)[C:29]#[N:30].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:24]3[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=3)[C:29]#[N:30])=[CH:21][N:22]=2)[CH:19]=1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3nccn3c2)c1
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cnc3ccc(N4CCCC4c4cc(F)ccc4F)cn23)ccc1F
Temperature: 90 °C

Procedure:
In step 13-3, a sealed vial was charged with 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine (30 mg, 0.1 mmol), 5-bromo-2-fluorobenzonitrile (20 mg, 0.1 mmol), Pd(OAc)2 (1 mg, 0.005 mmol), Xantphos (6 mg, 0.01 mmol), Cs2CO3 (49 mg, 0.15 mmol), Bu4NHSO4 (3 mg, 0.01 mmol) and 1,4-dioxane (0.5 ml), and the mixture was heated to 90° C. overnight. The mixture was filtered through celite. The filtrate was concentrated and purified by preparative LC-MS to give 5-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)-2-fluorobenzonitrile (12-3). LC-MS: 419.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([NH:15][C:16]([NH:10][S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])(=[O:9])=[O:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccsc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 150 ml of acetone and 3-methyl-2-thiophenesulfonamide was added 11 g of n-butyl isocyanate and 14 g of anhydrous potassium carbonate. After stirring at ambient temperature for 24 hours, the mixture was concentrated to 2/3 of its volume and poured into ice-water. The pH was adjusted to 3 by the addition of hydrochloric acid and the solid thus obtained was filtered, air dried and triturated with 1-chlorobutane to yield 10.6 g of N-(butylaminocarbonyl)-3-methyl-2-thiophenesulfonamide melting at 144°-146°. It showed absorption peaks by NMR (60 MC) at 2.6 δ (singlet, CH3), 1-1.8 δ (mult., C3H7), 3.42 δ (trip., N--CH2 -- of butyl) and at 7.1 δ and 7.7 δ (2 doublets for CH's of thiophene) consistent for the desired structure.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=[N:17]C=2C=1.C(Cl)CCl>CC#N.[NH4+].[OH-]>[CH3:1][C:2]1([C:8]([NH2:17])=[O:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCOCC1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCCl
Product: CC1(C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 4-methyltetrahydro-2H-pyran-4-carboxylic acid (2.60 g, 18.0 mmol), HOBt (2.76 g, 18.0 mmol) and EDC (4.49 g, 23.4 mmol) in MeCN (75 mL) was stirred at RT for 3 h, treated with NH4OH (˜15M, 7 mL, −105 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, and the residue was partitioned between satd. Brine (40 mL) and DCM (100 mL). The aqueous was extracted with THF (50 mL) and DCM (5×30 mL). The combined organics were washed with 10% aq K2CO3 (50 mL), dried over Na2SO4 and concentrated in vacuo to afford 4-methyltetrahydro-2H-pyran-4-carboxamide (1.83 g, 70%). 1H NMR (400 MHz, DMSO-d6): δ 7.14 (s, 1H), 6.86 (s, 1H), 3.60 (dt, J=11.7, 4.5 Hz, 2H), 3.36 (m, 2H), 1.91-1.89 (m, 2H), 1.30 (m, 2H), 1.08 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][C:15](Cl)=[N:16][CH:17]=1)=[O:11].[Cl:23][C:24]1[N:25]=[N:26][C:27]([N:32]2[CH2:37][CH2:36][NH:35][C@H:34]([CH3:38])[CH2:33]2)=[C:28]([CH3:31])[C:29]=1[CH3:30]>ClCCl>[CH3:8][O:9][C:10]([C:12]1[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[N:26]=[N:25][C:24]([Cl:23])=[C:29]([CH3:30])[C:28]=3[CH3:31])[CH2:33][C@H:34]2[CH3:38])=[N:16][CH:17]=1)=[O:11]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.0 mL, 14.4 mmol, 2.9 eq) is added to a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (1.25 g, 5.0 mmol, 1 eq), 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (1.20 g, 5.0 mmol, 1 eq) in dichloromethane (40 mL) and the resulting solution is stirred at rt for 2 h. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (25 mL), then brine (25 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (10-75% EtOAc/heptane) as a white solid (1.83 g, 82%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)[CH2:3][OH:4].[N:18]#[C:19]Br>>[F:16][C:14]([F:17])([F:15])[C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)=[N:9][CH:10]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCOc1ccc(C(F)(F)F)cn1
Product: NC1=N[C@@H](CCOc2ccc(C(F)(F)F)cn2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(5-trifluoromethyl-pyridin-2-yloxy)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 276.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:31])[C@H:13]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:14][N:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:16]=[O:17])[C:3]=1[F:32].Cl.[NH:34]1[CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:34]1([C:2]2[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:31])[C@H:13]([CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][N:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:16]=[O:17])[C:3]=2[F:32])[CH2:37][CH2:36][CH2:35]1
Reactant: CSc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Reactant: C1CNC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CCC2)n1
Temperature: 67.5 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a pressure tube was added [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.100 g, 0.204 mmol), azetidine hydrochloride (19.1 mg, 0.204 mmol), DIPEA (71.2 μL, 0.408 mmol) and DMSO (2 mL). The tube was sealed and was heated to 65-70° C. with stirring for 3 days. The reaction mixture was then cooled to RT and purified by RP-HPLC to afford [(2R)-3-{2-[6-(1-azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (68 mg, 65%). LCMS: (M+H)+: 511.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]1[CH:15]=[CH:16][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([O:17][CH3:18])[CH:8]=1
Reactant: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Reactant: OCCCCCCCl
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Yield: 79.3 %

Procedure:
Following the procedure of Example 1 and using 1.38 g (5.50 mmol) (E)-4butoxy-3-methoxycinnamic acid, 0.84 g (5.50 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) and 0.68 g (5.0 mmol) 6-chlorohexanol gave 1.39 g (79%) (E)-4-butoxy-3-methoxycinnamic acid 6-hydroxyhexyl ester as colourless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].Br[C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:25])=[CH:22][C:21]=1[F:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([NH:3][C:4]([CH:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]1[CH2:7][CH2:8][N:9]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])=[O:25])=[CH:22][C:21]=2[F:34])[CH2:10][CH2:11]1)=[O:18])[CH3:2]
Reactant: CCC(CC)NC(=O)c1ccc(Br)c(F)c1
Reactant: CCNC(=O)C(c1ccccc1)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc(C(=O)NC(CC)CC)cc2F)CC1
Temperature: 100 °C
Yield: 1.5 %

Procedure:
A mixture of N-ethyl-2-phenyl-2-piperidin-4-yl-acetamide (90 mg, 0.3 mmol), 4-bromo-N-(1-ethyl-propyl)-3-fluoro-benzamide (prepared as in Example 113, Step A; 120 mg, 0.4 mmol), Pd2(dba)3 (6 mg, 0.007 mmol), X-Phos (3 mg, 0.006 mmol), and NaOtBu (70 mg, 0.7 mmol) in toluene (3 mL) was heated at 100° C. for 18 h. The solids were removed by filtration and the filtrate was concentrated to give an oil, which was purified by PTLC to give a white solid (2 mg, 1%). MS (ESI): mass calcd. for C27H36FN3O2, 453.59; m/z found, 454.5 [M+H]+. 1H NMR (CDCl3): 7.69-7.67 (m, 2H), 7.60-7.58 (m, 2H), 7.44-7.43 (m, 1H), 7.41 (s, 1H), 7.36-7.31 (m, 4H), 6.89 (t, J=8.5, 1H), 5.64-5.62 (m, 1H), 5.48-5.45 (m, 1H), 3.99-3.96 (m, 1H), 3.74-3.70 (m, 1H), 3.56-3.53 (m, 1H), 3.44-3.41 (m, 1H), 3.36-3.30 (m, 1H), 3.21-3.15 (m, 1H), 2.91-2.88 (m, 1H), 2.80-2.75 (m, 1H), 2.64-2.58 (m, 1H), 2.29-2.26 (m, 1H), 2.04-2.00 (m, 1H), 1.65-1.61 (m, 1H), 1.49-1.43 (m, 1H), 1.27-1.23 (m, 1H), 1.09 (t, J=7.3, 3H), 0.93 (t, J=7.4, 6H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]([CH3:16])([CH3:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([CH:17]([CH3:19])[CH3:18])[C:3]=1[C:20](=O)[CH3:21].Cl.[CH3:24][O:25][NH2:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:24][O:25][N:26]=[C:20]([C:3]1[C:4]([CH:17]([CH3:19])[CH3:18])=[N:5][N:6]([C:7]([CH3:16])([CH3:15])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2]=1[OH:1])[CH3:21]
Reactant: CON
Reactant: CC(=O)c1c(C(C)C)nn(C(C)(C)Cc2ccccc2)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C)c1c(C(C)C)nn(C(C)(C)Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
150 mg (0.50 mmol) of 1-(5-hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)ethanone, 209 mg (2.50 mmol) of methoxyamine hydrochloride and 286 mg (3.49 mmol) of sodium acetate were mixed with 1.3 ml of distilled water and 1.3 ml of ethanol and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 4 g, ethyl acetate:hexane=1:99) to give 70 mg of the desired product as an orange oil.
Reaction SMILES: C[N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=[O:9].ClC(OCCCl)=O>C(Cl)(Cl)Cl>[CH:3]12[NH:2][CH:6]([CH2:5][CH2:4]1)[CH2:7][C:8](=[O:9])[CH2:10]2
Reactant: CN1C2CCC1CC(=O)C2
Agent: O=C(Cl)OCCCl
Solvent: ClC(Cl)Cl
Product: O=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 g of tropinone was dissolved in 100 mL of chloroform, and 50 mL of chloroethyl chloroformate was added thereto, and stirred at room temperature for 6 hours. The reaction liquid was concentrated, and 100 mL of methanol was added thereto, and heated overnight under reflux. The reaction liquid was cooled to room temperature, and concentrated to obtain a crude product of the entitled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].CO.[BH4-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[OH:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(C(O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 20 parts of (4-amino-3-nitrophenyl)(4-fluorophenyl)methanone in 120 parts of methanol were added 3.8 parts of sodium tetrahydroborate. The whole was stirred for 30 minutes at room temperature. 12 Parts of acetic acid were added and the mixture was stirred for 15 minutes. After evaporation, water was added to the residue. The product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated, yielding 20 parts (99%) of 4-amino-α-(4-fluorophenyl)-3-nitrobenzenemethanol as a residue (int. 3).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCOc1ccc2ccccc2c1

Procedure:
A mixture of 14.5 g (0.1 mole) of 2-naphthol, 30.3 g (0.15 mole) of 1,3-dibromopropane, 15 g of anhydrous potassium carbonate, and 1 g of sodium iodide in 125 ml of methyl ethyl ketone was stirred at reflux for one day. After cooling, the mixture was filtered to remove insolubles and the filtrate was concentrated in vacuo to dryness. The residue was dissolved in dichloromethane, washed twice with 10% aqueous sodium hydroxide, and redried thoroughly in vacuo. The residue was dissolved in hot pentane and filtered hot, and the filtrate was then concentrated under a stream of nitrogen and cooled in a refrigerator, giving the title compound, m.p. 53°-55°.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:17]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=3[S:19][CH:20]=2)[C:6]=1[C:26]([OH:28])=[O:27])(O)=[O:2].FC1C=C2[C:36](=CC=1)[N:35](CC1C3C=C(F)C=CC=3SC=1)[C:34]1C(=O)OC(=O)CC2=1.CNC>>[CH3:34][N:35]([CH3:36])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:17]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=3[S:19][CH:20]=2)[C:6]=1[C:26]([OH:28])=[O:27])=[O:2]
Reactant: O=C1Cc2c(n(Cc3csc4ccc(F)cc34)c3ccc(F)cc23)C(=O)O1
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccc(F)cc12
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
3-Carboxymethyl-5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid (from Example 60) was converted to 6-fluoro-9-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was reacted with dimethyl amine as described in Example 68.2. to give the title compound as a white solid. MS: 427.2 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-])=O)=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9]>CO.[Pd]>[NH2:10][C:4]1[C:3]([O:2][CH3:1])=[C:8]([CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: COc1c(C)ccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(C)ccnc1N
Reaction time: 2 h
Yield: 103.4 %

Procedure:
The 3-methoxy-4-methyl-2-nitropyridine (1 g) obtained in (A) was dissolved in methanol (50 ml), added with 5% Pd/C (200 mg), and stirred at a pressure of 40 psi for 2 hours under hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was evaporated under reduced pressure to obtain the title compound (850 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:14])[C:10]=1[O:11][CH2:12][CH3:13])C(O)=O.[H-].[Na+].ICC.C[N:21](C=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:14])[C:10]=1[O:11][CH2:12][CH3:13])[NH2:21]
Reactant: CN(C)C=O
Reactant: CCOc1c(Cl)cc(C(=O)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOc1c(Cl)cc(N)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4-Amino-2,6-dichlorophenol (1) (1.00 g, 5.62 mmol) was dissolved in dry DMF (9 mL) and cooled to 0° C. Sodium hydride (142 mg, 5.90 mmol) was added to the mixture portionwise. The dark purple solution was stirred for 1 h at RT, then iodoethane (468 μL, 5.79 mmol) was added. The reaction mixture was stirred for 3 h and partitioned between EtOAc and aqueous NaOH (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/isohexane) to afford 3,5-dichloro-4-ethoxyaniline (2) (460 mg, 40%): m/z 206 [M+H]+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 6.60 (2H, s), 4.01 (2H, q), 3.60 (2H, s), 1.42 (3H, t).