Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][N:11]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]1[CH2:33][C:25]2[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=2[C:23](=[O:34])[CH2:22]1>>[C:1]([O:5][C:6](=[O:19])[N:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH:22]2[CH:21]([CH3:20])[CH2:33][C:25]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=3[C:23]2=[O:34])=[O:17])=[CH:12][N:11]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)C2C(=O)c3sc(NC(C)=O)nc3CC2C)cn1

Procedure:
A-14 is prepared via general procedure A1 starting from (5-chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acid tert-butyl ester (A-09) (7.62 g, 26.8 mmol) and N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06) (5.00 g, 22.3 mmol). After evaporation of the solvent 8.62 g of A-14 are obtained which is used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][N:9]([C@H:10]([C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:11][CH2:12][CH3:13])[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([CH3:34])[CH:33]=[C:25]([CH3:24])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CCC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC[C@H](N(NC(=O)OC(C)(C)C)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
(S)—N′-(1-tert-Butyl-butyl)-hydrazinecarboxylic acid tert-butyl ester (1 g, 4.09 mmoles) was dissolved in ca. 3 mL methylene chloride in a vial with a magnetic stir bar. A solution of 0.8 g K2CO3 (5.79 mmoles) in ca. 2 mL water was added, followed by 0.81 g (4.80 mmoles) 3,5-dimethylbenzoyl chloride. The reaction was stirred overnight, first on ice, and then allowed to warm to room temperature. Several mL each water and methylene chloride were then added to dissolve all solids. The aqueous layer was removed and the organic layer was dried over solid MgSO4. TLC indicated that the reaction was ca. 95% complete. The mixture was filtered through some glass wool into a vial. Solvent was evaporated with a stream of N2, chasing with 3:1 hexanes:ether and pentane. The residue was manipulated with a spatula to initiate crystallization, and after complete solidification, was triturated thrice with 2-3 mL pentane in a small fritted glass funnel. After drying in air, 300 mg (19.5%) (S)—N′-(1-tert-Butyl-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester was obtained, indicated by TLC to be quite pure, chiral HPLC indicated e.e=93.3%. The product was dried in a vacuum oven at 50° C. for melting point determination. Rf=0.42 (4:1 hexanes:ethyl acetate, UV (strong), 12 (weak) visualization); mp=115.5-117.5° C.; [α]25589 −30.18 (c 2.02, CH3OH), 1H NMR (400 MHz, CDCl3) δ 7.15-7.03 (m, 3H), 6.07+6.00 (s+d, 1H), 4.52+4.40 (2 dd, 1H), 2.32+2.28+2.23 (3 s, 6H), 1.85-0.89 (m, 25H).
Reaction SMILES: [C:1](=O)([O-])OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1.IC.[CH2:30]([C@@H:32]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[C:38](F)[CH:39]=2)[N:34]([CH2:53]CC)[C:33]1=[O:56])[CH3:31]>>[CH2:30]([C@@H:32]1[N:41]([S:42]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)(=[O:43])=[O:44])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH3:1])[CH:39]=2)[N:34]([CH3:53])[C:33]1=[O:56])[CH3:31]
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2ccc(C)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-3-ethyl-4-[(4-hydroxyphenyl)sulfonyl]-1,6-dimethyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−123° (c=0.0057 G/ML, DMSO); MS (ESI) m/z 361 ([M+H]+); MS (ESI) m/z 359 ([M−H]−); Anal. Calcd for C18H20N2O4S: C, 59.98; H, 5.59; N, 7.77. Found: C, 57.75; H, 5.20; N, 7.42.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32]>>[OH:33][C@@H:31]([CH3:32])[CH2:30][NH:29][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:28]
Reactant: C[C@H](O)CN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC[C@H](C)O)cc2)CC1
Yield: 81 %

Procedure:
By the same procedure as described in the example 31, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using (S)-(+)-1-amino-2-propanol. Then, the product was recrystallized using isopropanol and tetrahydrofuran to give the desired compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][CH2:25]3)[CH:23]=2)[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][CH2:25]3)[CH:23]=2)[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cn(C4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cn(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A mixture of 243g (80 mg, 0.12 mmol) and lithium hydroxide (100 mg, 2.4 mmol) in i-propanol/THF/water (2:2:1, 8 mL) was stirred at 35° C. for 30 mins. The reaction mixture was then concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with dichloromethane three times. The combined organic layer was concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 243 (28.0 mg, 30%). MS-ESI: [M+H]+ 625.4. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J=6.5 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.35-7.34 (m, 2H), 7.11 (d, J=1.0 Hz, 1H), 6.58 (s, 1H), 5.14 (bs, 1H), 4.54 (t, J=7.5 Hz, 2H), 4.43-4.40 (m, 4H), 4.23-4.11 (m, 3H), 3.99-3.96 (m, 1H), 3.91-3.84 (m, 1H), 3.59 (s, 3H), 3.43-3.39 (m, 1H), 2.77-2.76 (m, 2H), 2.62-2.57 (m, 2H), 2.47-2.46 (m, 2H), 1.94-1.89 (m, 6H), 1.79-1.78 (m, 2H), 1.69-1.66 (m, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O.CCOC(C)=O>C1COCC1.O>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:42][C:43]([F:46])([F:45])[F:44])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)Nc2c(C)cc3cn(CC(F)(F)F)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and NaH (60%) (67 mg, 1.6 mmol) in THF (5 mL) was stirred for 1 hour at ambient temperature, and was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (246 mg, 1.06 mmol). The resulting reaction mixture was stirred for 4 hours at 60° C. AcOEt and water was added. The phases were separated. The aqueous layer was extracted with AcOEt. The organic layers were washed with water, combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, Toluene/AcOEt 7:3) afforded the title compound as a colorless crystalline solid. M.p. 178-181° C., LC/MS: 550 (M+H)+, 572/574 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([OH:22])=[O:21])O)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C(O)CC1(O)CCc2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Trifluoroacetic acid (100 mL) was added to a stirred, chilled (ice-methanol bath) solution of 2-(6-Fluoro-1-hydroxy-1-indanyl)acetic acid (37.5 g, 0.18 mol) in dichloromethane (900 mL). After 15 min, the mixture was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as a yellowish-tan solid (33.0 g, 95%), m.p., 203°-205° C.;
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)=[O:5])C.C[O-].[Na+]>CO>[CH3:1][O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH:7]1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)=[O:5]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1c1ccc(F)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1c1ccc(F)c(F)c1
Temperature: 25 °C

Procedure:
A mixture of 2.2 g (5.9 mmol) (3SR,4RS)-3-(3,4-Difluoro-phenyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester and 0.18 mL NaOMe (5.4N in methanol) in 60 mL methanol was first stirred at room temperature and subsequently ar reflux until consumption of the starting material. The mixture was evaporated to dryness and the residue subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to afford after evaporation of the product containing fractions 1.5 g (71%) of the title compound as colorless oil. MS (m/e): 256.1 [(M+H-Boc)+].
Reaction SMILES: C([O-])(=O)C.[NH4+].[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:16]=O)=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:18]([F:21])([F:20])[F:19].[N+:22]([CH3:25])([O-:24])=[O:23]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11](/[CH:16]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=Cc1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])/C=C/c1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Yield: 49 %

Procedure:
Nitromethane (20 ml) and ammonium acetate (1.6 g) were added to 6-chloro-5-(trifluoromethyl)indole-3-carbaldehyde (3.25 g) and the mixture was heated under reflux for 1 hr. The reaction mixture was allowed to cool, and the precipitated solid was collected by filtration, washed with methanol-water (1:1) and dried to give a brown solid. This solid was washed in a suspension state with diethyl ether, collected by filtration and dried to give 6-chloro-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)-1H-indole (1.86 g, yield 49%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C=O)C>[OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1csc(-c2ncccc2O)n1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1csc(-c2ncccc2O)n1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A suspension of 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylic acid (200 mg) and N,N'-carbonyldiimidazole (hereinafter, referred to as CDI) (291.9 mg) in dry DMF (7 ml), prepared under argon atmosphere, was heated at 80° C. for 1.5 hours. A solution of 5-aminotetrazole (91.9 mg) in dry DMF (3 ml) was added dropwise thereto and allowed to react at 85° C. for 3.5 hours. Then the reaction mixture was cooled to room temperature. The produced solids were filtered with suction, washed with DMF and THF and dried to give white solids of 2-(3-hydroxy-2-pyridyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (140 mg, 54%), m.p. above 300° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: O=C(O)c1cc(S(=O)(=O)NC2CC2)c(F)cc1Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC3CC3)c(F)cc2Cl)CC1
Yield: 43 %

Procedure:
0.335 g (0.75 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.242 g (0.83 mmol) 2-chloro-4-fluoro-5-[(cyclopropylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1% TFA in water in acetonitrile. 0.231 g obtained (43% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.38-8.47 (br, 1H), 7.72-7.92 (m, 2H), 7.33-7.51 (m, 3H), 7.20-7.28 (m, 2H), 7.01-7.16 (m, 3H), 4.45-4.57 (m, 1H), 4.06-4.12 (m, 1H), 3.87-3.98 (m, 1H), 3.21-3.42 (m, 6H), 2.97-3.10 (m, 1H), 2.44 (s, 3H), 2.23-2.42 (m, 2H), 1.95-2.17 (m, 2H), 1.72-1.92 (m, 8H), 1.55-1.65 (m, 2H), 0.34-0.53 (m, 4H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].N[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.N([O-])=O.[Na+]>O.Cl.C(Cl)(Cl)Cl>[N:1]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccnc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
Sodium azide (1.5 g) dissolved in 5 ml of water was dropped into a solution of 2.0 g of 3-aminopyridine in 15 ml of 10% hydrochloric acid under cooling with ice. After the reaction solution was stirred for 20 minutes under cooling with ice, 1.8 g of sodium nitrite dissolved in 5 ml of water was dropped in the reaction solution. After temperature of the reaction solution was raised up to room temperature, it was stirred for 1 hour. The reaction solution was diluted with chloroform, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 2.5 g of the title crude compound as a brown oily substance.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[CH:9]1([CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCOCC1CCCCC1
Product: O=[N+]([O-])c1ccc(CCCCCCOCC2CCCCC2)cc1
Yield: 25.9 %

Procedure:
General procedure M was used to convert 5.21 mmol of 11b and 5.73 mmol of 1-bromo-4-nitrobenzene to 1.35 mmol (26%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12](O)(=O)[CH2:13][CH2:14][CH2:15][CH3:16]>P(Cl)(Cl)(Cl)=O>[CH2:13]([C:12]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1nc2cc([N+](=O)[O-])ccc2[nH]1

Procedure:
11.5 g (0.075 mol) of 4-nitro-o-phenylenediamine are introduced in portions at ambient temperature into a mixture of 8.66 g (0.085 mol) of valeric acid and 120 ml of phosphorus oxychloride. The mixture is then heated for 3 hours under reflux. The reaction mixture is separated in 1.5 kg of iced water, rendered alkaline using concentrated ammonia and extracted three times using 500 ml of ethyl acetate. The organic phase is separated off, dried using magnesium sulphate and rotary evaporated. The oily residue is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/0-2% ethanol). The homogeneous fractions are evaporated to dryness.
Reaction SMILES: [CH2:1]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]=1)[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:2]([C:3]1[N:4]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:1][C:12]1[N:13]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: c1ccc2[nH]c(CCc3nc4ccccc4[nH]3)nc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(CCc3nc4ccccc4n3Cc3ccccc3)nc3ccccc32)cc1
Yield: 41.5 %

Procedure:
To a flask were added 0.5 g 2,2′-ethane-1,2-diylbis(1H-benzimidazole), 0.7 g potassium carbonate, 30 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 0.6 g Benzyl chloride were added and the mixture was heated to 60 C for 16 hours. Another 0.5 g benzyl chloride were added and the reaction was heated to 70 C for another 20 hours and then cooled to 22 C. The reaction was quenched with 30 ml water and the product was filtered and washed with water. The product was re-slurried in 80 ml hot acetonitrile, cooled, filtered and dried resulting in 0.35 g of a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14]C(OCC)C)[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 2-benzyl 3-methyl (2S,3S,5R)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate (5.70 g, 0.0125 mol) in 100 mL of THF was added 20 mL of water followed by 20 mL of 1N HCl. The mixture was stirred at rt for 1 h. After diluted with EtoAc, the mixture was neutralized with 1N NaOH, washed with brine, dried. The residue obtained after concentration was applied on silical, eluting with 0 to 50% EtOAc in hexane, to provide the alcohol compound (4.80 g, 89.6%). MS (ESI): (M+H)+=384.2.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][CH:5]([O:4][C:2]([N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1)=[O:3])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=S1(=O)CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)N1CCS(=O)(=O)CC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.32 g, 1 mL, 9.27 mmol) was reacted with thiomorpholine 1,1-dioxide (1.1638 g, 8.61 mmol) and pyridine (783 mg, 801 μl, 9.9 mmol) in methylene chloride (15 mL) at room temperature for 3 h to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester. A portion of 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester (577 mg, 1.614 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.5 mg, 0.244 mmol) in the presence of cesium carbonate (598.4 mg, 1.84 mmol) in dimethylformamide (7 mL) overnight to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-ethyl ester as an off-white solid (175.3 mg, 87% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O8S: [(M+H)+]: 821, found: 821
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][OH:22])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(N1CCC(C2NNC(=O)C=2C)CC1)=O)(C)(C)C.CI.C(I)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][O:22][CH3:24])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCn1nc(CO)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Solvent: CCI
Solvent: CI
Product: CCn1nc(COC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(1-ethyl-3-hydroxymethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Piperidine 19, Step C) using a procedure analogous to that described for Piperidine 15, Step E, except methyliodide was substutited for ethyliodide. RF: 0.47 (3:2 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.39 (t, J=7.2, 3H), 1.49 (s, 9H), 1.69–1.71 (m, 2H), 1.85–1.94 (m, 2H), 2.08 (s, 3H), 2.75–2.81 (m, 3H), 3.39 (s, 3H), 4.12 (q, J=7.2, 2H), 4.14–4.27 (m, 2H), 4.38 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2S(C)(=O)=O)[N:4]=1.[CH3:24][O-:25].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[O:25][CH3:24])[N:4]=1
Reactant: C[O-]
Reactant: COc1cc(OC)nc(-n2c(S(C)(=O)=O)nc3ccccc32)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(-n2c(OC)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
1-(4,6-dimethoxypyrimidin-2-yl)-2-methylsulfonylbenzimidazole (0.40 g) was dissolved in tetrahydrofuran (20 ml), and sodium methylate (0.50 g) was added thereto under cooling with ice, followed by stirring for 1 hour. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the mixture was purified by silica gel column chromatography to obtain 0.40 g of the desired product as a white powder (m.p. 121-122° C.).