Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH:20]=O)[CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[N:10]=[CH:11][CH:12]=[CH:13]2)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2cccnc12
Product: CCOC(CNCc1cccc2cccnc12)OCC
Reaction time: 8 h
Yield: 91.1 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (2.18 ml, 15 mmol) was reacted with 8-quinolinecarboxaldehyde (1.89 g, 12 mmol) to obtain the title compound (3.0 g, 73%).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[S:19]([CH3:21])=[O:20])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:34])(=O)=O>C(#N)C>[CH3:21][S:19]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[NH:8][C:6]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7])(=[NH:34])=[O:20]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COc1cc(NC(=O)N2CCCC2)c(S(C)=O)cc1OC
Solvent: CC#N
Product: COc1cc(NC(=O)N2CCCC2)c(S(C)(=N)=O)cc1OC

Procedure:
A reaction mixture containing 51.7 g. of N-pyrrolidinylcarbonyl-2-methylsulfinyl-4,5-dimethoxyaniline and 0.48 mole of O-mesitylenesulfonylhydroxylamine (prepared by the procedure of Tamura et al., J. Org. Chem. 38, 1239, 1973) and 1 l. of acetonitrile was stirred for 48 hours at ambient temperature. The reaction was then concentrated at reduced pressure and the resulting residue dissolved in 2 l. of methylene chloride. The methylene chloride solution was shaken with 1500 ml. of cold water containing 200 ml. of 14 N aqueous ammonium hydroxide. The organic layer was separated, washed with water, and dried. Evaporation of the methylene chloride solvent in vacuo yielded a residue comprising S-methyl-S-[2-(pyrrolidinylcarbonylamino)-4,5-dimethoxyphenyl]sulfoximine. Crystallization of the residue from a chloroform-cyclo hexane solvent mixture yielded 38 g. of crystalline material (70 percent yield) melting at 312°-314° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C@H:18]([OH:20])[C@@H:17]2[C@H:15]1[C@H:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O1CCCC1>[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C@H:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:17]2[C@H:15]1[C@H:16]2[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](OS(C)(=O)=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Yield: 126.2 %

Procedure:
Methanesulfonyl chloride (224.61 μL, 2.90 mmol) is added to di-tert-butyl (1S,2S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (400 mg, 967 μmoles) and triethylamine (472 μL, 3.39 mmol) in tetrahydrofuran (4.84 mL) at 0° C. and stirred. Cooling bath is removed and the reaction is allowed to warm to room temperature and stirred overnight. Dilute with water and saturated aqueous sodium bicarbonate then extract with ethyl acetate. The combined organics are washed with brine, dried over sodium sulfate, filtered, and concentrated to under reduced pressure to give the title compound (600 mg, 1.22 mmol, 100%).
Reaction SMILES: [CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]1[N:11]=[C:10]([C:12]2[CH:24]=[CH:23][C:22]([C:25](=[O:40])[NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:29])=[O:28])=[CH:21][C:13]=2[C:14]([O:16]C(C)(C)C)=[O:15])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]1[N:11]=[C:10]([C:12]2[CH:24]=[CH:23][C:22]([C:25](=[O:40])[NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:28])=[O:29])=[CH:21][C:13]=2[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 2-(2-(dibutylamino)pyrimidin-4-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoate (110 mg, 0.18 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo to give the title compound (95 mg, 95%), which was used in subsequent reaction without purification. MS(ESI+) m/z 561.2 (M+H)+.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[O:19][CH:20]=2)[N:11]=1.C(C#N)(C)=[O:29]>O=[Mn]=O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:29])[OH:22])[O:19][CH:20]=2)[N:11]=1
Reactant: O=C(Nc1cnn(Cc2coc(CO)n2)n1)OCc1ccccc1Cl
Reactant: CC(=O)C#N
Agent: O=[Mn]=O
Agent: N#N
Product: O=C(Nc1cnn(Cc2coc(C(O)O)n2)n1)OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-hydroxymethyl-oxazol-4-ylmethyl)-2H-[1,2,3]triazol-4-yl]-carbamic acid 2-chloro-benzyl ester (37 mg, 0.10 mmol) in AcCN (3.0 mL) was treated at rt with MnO2 (49 mg, 0.51 mmol) and the reaction mixture was stirred at rt for 16 h before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a brown solid. TLC: rf (EA)=0.48. LC-MS-conditions 02: tR=0.83 min; [M+H]+=380.69.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:11](O)=[O:12].O>CN(C)C=O>[OH:17][CH2:16][CH2:15][CH2:14][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: O=C(O)C(Br)CCCO
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1CCCO
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 6.26 g of 2-aminothiophenol in 50 ml of dimethylformamide was added 9.85 g of 2-bromo 5-hydroxyvaleric acid. The mixture was stirred at room temperature for 2 hours and at 100° C. for 1 hour. The reaction solution was cooled, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure. The concentrate was subjected to a column chromatography on silica-gel (200 g). From the eluate with hexane-acetone (2:1, v/v) was obtained 3.7 g (31.6%) of 2-(3-hydroxypropyl)-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate-hexane gave prisms, m.p. 59°-60° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:19][CH2:20][CH:21]([CH3:22])[N:8]3[CH:7]=[C:6]([C:23]([O:25][CH2:26][C@@H:27]3[CH2:31][O:30]C(C)(C)[O:28]3)=[O:24])[C:5]2=[O:34])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:19][CH2:20][CH:21]([CH3:22])[N:8]3[CH:7]=[C:6]([C:23]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:31][OH:30])=[O:24])[C:5]2=[O:34])[C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC[C@@H]4COC(C)(C)O4)cn1c23
Solvent: CC(=O)O
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC[C@@H](O)CO)cn1c23
Temperature: 75 °C
Yield: 84 %

Procedure:
(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate (5.67 g, 10.8 mmol) was dissolved in 80% aqueous acetic acid (45 mL). The reaction mixture was heated at 75° C. for 8 hrs. The solvent was removed under reduced pressure. Toluene was added to the residue and the solvent again removed under reduced pressure. The product was purified by column chromatography (10%, followed by 20%, 30%, and 75% methanol/chloroform as eluent) to give the title compound as an off-white solid in 84% yield.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([Br:34])[CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2)=[O:24].[SiH](CC)(CC)CC>C(Cl)Cl>[Br:34][C:27]1[CH:28]=[C:29]2[C:33](=[C:25]([C:23]([O:22][CH3:21])=[O:24])[CH:26]=1)[NH:32][CH:31]=[C:30]2[CH2:7][CH:4]1[CH2:3][CH2:2][S:1][CH2:6][CH2:5]1
Reactant: O=CC1CCSCC1
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(CC3CCSCC3)c[nH]c12
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of tetrahydro-thiopyran-4-carbaldehyde (1.3 g, 9.84 mmol) in DCM (20 mL) was added TMSOTf (3.5 mL, 19.7 mmol) at 0° C. To this mixture 5-Bromo-1H-indole-7-carboxylic acid methyl ester (2.5 g, 9.84 mmol) was added. After 2 hours, Et3SiH (6.2 mL, 39.4 mmol) was added at 0° C., and stirring continued for 18 hours. The reaction mixture was quenched with sodium bicarbone solution and extracted with DCM. The combined organic layers were dried (MgSO4), concentrated, and purified by column chromatography on silica gel, giving 1.6 g (44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][C@@H:18]([CH3:23])[C:19]([F:20])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:33][CH2:32][C:30]2[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: C[C@H](Oc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: C[C@H](Oc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)cc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinic acid (Example AO) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; MS: 493.1 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1oc(-c2ccccc2)nc1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 69 %

Procedure:
Intermediate 61 was prepared as described above for the preparation of intermediate 52. From 465 mg of N-(Boc)-L-Tyrosine methyl ester and 320 mg of Intermediate 8G was prepared 520 mg of BOC-protected intermediate methyl ester (69% yield; 1H NMR (CDCl3, 300 MHz) δ8.09-8.06 (m, 2H), 7.47-7.46 (m, 3H), 7.08 (d, 2H, J=8.7), 6.97 (d, 2H, J=8.7), 5.02 (s, 2H), 5.01 (s, 1H), 4.59-4.55 (m, 1H), 3.74 (s, 3H), 3.08-3.02 (m, 2H), 2.83 (q, 2H, J=7.5), 1.45 (s, 9H), 1.32 (t, 3H, J=7.5); From 510 mg of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 61. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 315 mg of intermediate 61; 1H NMR (DMSO-d6, 300 MHz) δ7.96-7.94 (m, 2H), 7.52-7.51 (m, 3H), 7.18 (d, 2H, J=8.4), 6.95 (d, 2H, J=8.4), 4.97 (s, 3H), 3.10-3.05 (m, 1H), 2.86-2.79 (m, 4H), 1.22 (t, 3H, J=7.5); low resolution MS (ES+)m/e 366.86 (MH+); TLC Rf=0.52 (4/1, DCM/MeOH).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2([OH:30])[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2([OH:30])[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((tert-butoxycarbonyl)amino)propanoate in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to rt after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC (CH2Cl2:MeOH=10:1) to afford the (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-aminopropanoate (8 mg, 43% yield) as a white solid. LRMS (M+H+) m/z 458.5. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.17 (d, J=9.6 Hz, 1H), 5.02 (m, 1H), 3.54 (m, 1H), 2.43-2.48 (m, 1H), 1.08-2.15 (m, 24H), 0.88 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=3)[CH2:19][S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=O)[CH:24]=[CH:25][CH:26]=3)=[O:15])=[C:9]([C:34](=[O:51])[NH:35][C:36]3[CH:40]=[CH:39][N:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:37]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C[NH:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][C:74]([O:76]C(C)(C)C)=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:30]=[C:28]([NH:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])[CH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:20][CH2:19][C:18]2[CH:31]=[CH:32][CH:33]=[C:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][C:9]=3[C:34](=[O:51])[NH:35][C:36]3[CH:40]=[CH:39][N:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[N:37]=3)[CH:17]=2)[CH:22]=1
Reactant: O=C(O)Cc1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)CCOCCOCCOCCNC(=O)Cc1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
Into a round bottom flask was placed a solution of 2-(3-((3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)-phenyl)acetic acid 23 (0.119 mmol, 1 equiv) in acetonitrile (0.5 mL), and DIPEA (78.9 mg, 0.612 mmol, 4 equiv). To this was added a solution of tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate 8b (33.08 mg, 0.127 mmol, 1.1 equiv) in acetonitrile (0.5 mL), followed by HATU (57.9 mg, 0.153 mmol, 1.2 equiv). The mixture was stirred at room temperature. The reaction progress was monitored by LCMS. After 1 h, more 8b (15 mg) was added to the solution, and the solution was stirred another 30 min. The solvent was removed by evaporation at reduced pressure. The residue was dissolved in DCM (1 mL). To this was added TFA (0.5 mL). The solution was stirred for 1 h and then the solvent was evaporated at reduced pressure. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. Lyophilization gave 37 mg of product. 1H NMR (400 MHz, dmso) δ 11.55 (s, 1H), 11.46 (s, 1H), 8.65 (d, J=2.6 Hz, 1H), 8.33 (d, J=8.5 Hz, 1H), 8.16 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 8.05 (t, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.78-7.67 (m, 3H), 7.61 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.4 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.22 (s, 1H), 7.17 (d, J=4.9 Hz, 3H), 7.01 (s, 3H), 4.30 (s, 3H), 3.54 (t, J=6.4 Hz, 4H), 3.43 (s, 14H), 3.41-3.16 (m, 15H), 3.16-3.09 (m, 3H), 2.39 (t, J=6.4 Hz, 3H), 1.76-1.66 (m, 4H), 1.61-1.52 (m, 2H). MS (ES, m/z) 917 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CC#N
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
1.50 g (10 mmol) of 4-tert.-butyl phenol were dissolved in 40 ml acetonitrile. 1.34 g (10 mmol) of NCS were added and the reaction mixture was stirred at rt over night. The reaction mixture was heated for 1.5 h to reflux. Then additional 134 mg (1 mmol) of NCS were added and the reaction mixture was heated to reflux for 2 h. The solvent was evaporated and the residue was stirred with diethyl ether for 15 min. The solid was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (100 silica gel, DCM) to yield 1.49 g (81%) of 4-tert.-butyl-2-chloro-phenol as a colorless viscous oil. 1H NMR (DMSO-d6, 300 MHz): δ 9.85 (s, 1H), 7.26 (s, 1H), 7.14 (d, 2H), 6.88 (d, 2H), 1.22 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:23]([Cl:22])[CH:24]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1nc(NCCNCc2ccc(Cl)c(Cl)c2)c2ncn(C3CCCC3)c2n1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.2 ml of 3,4-dichloro-benzaldehyde and 0.2 ml of acetic acid are mixed together and the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 278.4 mg of expected product is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[C:3](=[O:6])[CH2:4][Cl:5].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:9]1[CH2:10][CH2:12][O:11][CH:8]1[CH2:7][N:2]([CH3:1])[C:3](=[O:6])[CH2:4][Cl:5]
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: OCCO
Product: CN(CC1OCCO1)C(=O)CCl
Temperature: 25 °C

Procedure:
N-Methyl-N-(2,2-dimethoxyethyl)-2-chloroacetamide (19.5 grams; 0.10 mole), ethylene glycol (6.82 grams; 0.11 mole) and 10 drops of a solution of one gram of p-toluenesulfonic acid in 100 ml of diethyl ether were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distillation head and condenser. The mixture was stirred and heated to about 100° C. to 110° C. Byproduct methanol was distilled off. When no further methanol was evolved, the mixture was cooled to room temperature, sodium carbonate (2 grams) was added and the slurry was stirred for a period of about 1 hour. The slurry was then filtered and the filtrate fractionally distilled under reduced pressure. The desired product N-(1,3-dioxolan-2-ylmethyl)-N-methyl-2-chloroacetamide was obtained as a fraction boiling at 124° C. at 0.30 mm Hg and at 119° C. at 0.15 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:35][C@@H:34]([CH2:36][CH2:37][NH2:38])[CH2:33][O:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:35][C@H:34]([CH2:33][OH:32])[CH2:36][CH2:37][NH:38][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (431.4 mg, 1.00 mmol) prepared in Example 1d, 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (217.5 mg, 1.5 mmol), HATU (570.30 mg, 1.50 mmol) and iPr2NEt (258.6 mg, 2.00 mmol) in CH2Cl2 (20 mL) was stirred at rt for 1 hour. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was treated with PPTS (cat) in MeOH (20 mL) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by SiO2 flash column (5% of MeOH in EtOAc) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (450.0 mg, 86.7%) as a white amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCCCC2)nc1
Temperature: 60 °C
Yield: 99.6 %

Procedure:
To a slurry of 2-chloro-5-nitropyridine (100 g, 632 mmol) in ethanol (2000 mL) at room temperature was added piperidine (206 mL, 2.08 mol) and the mixture heated to 60° C. for 30 minutes. The cooled mixture was concentrated and the residue taken up in CH2Cl2 then washed with saturated NaHCO3 and brine. The mixture was dried (Na2SO4), filtered, and concentrated to provide the title compound as a yellow solid (130.4 g, 99% yield). 1H NMR (400 MHz, DMSO-D6) δ 8.94 (d, J=2.9, 1H), 8.17 (dd, J=9.6, 2.9, 1H), 6.93 (d, J=9.6, 1H), 3.79-3.73 (m, 4H), 1.69-1.64 (m, 2H), 1.61-1.51 (m, 4H).