Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([NH:21][NH2:22])=[O:20].[C:23](=S)=[S:24]>CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[O:20][C:23](=[S:24])[NH:22][N:21]=1
Reactant: S=C=S
Reactant: NNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: S=c1[nH]nc(Cc2ccccc2Nc2c(Cl)cccc2Cl)o1
Yield: 69.1 %

Procedure:
Potassium hydroxide (363.0 mg, 5.50 mmol) is added to a 0° C. suspension of 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, hydrazide (1.556 g, 5.01 mmol) and carbon disulfide (700 μl, 11.87 mmol) in 30 ml of methanol. The mixture is heated at reflux overnight under an atmosphere of nitrogen. The solution is concentrated in vacuo and the residue dissolved in water. The resulting aqueous solution is acidified with 1N hydrochloric acid and the resulting solids extracted into a 1:1 mixture of ether and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed, eluting with hexane:ethyl acetate (1:1), providing a white solid. Drying in vacuo at 65° C. for five days gives 1.22 g (65%) of product, mp 168°-170° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](OCCCC)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH2:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([NH:43][C:44]4[NH:48][N:47]=[N:46][N:45]=4)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)c1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: Nc1nnn[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)c2ccc(OC(F)(F)F)cc2)C2CCc3cc(C(=O)Nc4nnn[nH]4)ccc32)CC1

Procedure:
Butyl 1-{(trans-4-tert-butylcyclohexyl)[4-(trifluoromethoxy)benzoyl]amino}indane-5-carboxylate, enantiomer A (50 mg) or enantiomer B (70 mg), was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 1-{(trans-4-tert-butylcyclohexyl)[4-(trifluoromethoxy)benzoyl]amino}-N-1H-tetrazol-5-ylindane-5-carboxamide. Enantiomer A: HPLC/MS: m/z=571.2 (M+1), Rt=2.65 min. 1H NMR (DMSO-d6): δ 12.34 (1H, br s), 7.95 (1H, s), 7.90 (1H, d, J=8.0 Hz), 7.52 (2H, d, J=8.0 Hz), 7.44 (2H, d, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 5.05 (1H, m), 3.35 (1H, m), 3.15 (1H, m), 2.96 (1H, m), 2.55 (1H, m), 2.36 (1H, m), 2.12 (1H, m), 1.77 (6H, m), 0.99 (1H, m), 0.84 (1H, m), 0.79 (9H, s). Enantiomer B: HPLC/MS and 1H NMR (DMSO-d6) are identical to those of enantiomer A.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 93.9 %

Procedure:
A solution of 1-acetyl-4-(4-nitrophenyl)piperazine (28.8 g) in ethanol (400 ml) was hydrogenated at 4 bar in the presence of 10% palladium/carbon (0.5 g) until no further hydrogen was taken up. The catalyst was filtered off and the filtrate was evaporated. The residue was triturated with diethyl ether, filtered and dried to give the title compound (23.8 g), m.p. 142°-144° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCO
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Product: Cc1cc(F)ccc1N1CCc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in 3-amino-1-propanol(5.0 ml). The reaction mixture was reacted at the same condition of Step 3 in the Example 42 to obtain 520 mg of desired compound as solid in 84% of yield.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 690.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>CO>[CH2:1]([NH:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: OCC1CO1
Solvent: CO
Product: CCCCCCCCCCCCNCC(O)CO
Temperature: 70 °C
Yield: 59 %

Procedure:
The procedures of Ulsperger et al., J. Prakt. Chemie, Vol. 27, pp. 195-212 (1965), the disclosures of which are hereby incorporated herein by reference in their entirety, were substantially followed. Specifically, 18.54 g laurylamine (0.1M) and 7.4 g glycidol (0.1M) were mixed in 150 ml methanol at 60° C. for 5 hours. The mixture was refluxed for 1 hour at 70° C. The methanol was then removed by rotary evaporation. The product was a solid, 15.3 g (59% yield). After recrystallization from hexane, LDP, was recovered as a white crystal, m.p. 75°-76° C. (m.p. 76°-76.5° C., lit.).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:21]1[CH:22]=[C:23]2[CH:29]=[CH:28][NH:27][C:24]2=[CH:25][N:26]=1.[Na+].[Cl-]>C(Cl)Cl>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:21]1[CH:22]=[C:23]2[C:29]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[CH:28][NH:27][C:24]2=[CH:25][N:26]=1
Reactant: CCC(CC)C(=O)Cl
Reactant: Cc1cccc(C)c1-c1cc2cc[nH]c2cn1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)C(=O)c1c[nH]c2cnc(-c3c(C)cccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Ethyl-butyryl chloride (0.799 mL, 5.8 mmol) is added to a suspension of AlCl3 (770 mg, 5.8 mmol) in DCM (20 mL) at −10° C. The resultant solution is stirred for 15 min at the same temperature, and 5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (0.5 g, 2.2 mmol) is added as a solution in DCM (3 mL). The mixture is stirred for 18 h at room temperature. A saturated aqueous NaCl solution (30 mL) is carefully added to the mixture, and stirring is continued for 2 h. Organic layer is separated, and the aqueous solution is extracted with DCM. The combined organic solutions are washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel 10% MeOH-DCM affords 1-[5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][NH:11][C:10](=[O:17])[CH:9]=1)=O>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]1[N:14]=[C:13]2[CH2:12][NH:11][C:10](=[O:17])[CH:9]=[C:8]2[N:7]=1
Reactant: COc1cc(SC)ccc1C(=O)Nc1cc(=O)[nH]cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(SC)ccc1C1=NC2=CC(=O)NCC2=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.6 g of crude 4-(2-methoxy-4-methylmercapto-benzoylamino)-5-nitro-1H-pyridin-2-one were dissolved in 10 ml of glacial acetic acid, the solution was mixed with two spatula tipsful of iron powder, and the mixture was stirred for 30 minutes at room temperature. The mixture was then refluxed for 20 minutes, filtered, and the filtrate was evaporated in vacuo. The product thus obtained were purified by chromatography on silica gel (eluant: methylene chloride/ethanol=100:2 to 100:15).
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[CH:17][N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]N1C(=O)CCC1=O>>[C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[C:17]([Cl:21])[N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Product: O=[N+]([O-])C(Cl)=C1SCCCN1S(=O)(=O)Cc1ccccc1

Procedure:
was prepared, as a yellow solid, m.p.: 150°-151° C. (with decomposition), by treating (5A) with N-chlorosuccinimide according to the procedure described in Example 2.
Reaction SMILES: [CH3:1][C:2]1([C:8](O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B#B>O1CCCC1>[CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCCCC1
Agent: B#B
Solvent: C1CCOC1
Product: CC1(CO)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
To a solution of 1-methyl-1-hydroxycarbonylcyclohexane (10 g, 70 mmol) in tetrahydrofuran (300 mL) at 0° C. was added 1 M diborane in tetrahydrofuran (200 mL, 200 mmol) over 90 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for two days. The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling. Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed. The organic layer washed with water and saturated sodium chloride, dried, filtered and concentrated. The residue was purified by flash chromatography using 20% diethylether in hexanes to give 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol, 69%).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:28]=[C:27]([N:29]([C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[C:36]([C:43]#[N:44])[CH:35]=4)[S:30]([CH3:33])(=[O:32])=[O:31])[C:26]([CH:45]4[CH2:47][CH2:46]4)=[CH:25][C:19]=3[C:20]=2[C:21]([NH:23][CH3:24])=[O:22])=[CH:12][CH:11]=1>O.C1COCC1>[NH2:40][C:37]1[CH:38]=[CH:39][C:34]([N:29]([C:27]2[C:26]([CH:45]3[CH2:47][CH2:46]3)=[CH:25][C:19]3[C:20]([C:21]([NH:23][CH3:24])=[O:22])=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=4)[O:17][C:18]=3[CH:28]=2)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:35][C:36]=1[C:43]#[N:44]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A solution of Na2S2O4 (4.98 g, 28.6 mmol) in water (50 mL) was added dropwise to a solution of 2-(4-chlorophenyl)-6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (2.70 g, 4.77 mmol) in THF at room temperature under N2. The mixture was stirred overnight. More water was added and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4. Concentrated under reduced pressure, the crude residue was purified by chromatography on silica gel eluted with 0-15% EtOAc in DCM to give the product (2.3 g, 83%) as a white solid. LCMS (m/z, ES+)=535 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[C:23](C)[CH:24]=1)=[CH:16][CH:15]=3.Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1
Reactant: BrCCOC1CCCCO1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOC5CCCCO5)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(5-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one described in Example 39 and 2-(2-bromoethoxy)tetrahydropyran (Collect. Czech. Chem. Commun.; EN; 69; 10; 2004; 1843-1876).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([NH2:24])=[O:8])([O-:3])=[O:2]
Reactant: N
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1Oc1ccccc1
Product: NC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
3-Nitro-4-phenoxy-5-sulphamyl-benzoyl chloride (4 g) was added in portions to liquid ammonia (40 ml). Then excess of ammonia was distilled off, and the residue was triturated with water (50 ml). The precipitated 3-nitro-4-phenoxy-5-sulphamyl-benzamide was isolated by filtration and recrystallized twice from aqueous ethanol. After drying in vacuo, the compound was obtained with a melting point of 255°-256°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28](C)[CH:29]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3,5-dimethylphenylboronic acid in step 1.F.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]([CH2:8][OH:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[H]1[BH2][H][BH2]1.CO>C1COCC1>[OH:9][CH2:8][CH:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN1C(=O)C(CO)C[C@H]1COc1cccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CC(CO)C[C@H]1COc1cccnc1

Procedure:
A 401 mg (2 mmol) sample of 3-(1-methyl4-hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine, from step 48a above, was dissolved in 6 mL of THF and 6 mL of 1M B2H6 was added. The reaction mixture was heated at reflux for 2 hours, then stirred at room temperature for 15 minutes after methanol was added. The solvent was removed under pressure, and the residue was dissolved in 4 mL of ethanol. The this solution was added 251 mg of CsF, and the reaction mixture was heated at reflux for 16 hours. The solvent was removed, and the residue was purified on a column of silica gel, eluting with 100:5 to 10:1 chloroform:methanol 78 mg of a mixture of cis and trans product. cis compound: MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (m, 1H), 8.23 (t, 1H, J=3 Hz), 7.21 (m, 1H), 4.16-3.94 (m, 2H), 3.77-3.54 (m, 2H), 3.09-3.01 (m, 1H), 2.88-2.64 (m, 1H), 2.58-2.47 (m, 1H), 2.46 (m, 1H), 2.46 (s, 1H), 2.38-2.29 (m, 1H), 1.98-1.81 (m, 1H). trans compound: MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) d: 8.33 (m, 1H), 8.23 (m, 1H), 7.23 (m, 1H), 4.20-3.96 (m, 2H), 3.74-3.59 (m, 2H), 3.42-3.26 (m, 1H), 2.97-2.83 (m, 1H), 2.54 (s, 1H), 2.48-2.23 (m, 1H), 2.04-1.80 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH:15]([SH:18])([CH3:17])[CH3:16].[OH-].[Na+]>CS(C)=O>[CH:15]([S:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])([CH3:17])[CH3:16]
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
To a solution containing 112.8 g (0.5 mole) of 2-chloro-5-nitrobenzotrifluoride and 46 g (0.6 mole) of isopropyl mercaptan in 400 ml of DMSO was added dropwise over 0.5 hour 40 g of 50% aqueous sodium hydroxide. This addition was exothermic to 50° C. After 24 hours, the reaction mixture was poured into ice water and extracted with 3×200 ml of methylene chloride. The combined extracts were washed with water, dried and concentrated to give 132 g (99%) of product as an orange liquid.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CS(=O)(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and methylsulfonyl chloride (9.3 μl) were reacted and treated in the same manner as in the method described in Example 30 to obtain the title compound.
Reaction SMILES: Br.Cl[C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:15][CH2:16][CH3:17].[Na+]>C(O)C>[CH2:16]([O:15][C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:17]
Reactant: CC[O-]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.006; 4 g) were dissolved in ethanol (120 ml), admixed under argon with sodium ethoxide (5.86 g) and stirred at 60° C. for 1 h. Then the mixture was dried and the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 3.24 g of the title compound were obtained, which still contained residual amounts of dichloromethane. LC-MS rt: 0.53 min [M+H]+: 208.1 (met. b)
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]2[O:34][CH2:18]2)[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4-pentenoate 16a (2.0 g, 5.8 mmol) in CH2Cl2 (15 mL), NaHCO3 (0.58 g, 7 mmol) and water (10 mL) at 0° C., is added slowly m-chloroperbenzoic acid (3.3 g, 11.6 mmol, 57-86%). The reaction mixture is stirred overnight. The resulting mixture is diluted with aqueous NaHCO3, and the mixture is extracted three times with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (4:6) to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:24])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1ccnc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Temperature: 0 °C
Yield: 59 %

Procedure:
A mixture of 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412 mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was heated at reflux for 1 hour. The mixture was diluted with toluene and the volatiles were removed by evaporation. The residue was suspended in methylene chloride, cooled to 0° C. and aqueous sodium hydrogen carbonate solution was added. The resulting precipitate was collected by filtration and dried under vacuum to give 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (258 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:35][CH2:36][O:37][CH2:38][CH2:39]Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:32]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOCCBr
Reactant: NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Solvent: CN(C)C=O
Product: O=C(NC(CO)c1ccc(F)c(Cl)c1)c1cc(-c2n[nH]cc2-c2ccc(CN3CCOCC3)c(Cl)c2)c[nH]1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl amine 11 (0.05 mmol) in DMF (3 mL) was added TEA (0.15 mmol) and 2-bromoethyl ether (0.05 mmol). The resulting solution was stirred for 18 h at 70° C. The solvent was removed under vacuum and the crude products purified by preparatory HPLC to afford II-6 as a yellow oil.