Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:16]([CH3:25])=[C:17]([CH3:24])[C:18]([Br:23])=[C:19]([CH3:22])[C:20]=1[CH3:21].CC(C)([O-])C.[Na+]>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].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[Br:23][C:18]1[C:17]([CH3:24])=[C:16]([CH3:25])[C:15]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:20]([CH3:21])[C:19]=1[CH3:22]
Reactant: Cc1c(C)c(Br)c(C)c(C)c1Br
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Product: Cc1c(C)c(N(c2ccccc2)c2ccccc2)c(C)c(C)c1Br

Procedure:
An apparatus for working under inert conditions and exclusion of moisture is initially charged with 0.1 mol of diphenylamine, 0.4 mol of dibromodurene and 0.12 mol of sodium tert-butoxide. The catalyst used for C—N coupling is Pd2(dba)3/(t-Bu)3P=⅙ in a concentration of 1 mol % based on the amine. The reaction solution is heated at reflux until diphenylamine can no longer be detected by TLC comparison. For workup, the reaction solution is washed to neutrality and the organic phase is extracted. Afterward, the solvent is removed under reduced pressure, 200 ml of cyclohexane are added and the insoluble crystal slurry is filtered off with suction from dibromodurene. The filtrate is concentrated until crystallization commences again and chromatographed on silica gel with cyclohexane. Checking by HPLC-MS coupling (C18RP/10 μm/methanol/RT=7.06 min/99%, M+=379).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethene (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMR τ (CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:13])([CH3:12])[C:9](=O)[NH:10][C:4]=2[CH:3]=1.C1COCC1>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:13])([CH3:12])[CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ncc21
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CNc2cc(Cl)ncc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
6-Chloro-3,3-dimethyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (1.4 g, 7.14 mmol) was dissolved in a solution of borane-dimethyl sulfide complex in THF (2 M, 36 mL, 71.4 mmol) and heated to 65° C. for 3 h, then cooled to ambient temperature. MeOH was added and the reaction heated at reflux for 1.5 h. After stirring overnight, the solvent was removed in vacuo. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave the title compound (1.23 g, 95%) as a colourless solid. 1H NMR (Me-d3-OD): 7.65 (1H, s), 6.42 (1H, s), 3.43 (2H, s), 1.34 (6H, s).
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=[CH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[CH2:24][CH2:23]3)[C:12]3[C:13]([O:18][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[N:14][CH:15]=[CH:16][CH:17]=3)(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C([C:46]([O:48][CH2:49][CH3:50])=[O:47])#N.[Cl-].[NH4+].[Cl-].[Na+]>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH:19]=[C:11]3[C:12]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[O:18][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([C:1](=[O:3])[CH2:2][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:9]=4[CH2:10]3)[CH2:23][CH2:24]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C#N
Reactant: CC(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 315 (250 mg) in THF (3.0 ml) was added LDA (0.51 mol/L THF-hexane solution, 3.0 ml) at −78° C., and the mixture stirred at room temperature for 20 minutes. The reaction mixture was cooled to −78° C. again, and added ethyl cyanoformate (76 μl), stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride and aqueous sodium chloride were added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with chloroform-methanol (10:1) to give the titled compound (280 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: NCc1cccc(Cl)c1
Solvent: CCO
Product: N#CCC(=O)NCc1cccc(Cl)c1
Reaction time: 8 h

Procedure:
A solution of 38.5 g. (0.34 mole) of ethyl cyanoacetate and 48.1 g. (0.34 mole) of 3-chlorobenzylamine in 120 ml. of 95% ethanol is refluxed for 5 hours and then allowed to stand overnight at ambient temperature. Agitation causes crystallization. Filtration is followed by washing of the solid with a small amount of ether to give 28.7 g. of the desired product as small, white needles, m.p. 123°-5° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH2:41][C:25]5([CH2:28][C:27]([C:35]([O:37]C(C)C)=[O:36])([C:29]([O:31]C(C)C)=[O:30])[CH2:26]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[CH2:4][CH2:3]2.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH2:41][C:25]5([CH2:28][C:27]([C:29]([OH:31])=[O:30])([C:35]([OH:37])=[O:36])[CH2:26]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]1[CH2:53][CH2:54][O:55][CH2:56][CH2:57]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-morpholinoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (9 mg, 0.011 mmol) in 1,4-dioxane (1 mL) and MeOH (0.5 mL) was added 1N NaOH (0.5 mL, 0.500 mmol)). The mixture was stirred at 50° C. for 3 h. The crude product was purified by Prep HPLC using method 14 to give desired product in 74% yield as a solid. MS: m/e 703.6 (M+H)+, 2.42 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 5.96 (s, 1H), 5.54 (dd, J=6.1, 1.6 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.80-3.67 (m, 4H), 3.15-3.01 (m, 2H), 2.94-2.76 (m, 2H), 2.76-2.58 (m, 8H), 2.52 (br. s., 2H), 2.22-2.14 (m, 1H), 2.10-1.87 (m, 2H), 1.83-1.07 (m, 19H), 1.76 (s, 3H), 1.24 (s, 3H), 1.18 (s, 4H), 1.09 (s, 6H), 0.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:11])[N:14]([CH3:13])[N:15]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: Cn1nc(-c2ccc(Cl)cc2)cc1N
Yield: 46 %

Procedure:
A solution of 3-(4-Chloro-phenyl)-3-oxo-propionitrile (1.8 g, 10 mmol) and N-Methylhydrazine (1 mL, excess) in EtOH (30 mL) was stirred to reflux 3 hours. After cooling the precipitate was filtered off, to give the title compound (950 mg, 4.6 mmol) as white crystals in a 46% yield.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:13]=1)=[CH:8]2
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 4-chloro-3-oxobutyrate (0.55 g) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.38 g, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 117-118° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].Cl[C:20](OCC)=[O:21]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]2[O:17][C:20](=[O:21])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(Br)ccc2oc(=O)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
Step 1 A solution of 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide (Intermediate 16-1, 40 mg, 0.131 mmol) in pyridine (1 mL) was treated with ethyl chloroformate (0.015 mL, 0.157 mmol) at rt and the mixture was heated to 100° C. for 2 h. Additional ethyl chloroformate (0.015 mL, 0.157 mmol) was added and the mixture was stirred at 100° C. for 15 h. The mixture was cooled and diluted with EtOAc (80 mL), and the solution was washed with NaHCO3 (aq) (10 mL), water (2×10 mL) and brine (10 mL), and dried and concentrated. The residue was purified by column chromatogaphy (eluting with a gradient from 95:5 to 70:30 hexane-EtOAc) to give 6-bromo-5-methyl-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (19 mg, 44%). 1H NMR (400 MHz, chloroform-d) δ 7.90 (1 H, d, J=9.02 Hz), 7.43-7.68 (3 H, m), 7.27-7.40 (2 H, m), 7.12 (1 H, d, J=8.80 Hz), 2.90 (3H, s). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:34])[C:19]1[CH:20]=[C:21]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:22]=[CH:23][C:24]=1[F:25]>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:21]3[CH:22]=[CH:23][C:24]([F:25])=[C:19]([N:18]([CH3:34])[CH3:17])[CH:20]=3)=[O:32])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CN(C)c1cc(-c2ocnc2C(=O)O)ccc1F
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Product: CN(C)c1cc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)ccc1F

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-(dimethylamino)-4-fluorophenyl)oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].CCN(CC)CC.NCCS(O)(=O)=[O:43].Cl>CN1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([OH:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCS(=O)(=O)O
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 26.6 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (223 mg, 0.5 mmol) in N-methylpyrrolidine (5 mL) was added Et3N (0.1 mL) followed by 2-aminoethanesulfonic acid (200 mg, 1.5 mmol, 3 eq) and the reaction mixture was heated to 5° for 12 h. 1 M aq HCl was then added dropwise till pH 3. The reaction mixture was then extracted with EtOAc (2×20 mL). Organic layers were combined, washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was then purified by flash chromatography to give an oily product, which was then recrystallized from methanol:H2O (3:1) to afford 51 mg of pure 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-hydroxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 2.24 (s, 3H), 6.31 (d, 1H, J=9.8 Hz), 7.02 (m, 5H), 7.23 (m, 1H), 7.352 (m, 1H), LC MS (m/e)=384.2 (MH+). Rt=1.65 min.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[OH:28])[CH2:22][CH2:23][NH2:24].C(O)CCC>O>[ClH:13].[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:5][CH:4]2[C:25]3[C:21](=[CH:20][C:19]([OH:18])=[C:27]([OH:28])[CH:26]=3)[CH2:22][CH2:23][NH:24]2)=[CH:12][CH:11]=1
Reactant: CCOC(CNc1ccc(Cl)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Oc1cc2c(cc1O)C(CNc1ccc(Cl)cc1)NCC2

Procedure:
p-Chloroanilinoacetaldehyde diethyl acetal (486 mg) and 3,4-dihydroxyphenethylamine hydrochloride (378 mg) were added to a mixture of n-butyl alcohol (4 ml) and water (0.4 ml) and then the mixture was refluxed for 3.5 hours. The above-mentioned acetal (0.24 g) was further added thereto and the resultant mixture was refluxed for 3 hours. The reaction mixture was treated in a conventional manner to give 1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This product was identified by thin-layer chromatography on silica gel [Developing solvent: (n-butyl alcohol:acetic acid:water=8:1:1)] with an authentic sample, mp 91° to 93° C., which was obtained by reacting 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Example 1(D) with conc. hydrochloric acid and acetic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(N(C(C)C)CC)(C)C.ClCCl>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:14][CH:13]=[CH2:12])=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: C=CCBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1ccc(CO)cc1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 4-hydroxymethylbenzoic acid (0.5 g, 3.3 mmol) in CHCl3 (10 mL) was added allyl bromide (0.6 mL, 0.84 g, 6.9 mmol) and diisopropylethylamine (1.3 mL, 0.96 g, 7.5 mmol). The resulting reaction mixture was allowed to reflux under nitrogen for 2.5 h. Upon cooling to rt, dichloromethane (50 mL) was added and the organic layer was washed with 0.1 N HCl (3×30 mL), 5% NaHCO3 solution (1×30 mL) and brine (1×30 mL). Upon drying (MgSO4), filtration of the drying agent and concentration, the resulting oily residue was chromatographed on silica gel (30% ethyl acetate/hexane) to give 440 mg (70%) of a colorless oil. 1H NMR (CDCl3) 8.06 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 6.11-5.98 (m, 11H), 5.42 (dd, J=17.2, 1.5 Hz, 11H), 5.30 (dd, J=10.4, 1.2 Hz, 1H), 4.83 (dd, J=5.6, 1.2 Hz, 2H), 4.78 (s, 2H), 1.80 (br s, 1H). MS 192 (M+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[N:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=3)[N:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nccc(NCC3CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2nccc(NCC3CC3)n2)cc1
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Dissolve 4-[4-(cyclopropylmethyl-amino)-pyrimidin-2-yl]-N-(tert-butoxycarbonyl)-benzylamine (100 mg, 0.28 mmol) in DCM (3 mL) containing trifluoroacetic acid (2 mL). Stir under nitrogen for 3 h. Concentrate in vacuo and purify the crude mixture by SCX chromatography (5 g) to obtain the title compound (68.5 mg, 90%) suitable for use without additional purification. MS (ES+) m/z: 255 (M+H)+.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[CH:11]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>ClCCl>[CH:11]1([CH2:16][CH2:17][O:18][S:2](=[O:3])(=[O:4])[NH2:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCCC1CCCC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=CO
Solvent: c1ccncc1
Product: NS(=O)(=O)OCCC1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To chlorosulfonyl isocyanate (275 mL, 3.15 mol) at 0° C. was added formic acid (119 mL, 3.15 mol), dropwise. The resulting solid was allowed to stir at 0° C. for a further 20 minutes. The residue was diluted with dichloromethane (875 mL) and warmed to room temperature for one hour. The reaction mixture was cooled in an ice/salt bath and a solution of 2-cyclopentyl ethanol (240 g, 2.1 mol) in pyridine (255 mL, 3.15 mol) and dichloromethane (2.1 L) was added, keeping the temperature below 7° C. After 2 hours, the reaction was concentrated in vacuo, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a colourless oil. The residue was purified by column chromatography on silica gel, eluting with 90:10 to 50:50 heptane:ethyl acetate, to afford the title compound as a colourless oil in 95% yield (276 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28](OC(C)=O)=[O:29]>CC(O)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[CH3:27])[CH:7]=[CH:6][CH:5]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 4-(3-amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 70) by treatment with Ac2O in HOAc at 80° C. Obtained as a light yellow solid (9 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:41]C)[CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:22][C:15]=2[N:14]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]4[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][OH:41])[CH2:37][CH2:38]4)=[O:32])[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: COCCN1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Solvent: ClCCl
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)C4CCN(CCO)CC4)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide (1 eq) in methylene chloride at 78° C. was added 1M borontribromide in methylene chloride (10 eq) and the resulting mixture and the resulting mixture was stirred at −78° C. for 1 h. It was then brought to ambient temperature and stirred for 2 h. LC/MS showed formation of the product. The reaction was quenched with saturated sodium carbonate solution at 0° C. The mixture was concentrated and then brought to pH=9. It was then extracted with ethyl acetate and the organic layer was dried with sodium sulfate and concentrated and purified on preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-hydroxyethyl)-piperidine-4-carboxamide. MS: MH+=573.6.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].N(O)=O.C([O-])(O)=O.[Na+].[C:24]([Cu])#[N:25].[C-]#N.[Na+]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[C:24]#[N:25]
Reactant: N#C[Cu]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: O=C([O-])O
Agent: O=NO
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound of example 168 (20 g, 92.2 mmol) was dissolved in 10% aqueous H2SO4 (100 mL) and the solution was cooled to 0° C. A solution of NaNO2 (7.64 g, 110 mmol) in water (20 mL) was added dropwise maintaining the temperature between 0-5° C. The mixture was stirred for 10 min., excess nitrous acid was neutralized using a saturated aqueous NaHCO3 solution. The resulting mixture was then added to a precooled (0-5° C.) suspension of CuCN (9.46 g, 105 mmol) and NaCN (5.20 g, 106 mmol) in water (200 mL). It was stirred for 10 min., and allowed to attain room temperature. It was stirred for 0.5 h and finally heated on a steam bath for 0.5 h. Excess saturated FeCl3 solution was then added to the reaction mixture. It was extracted using EtOAc (3×200 mL). The organic extract was washed with water, dried (anhydrous Na2SO4), concentrated and purified using a silica gel column and CHCl3 petroleum ether (60-80° C.) (1:1) as eluant to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S-:14].[Na+]>CO>[CH3:12][O:11][C:4]1[N:3]=[C:2]([S:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: C[S-]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(SC)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.5 %

Procedure:
A methanol (100 ml) solution of 2-chloro-6-methoxy-3-nitropyridine (2.0 g, 10.4 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (805 mg, 10.9 mmol) while being cooled with ice, and the temperature thereof was raised to the room temperature and the mixed solution was stirred for 17 hours and the precipitated crystal was filtered to obtain 1.26 g (yield 59%) of 6-methoxy-2-methylthio-3-nitropyridine as a yellow powdery crystal,