Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:19]>CC#N.O>[Br:1][C:17]1[CH:18]=[C:10]([Cl:9])[C:11]([OH:19])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(Br)cc(Cl)c1O
Reaction time: 1 h
Yield: 93.9 %

Procedure:
N-Bromosuccinimide (2.38 g, 13.38 mmol) was added to a solution of 3-chlorosalicylic acid (2.1 g, 12.16 mmol) in CH3CN (10 mL) solution and stirred for 1 h. The reaction mixture was diluted with water (25 mL), solids were filtered and washed with water and dried to get 5-bromo-3-chloro-2-hydroxy-benzoic acid (2.87 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[N:12][N:13]=2)[CH:5]=[C:6](I)[CH:7]=1.[CH:22]1[C:34]2[NH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:31]1[C:32]2[N:33]([C:2]3[CH:3]=[C:4]([C:9]4[O:10][C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=5)=[N:12][N:13]=4)[CH:5]=[C:6]([N:33]4[C:34]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[C:27]5[C:32]4=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:7]=3)[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1cccc(-c2nnc(-c3cc(I)cc(I)c3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 5 h

Procedure:
To a solution of 2-(3,5-diiodophenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (1.0 g, 1.98 mmol), carbazole (1.0 g, 5.98 mmol), Cu (4.0 g, 62.95 mmol) in DMF (20.0 ml) was added potassium carbonate (6.0 g, 43.41 mmol) under nitrogen and stirring. Heating was started. The reaction was carried out at 150° C. for 5 h. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. THF was evaporated from the combined filtration solution. Water (150.0 ml) was added, the brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using toluene/ethyl acetate (9.7:0.3) as eluent. After evaporating solvent, the white solid was recrystallized from THF/methanol and finally dried under vacuum. Pure product was obtained as white solid in 0.99 g (86.0%) yield. 1H NMR (399 MHz, CDCl3, δ): 8.47 (d, J=2.4 Hz, 2H), 8.16 (d, J=8.0 Hz, 4 Hz), 8.01 (t, J=1.6 Hz, 1H), 7.69-7.64 (m, 2H), 7.58 (d, J=8.0 Hz, 4H), 7.45 (m, 4H), 7.41 (t, J=8.0 Hz, 1H), 7.34 (m, 4H), 7.08 (m, 1H), 3.87 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.72, 164.02, 159.99, 140.90, 140.21, 130.28, 128.58, 127.21, 126.21, 124.88, 123.76, 122.40, 120.57, 120.48, 119.33, 118.29, 111.61, 109.68, 94.23, 55.55. [M]+ calcd for C39H26N4O2, 582.2. found 582.2. Anal. Calcd for C39H26N4O2: C, 80.39; H, 4.50; N, 9.62. Found: C, 80.32; H, 4.41; N, 9.60.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: COCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(O)cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 1-(benzyloxy)-4-(2-methoxyethoxy)benzene (180 g), ethanol (2000 ml) and palladium on carbon catalyst (20 g) was stirred under an atmosphere of hydrogen, at room temperature and atmospheric pressure. After the theoretical quantity of hydrogen had been consumed, the reaction mixture was filtered. The filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and n-hexane to give 4-(2-methoxyethoxy)phenol as a solid (94.7 g) m.p. 97.9° C.; microanalysis, found: C, 64.3%; H, 7.4%; C9H12O3 requires: C, 64.3%; H, 7.2%; NMR: 3.35(3H,s), 3.6(2H,m), 3.95(2H,m), 6.7(4H,m) and 8.9(1H,s); m/z 169(M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:20]2[N:19]=1)=O.C(N(CC)C(C)C)(C)C>>[CH3:38][N:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[N:20]2[C:21]([CH:22]=[N:23][C:18]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:13][CH:12]=3)=[N:19]2)=[CH:24][CH:25]=1)[S:34]([CH3:37])(=[O:35])=[O:36]
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 4-(1-Methyl-piperidin-4-yl)-phenylamine (0.115 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-Methyl-N-(2-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanesulfonamide as a yellow solid (38 mg, 36%). LCMS (E/I+) 491.16 (M+H). NMR 1H (DMSO-d6)-9.39 (s, 1H), 9.33 (s, 1H), 8.50 (d, 1H, J=7.59 Hz), 7.74 (d, 1H, J=7.59 Hz), 7.50-7.62 (m, 3H), 7.06 (d, 2H, J=7.59 Hz), 6.98 (bs, 1H), 6.93 (bs, 1H), 3.10 (s, 3H), 2.90 (s, 3H), 2.85 (d, 2H, J=11.43 Hz), 2.30-2.40 (m, 1H), 2.18 (s, 3H), 1.92 (t, 2H, J=11.43 Hz), 1.52-1.72 (m, 4H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[O:33]1[CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]1>C1COCC1>[Br:11][C:12]1[C:13]([C:36]2([C:39]#[N:40])[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: N#CC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CCOCC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
KHMDS 1 M in THF (0.758 mL) was added dropwise to a mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 100 mg, 0.253 mmol) and tetrahydro-2h-pyran-4-carbonitrile (42.1 mg, 0.379 mmol) in THF (2.5 mL), under a nitrogen atmosphere. The RM was stirred at −70° C. for 1 h, and allowed to warm to RT overnight. The RM was quenched with water and the solvent was evaporated off under reduced pressure to afford 5-bromo-6-(4-cyanotetrahydro-2h-pyran-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.106 mmol), Pd(Ph3P)4 (18 mg, 0.016 mmol), pyrimidin-5-ylboronic acid (20 mg, 0.159 mmol), K3PO4 (68 mg, 0.319 mmol) and toluene (1.3 mL) were added to a vial, which was sealed, evacuated/purged with argon. The RM was stirred at 110° C. for 3 h, diluted with MeOH, filtered through a cartridge PL-Thiol MP-Resin and concentrated the combined filtrates were evaporated to dryness under reduced pressure. The crude product was purified by preparative SFC (Column 2-EP, gradient: 6% to 11% in 6 min) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.2 min, m/z=469.9 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 2.00 (d, J=13.55 Hz, 2H) 2.40 (td, J=13.08, 3.95 Hz, 2H) 3.52 (t, J=12.14 Hz, 2H) 3.94 (d, J=8.66 Hz, 2H) 7.39 (d, J=8.66 Hz, 2H) 7.86 (d, J=8.85 Hz, 2H) 8.30 (s, 1H) 8.96 (s, 2H) 9.23 (d, J=1.13 Hz, 1H) 9.32 (s, 1H) 10.67 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([F:13])([F:12])([F:11])([F:10])[F:9].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[CH:4][C:3]=1[S:8]([F:13])([F:9])([F:10])([F:11])[F:12]
Reactant: Fc1ccccc1S(F)(F)(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(S(F)(F)(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
A mixture of 1-fluoro-2-(pentafluoro-λ6-sulfanyl)benzene (2.00 g, 9.00 mmol) and sulfuric acid (4 mL) was cooled in an ice bath. Nitric acid (4 mL) was added to the reaction mixture; after 5 minutes, the cooling bath was removed and stirring was continued at room temperature for 3 hours. The reaction mixture was then poured into ice (150 mL), and the resulting mixture was extracted with diethyl ether (2×75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide an oil. After addition of a seed crystal, the product was obtained as a solid. Yield: 1.99 g, 7.45 mmol, 83%. 1H NMR (400 MHz, CDCl3) δ 7.45 (br dd, J=10, 9 Hz, 1H), 8.46 (br ddd, J=9.1, 3, 3 Hz, 1H), 8.72 (dd, J=5.8, 2.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].Br[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(CCC(OCC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-(cyclohexylmethoxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 8 equivalents of sodium hydride and 2.5 equivalents of bromomethylcyclohexane according to general procedure H.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH3:16][O:17]C(Cl)Cl>>[CH3:15][N:2]([CH3:1])[C:3](=[O:14])[CH2:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH3:12])=[C:9]([CH:16]=[O:17])[C:10]=1[CH3:11]
Reactant: Cc1cc(C)c(CC(=O)N(C)C)c(C)c1
Reactant: COC(Cl)Cl
Product: Cc1cc(C)c(CC(=O)N(C)C)c(C)c1C=O

Procedure:
N,N-Dimethyl-(3-formyl-2,4,6-trimethylphenyl) acetic acid amide was prepared by the formylation of N,N-dimethyl mesitylacetic acid amide with dichloromethyl methyl ether using standard conditions.
Reaction SMILES: [C:1]([NH:6][NH2:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH2:9][CH2:10][C:11]([CH3:13])=O>>[C:1]([NH:6][N:7]=[C:11]([CH3:13])[CH2:10][CH2:9][C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)NN
Reactant: CCCCOC(=O)CCC(C)=O
Product: CCCCOC(=O)CCC(C)=NNC(C)(C)CC
Yield: 90 %

Procedure:
Butyl levulinate t-amylhydrazone was prepared in 90% yield by refluxing an aqueous solution of t-amylhydrazine with an equimolar amount of butyl levulinate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CO>[ClH:29].[ClH:29].[C:23]1([CH2:22][CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(CCCc3ccccc3)CC2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(CCCN2CCC(C3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 20 ml of methanol was dissolved 3.425 g (8.860 mM) of 1-tert-butoxycarbonyl-1′-(3-phenylpropan-1-yl)-4,4′-bipiperidine, followed by addition of 5 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 6 hours. This reaction mixture was concentrated and crystallized from methanol-diethyl ether to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=NNS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(Cc2ccc3c(c2)OCO3)=NNS(=O)(=O)c2ccc(C)cc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(/C=C/c2ccc3c(c2)OCO3)cc(OC)c1
Temperature: 80 °C
Yield: 116.4 %

Procedure:
39.4 g of N-[1-(3,5-dimethoxyphenyl)-2-(3,4-methylenedioxyphenyl)ethylidene]-N′-tosylhydrazine (0.084 mol) prepared as in Example 30, 19.9 g of potassium ter-butoxide (0.177 mol) and 3.9 g of Triton X100® are introduced into a three-necked round-bottomed flask comprising 190 ml of toluene. The mixture is brought to reflux for 4 h, cooled to approximately 80° C. and 130 ml of water are introduced. Separation by settling is carried out and the aqueous phase is re-extracted with 90 ml of toluene. The toluene phases are washed with 50 ml of water and concentrated to result in 27.8 g of a brown solid, which is taken up in 30 ml of methanol and maintained for 1 h under agitation. The precipitate is filtered off, washed on the filter with methanol and dried. 16.6 g of (E)-3,5-dimethoxy-3′,4′-methylenedioxy-stilbene is recovered in the form of a brown solid, which exhibits a melting point of 96° C., i.e. a yield of 69% with respect to the starting hydrazone.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][C@H:3]([C:8]([O:10]CC)=[O:9])[N:2]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O1CCOCC1.O[Li].O>O>[C:16]([O:15][C:13]([N:2]1[CH:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH:6]2[CH:1]1[CH2:7]2)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)[C@H]1CCC2CC2N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C(=O)O)CCC2CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
(3R)-2-tert-butyl 3-ethyl 2-azabicyclo[4.1.0]heptane-2,3-dicarboxylate (D21) (600 mg, 2.22 mmol) was partitioned between dioxane (10 ml) and water (5 ml) prior addition of LiOH H2O (370 mg, 8.9 mmol). The mixture was stirred at RT for 18 hrs. Water (10 ml) and LiOH H2O (740 mg, 18 mmol) were added and the mixture left at RT for 66 h. Dioxane was evaporated off and remaining aqueous was washed with Et2O (3×20 ml). Aqueous solution was acidified with acetic acid up to pH 4 and extracted with EtOAc (3×30 ml). Collected organics were washed with NaCl sat., dried over Na2SO4 and evaporated in vacuo to afford the title compound (D22) (210 mg).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][C:18]=1[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].S1(CCCC1)(=O)=O>[I-].[K+].O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:28][CH2:27][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:17]=3[Cl:16])[NH:23][C:22](=[O:26])[CH2:21]4)[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Yield: 74.9 %

Procedure:
In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 1.25 grams (5.43 mmol) of 6-chloro-5-(2-chloroethyl)indolin-2-one; 50 mg of potassium iodide; 0.82 gram (5.94 mmol) of potassium carbonate and 3 ml of sulfolane. The contents of the flask were heated to 95° C. to 100° C. The reaction was monitored by HPLC. After completion of the reaction, 50 ml of DM water was added to the reaction mixture and stirred. The product was filtered off and washed with water and dried to obtain 1.41 grams (75%) of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. The crude product was purified by IPA and/or THF. The product matched the spectra of a standard NMR and showed the correct retention time by HPLC with 98.0% assay. The melting point of the compound was found to be 218° C.-220° C., and was found to conform with the melting point of 218°-220° C. as disclosed in U.S. Pat. No. 5,206,366.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[CH3:15][C:16]([CH3:18])=O>>[C:16](=[N:2][NH:1][C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCCCCC2
Product: CC(C)=NNc1cc2c(nn1)CCCCCC2

Procedure:
A solution of 0.5 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 15 cc of absolute acetone is heated on a water bath for 1 hour. After cooling the title compound crystallizes. M.P. 165°-167° (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21]Br>CC#N>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrCCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a mixture of 2-hydroxy-4-nitro-benzonitrile (2 g, 12.19 mmol) and K2CO3 (3.36 g, 24.39 mmol) in MeCN (20 mL) was added 1,2-dibromoethane (3.4 g, 18.29 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with brine (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated to give 2-(2-bromoethoxy)-4-nitrobenzonitrile (1.6 g, 49%) as a light red solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.94-7.92 (1H, m), 7.82-7.78 (2H, m), 4.52 (2H, t, J=6.4 Hz), 3.73 (2H, t, J=6.4 Hz).
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[C:7]([S:18][CH3:19])=[N:8][C:9]([OH:17])=[C:10]([CH:16]=1)[C:11]([O:13]CC)=[O:12])#[N:5]>C(O)C.O>[C:4]([C:6]1[C:7]([S:18][CH3:19])=[N:8][C:9]([OH:17])=[C:10]([CH:16]=1)[C:11]([OH:13])=[O:12])#[N:5]
Reactant: CCOC(=O)c1cc(C#N)c(SC)nc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(O)c(C(=O)O)cc1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4.16 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a solution of 11.8 g (49.5 mmol) of ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate in 100 ml of ethanol and 100 ml of water. The reaction mixture is stirred at 60° C. for 2 hours. The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=1). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 9.9 g (95%) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in the form of a brown powder.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]2([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(CNc2c(N)cnc3ccccc23)CCCCC1
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)OC(C)(C)C)CCCCC1
Yield: 37 %

Procedure:
Ethoxyacetyl chloride (9.00 g, 73.4 mmol) was reacted with tert-butyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate (27.2 g, 73.4 mmol) according to the method described in Part E of Example 9 and the resulting product was treated according to the method described in Part E of Example 9. After the solvent was removed to yield an oil, the oil was dissolved in ethanol (300 mL) and water (30 mL). Sodium hydroxide (4.3 g, 108 mmol) was added and the solution was heated at reflux for 6 h. The volatiles were removed under reduced pressure and the resulting brown oil was partitioned between dichloromethane (500 mL) and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a brown oil. Purification by flash chromatography (silica gel, 30% ethyl acetate/hexanes) provided tert-butyl 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexylcarbamate as a brown solid (11.9 g, 38%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH2:16][OH:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:15][C:11]1[C:10]([CH2:16][OH:17])=[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(F)c1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(F)c1CO
Reaction time: 1 h

Procedure:
Trimethylacetyl chloride (0.25 mL, 1.99 mmol) was added to a solution of (2-amino-6-fluorophenyl)methanol (268 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C., followed by the addition of DIEA (1.0 mL, 5.7 mmol). The mixture was stirred for 1 hr, followed by normal aqueous work-up to afford the expected crude product, N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide, as a colorless oil (415 mg, 97% yield), which was used directly in the next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9H), 2.64 (s, 1H), 4.78 (d, J=4.78 Hz, 2H), 6.75-6.84 (m, 1H), 7.23 (td, J=8.62, 5.92 Hz, 1H), 7.86 (d, J=8.31 Hz, 1H), 8.97 (s, 1H); Mass spec. 226.11 (MH+), Calc. for C12H16FNO2 225.12.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].C([O-])(=O)C.[NH4+]>C(O)C>[C:14]([C:16](=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 4 was repeated using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.9 g of ethyl cyanoacetate and 0.15 g of ammonium acetate in 10 ml of ethanol. Yield 0.87 g (57%), m.p. 205°-210° C.