Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>N1C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)nc12
Yield: 79.4 %

Procedure:
To a stirred solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (512 mg, 2 mmol) in pyridine at 90° C. was added benzyl chloroformate (3.3 ml, 23.4 mmol) in three portions over 6 hours. The reaction mixture was then evaporated to dryness and partioned between CH2Cl2 (50 ml) and saturated aqueous NaCl solution (50 ml), the aqueous phase was separated and extracted further with CH2Cl2 (2×50 ml) and the combined organic phases dried, filtered and evaporated. The crude residue was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (4:1) to afford the title compound as a white foam (620 mg, 79% yield), MS: m/e=391.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH2:23][C:19]1[N:20]=[C:21]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([C:11]([OH:13])=[O:12])=[N:7]2)[CH:22]=[CH:17][N:18]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To suspension of 6-bromo-1H-indazole-3-carboxylic acid (5 g, 20.77 mmol) in DMF (40 mL) was added NaH (60%, 1.7 g, 41.5 mmol). The mixture was stirred at RT for 10 min, followed by addition of 4-chloro-pyrimidin-2-ylamine (4.0 g, 31 mmol). The mixture was heated at 65° C. for 2 hr. The reaction cooled to RT, then another 1 eq NaH added (ca 0.78 g). Heating continued at 65° C. overnight. Reaction mixture was allowed to cool to RT. The mixture was quenched by portionwise addition to water (10 mL) resulting in formation of a precipitate. The mixture was acidified with 0.5M aq citric acid. The precipitate was collected by suction filtration through a fritted sinter funnel and washed with MeOH/EtOAc (1/1) and was thoroughly dried under high vacuum to give the title compound as a beige solid (5.8 g, LC-MS purity=88%); LC-MS: m/z=+333.85/335.80 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.P(Cl)(Cl)([Cl:26])=O>C(#N)C>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Ethyl 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoate (5.5 g) was suspended in acetonitrile (50 mL), and was treated with phosphorus oxychioride (3 mL, 36 mmol). The mixture was stirred at 90° C. for 4 h. The mixture was concentrated to remove all solvent, and redissolved in ethyl acetate (200 mL). The organic solution was washed with water (3×20 mL), brine (20 mL), and was dried over anhydrous Na2SO4, and concentrated in vacuo to give ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>O1CCCC1>[C:12]1([S:18]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of pyrrolo[2,3-b]-pyridine (1.0 g, 8.46 mmol) in tetrahydrofuran (15 mL) at room temperature (rt) was added NaH (280 mg of an 80% dispersion in oil, 9.31 mmol) in portions. After 20 min the solution was cooled to 0° C. and benzenesulfonyl chloride (1.13 mL, 8.88 mmol) was added over 10 min. After 30 min the reaction mixture was warmed to rt and stirred for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (40 mL). The organic layer was washed with 5% aqueous NaHCO3 then dried (MgSO4). Concentration and crystallization from EtOAc-hexanes gave 1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine as a solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]2[C:9](=[O:18])[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:20]([N:10]1[C:9](=[O:18])[C:8]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]1=2)[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2Sc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
0.14 grams of a 50% dispersion of sodium hydride in mineral oil was added to a solution of dibenz[b,f][1,4]thiazepin-11(10H)-one in 10 ml of dimethylformamide. After 15 minutes the mixture was warmed to 50° C. and stirred under argon for one hour. After allowing the mixture to cool to room temperature, 0.34 grams of 1-bromopropane was added slowly. The reaction mixture was stirred for 5 hours, after which time it was quenched with water and the product extracted with diethyl ether. The extracts were washed with a saline solution, dried (anhydrous magnesium sulfate) and concentrated to give a colorless oil which was purified by column chromatography (ethyl acetate/hexane, 5%, 10%, 20%) to provide 0.37 grams (91% of theory) of 10-n-propyl-dibenz[b,f][1,4]thiazepin-11(10H)-one as a white crystalline solid, m.p. 103°-104.5° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][C@H:5]2[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1O[C@H]1CCCNC1
Product: Nc1ncc(-c2ccc(-c3ccccc3O[C@H]3CCCNC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (S)-3-(2-bromophenoxy)piperidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.59-7.48 (m, 2H), 7.44 (d, J=8.1, 1H), 7.40-7.35 (m, 2H), 7.24 (d, J=8.3, 1H), 7.11-7.07 (m, 1H), 6.87 (s, 2H), 4.73-4.53 (m, 1H), 3.38-3.30 (m, 1H), 3.12-2.86 (m, 3H), 2.04-1.94 (m, 1H), 1.80-1.71 (m, 2H), 1.65-1.54 (m, 1H).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])CC(OCC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>C(O)(=O)C>[C:2]1([C:1]2[NH:19][O:20][C:10](=[O:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)[nH]o1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In accordance with the known process [Canadian Journal of Chemistry, 4s, 1371 (1970)], 154 g (0.8 mol) of ethyl benzoylacetoacetate were dissolved in 1 l of acetic acid, and 55.7 g (0.8 mol) of hydroxylamine hydrochloride were then added to the resulting solution, followed by heating under stirring at 100° C. for 5 hours. After the solvent was distilled off, ethyl alcohol was added to the residue to precipitate crystals. The crystals were collected and then washed with ethyl alcohol, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:47][CH:46]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:51]1([C:48]2[CH:47]=[CH:46][C:45]([C:37]3[N:36]([C:33]4[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]5[CH:58]=[CH:59][C:19]([OH:18])=[CH:20][CH:21]=5)=[CH:31][CH:32]=4)[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=3)=[CH:50][CH:49]=2)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1
Yield: 93.4 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-({4-[2-(4-cyclohexylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethyl}amino)-2-propanol (0.317 g, 0.396 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.21 g, 0.37 mmol).
Reaction SMILES: [CH3:1][S-:2].[Na+].[F:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1F)[NH:10][C:9](=[O:15])[C:8]2=[O:16]>CN(C)C=O>[F:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[S:2][CH3:1])[NH:10][C:9](=[O:15])[C:8]2=[O:16]
Reactant: C[S-]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(cc1F)C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Sodium thiomethoxide (5.93 g, 84.6 mmol) was added to a solution of 5,6-difluoroindole-2,3-dione (7.75 g, 42.3 mmol) in dimethylformamide (400 mL). The reaction was stirred at room temperature for 1 h, then poured onto ice (2 L). The resulting solid was collected by filtration, washed with water and dried at 40° C. under vacuum to give a brown solid (3.12 g, 35%): mp 296° C.; C9H6F1NO2S requires: C, 51.18; H, 2.86; N, 6.63; S, 15.18%. Found C, 50.95; H, 2.85; N, 6.58; S, 15.35%; IR νmax (Nujol)/cm−1 3285, 2925, 2854, 1760, 1714, 1611, 1465 and 1036; NMR δH (400 MHz, DMSO-d6) 2.58 (3H, s), 6.71 (1H, d, J 6.0 Hz), 7.38 (1H, d, J 9.0 Hz), 11.02 (1H, brs).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[C:22]([C:23](Cl)([N:25]=[CH:26][N:27]=2)[NH2:24])=[N:21][CH2:20]1)(=[O:3])[CH3:2].N[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2CN=C3C2=NC=NC3(N)Cl)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Nc4cccc(O)c4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 24.8 %

Procedure:
To a solution of O2′,O3′,O5′-tri-acetyl-6-chloroadenosine (5.4 g) in absolute ethanol (30 mL) were added 3-aminophenol (4.28 g) and dry triethylamine (3.96 g), and the mixture was refluxed 8 h at 60° C. The solution was allowed to cool and was concentrated in vacuo and the residue was chromatographed (ethyl acetate:petroleumether=2:1) to give O2′,O3′,O5′-tri-acetyl-N6-(3-hydroxylphenyl)adenosine as a white solid (1.51 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[Si:22]([O:14][CH2:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[CH3:15])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 97.1 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 10.00 g of 2-benzyloxycarbonylamino-2-methylpropanol, 7.35 g of imidazole, 150 ml of anhydrous dimethylformamide and 8.14 g of t-butyldimethylsilyl chloride were used, to give 14.68 g of the title compound having an Rf value of 0.73 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[CH2:28][C@@H:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[N:26]([C:35](=[O:49])[CH:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:25][C:24]=3[N:23]=[CH:22]2)=[CH:16][C:15]=1[CH3:50]>C(OCC)(=O)C>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[CH2:28][C@@H:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[N:26]([C:35](=[O:49])[CH:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:25][C:24]=3[N:23]=[CH:22]2)=[CH:16][C:15]=1[CH3:50])=[O:12])([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1N
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of phthalic acid (0.7223 g, 0.00435 mol) in ethyl acetate (10 ml) was added to a solution of (S)-1-(4-amino-3-methylphenyl)methyl-N,N-dimethyl-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]pyridine-6-carboxamide (II-2) (2.0077 g, 0.00396 mol) in ethyl acetate (30 ml) with stirring at room temperature. The mixture was stirred at room temperature for 23 hours, followed by filtration of the reaction mixture. The resulting white solid was washed with ethyl acetate (about 20 ml) and dried to obtain the objective compound (I-2, Compound No. 2) (2.4107 g; yield: 93.0%). MS 637 (EI): (M-18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)/C=C/c1ccc(-c2ccccc2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)/C=C/c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30.0 Gm (0.117 mol) of (E)-4-(2-chloro-4-biphenylyl)-3-butene-2-one, dissolved in 150 ml of 95% ethanol, were added in small amounts within 10 minutes to a solution of 2.7 gm (0.0714 mol) of sodium borohydride in 200 ml of 95% ethanol. Subsequently the mixture was stirred for 1 hour at room temperature. The excess reducing agent was removed by careful addition of 4 gm of glacial acetic acid. The solvent was then distilled off in a water aspirator vacuum. 500 ml of water were added to the residue, and the mixture was exhaustively extracted with ether. The combined ether extracts were washed with water, dried over sodium sulfate and evaporated. The residue, a colorless viscous oil, was distilled in a high vacuum, b.p. 175°-180°C at 0.1 mm Hg. Yield: 23.0 gm (76% of theory).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[O:17]C)(C)(C)C.[Cl-].[Li+]>CN(C=O)C>[F:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:19])=[O:5])=[C:10]([OH:17])[CH:11]=1
Reactant: COc1cc(F)c(F)cc1OCC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)COc1cc(F)c(F)cc1O
Temperature: 150 °C

Procedure:
A mixture of the product from step (ii) (0.75 g) and lithium chloride (0.345 g) in DMF (20 ml) was heated at 150° C. for 6 h, cooled and partitioned between ethylacetate/2M hydrochloric acid. The organics were dried and evaporated under reduced pressure, yield 0.7 g.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH3:5].S(Cl)([Cl:26])=O>ClCCl>[ClH:26].[CH2:2]([N:6]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 4-(3-dibutylaminopropoxy)benzoic acid hydrochloride [19a] (3.44 g, 10.0 mmol), thionyl chloride (5.87 g, 3.6 mL, 49.4 mmol) and dichloromethane (10 mL) was stirred under reflux conditions for 1 hour and evaporated under reduced pressure at 60-70° C. (water bath) to give 3.62 g (100% yield) of 4-(3-dibutylaminopropoxy)benzoyl chloride hydrochloride [15].
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:12][C:3]1[C:2]([NH:1][S:27]([C:21]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])(=[O:29])=[O:28])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Yield: 81.6 %

Procedure:
Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [NH3:1].[Cl:2][Ge:3]([Cl:11])([Cl:10])[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7]>C(Cl)(Cl)Cl>[Cl:2][Ge:3]([Cl:11])([Cl:10])[CH2:4][CH2:5][S:6]([NH2:1])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)CC[Ge](Cl)(Cl)Cl
Reactant: N
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)CC[Ge](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To chloroform solution (16.0 ml) saturated with ammonia, 2-trichlorogermylethanesulfonylchloride (500 mg, obtained by Example 7) in chloroform solution (2.0 ml) was added dropwise and stirred for 22 hours at room temperature.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:17]
Reactant: CC(O)CCO
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 1,3-butane diol (2.18 g, 24 mmol) and TEA (1.64 g, 16 mmol) in CH2Cl2 (15 mL) at 0° C. was added o-(trifluoromethyl)benzenesulfonyl chloride (2 g, 8 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 45 min. The organics were extracted with CH2Cl2 (150 mL) and washed with 0.5 M HCl (2×80 mL) and saturated aqueous NaCl (1×50 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (50% ethyl acetate in hexanes) yielded the desired product (2 g, 84%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.92 (m, 1H), 7.74 (m, 2H), 4.34 (m, 1H), 4.24 (m, 1H), 3.95 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.20 (d, 3H, J=6.3 Hz). Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.29; H, 4.28.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=O)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)c1ccc(Cl)s1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)N=C(c2ccc(Cl)s2)OC1=O

Procedure:
1.0 g (4.0 mmol) 2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid in 30 ml acetic anhydride are stirred for 1 h at 85° C. Then the reaction mixture is evaporated to dryness.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.ClCl>O>[C:1]([N:5]=[N:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC1(C#N)CCCCC1
Agent: ClCl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N=NC1(C#N)CCCCC1
Reaction time: 0.25 h

Procedure:
To a rapidly stirred mixture of 39.0 g. (0.2 m. ) 1-tert.-butylhydrazo-1-cyanocyclohexane, 200 ml. methylene chloride and 100 ml. water was added 14.3 g. (0.2 m.) chlorine at such a rate that the reaction temperature did not exceed 5 ° C. The reaction was stirred an additional 15 mins. after the addition was complete. The methylene chloride layer was separated, washed twice with 50 ml. portions of saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated on a rotating evaporator to obtain 35.0 g. of liquid product that assayed 86.5% by an ultra violet spectrophotometric analysis. Distillation gavea product, b.p. 71° C./1.2 mm. of Hg that assayed 97.6% as 1-tert.-butylazo-1-cyanocyclohexane. The infrared spectrum was in accord with this structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 55 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (500 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (586 mg) described in Preparation Example 53, the title compound (530 mg) was obtained.