Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22]1>C(O)C.N1CCCCC1>[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:27])[CH2:22]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)N2CC[C@H](N(C)C)C2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3S)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)3-dimethylamino-pyrrolidine-1-carbonyl)5-methyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 80%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[NH2:35][C:36]1[CH:37]=[C:38]([C:42]2[C:50]3[S:49][C:48]([C:51]([NH:53][C@@H:54]4[CH:59]5[CH2:60][CH2:61][N:56]([CH2:57][CH2:58]5)[CH2:55]4)=[O:52])=[CH:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:40][CH:41]=1.[CH3:62][O:63][CH2:64][C:65](O)=[O:66]>CN(C=O)C>[ClH:34].[N:56]12[CH2:57][CH2:58][CH:59]([CH2:60][CH2:61]1)[C@@H:54]([NH:53][C:51]([C:48]1[S:49][C:50]3[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:65](=[O:66])[CH2:64][O:63][CH3:62])[CH:37]=4)=[CH:43][CH:44]=[CH:45][C:46]=3[CH:47]=1)=[O:52])[CH2:55]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
96.4 mg (0.25 mmol) of HATU and 71.5 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 81) and 18.5 μl (0.24 mmol) of methoxyacetic acid in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 3 h. Purification by preparative HPLC is followed by concentration of the product fractions and, after addition of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, concentration again. Drying under high vacuum results in 7 mg (11% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH3:37])[C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)#[N:27].CN1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:34]([C:31]3[C:30]([CH3:37])=[CH:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=3)=[O:35])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a mixture of [(R)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (636 g, 1.77 mol) and 5-cyano-3-methylpyridine-2-carboxylic acid (301 g, 1.86 mol) was added THF (4.2 L) under N2 atmosphere at ambient temperature. To the stirring mixture was added N-methylmorpholine (428 mL, 3.89 mol) and the mixture was stirred to form a homogeneous solution. The reaction solution was cooled to 0-5° C. before addition of isobutyl chloroformate (256 mL, 1.95 mol) via an addition funnel while keeping the reaction temperature under 10° C. After the addition, the mixture was stirred at 0-10° C. for 1 h before filtration. The filtrate was evaporated in vacuo and the resulting residue was dissolved in the mixture of CH2Cl2 (3 L) and methanol (1 L). The mixture was concentrated in vacuo at 400 mbar/35° C. till no more volatile coming out to give a slurry. The slurry was filtered and the filter cake was washed with methanol till the wash getting colorless. The wet cake was dried in a vacuum oven at 45° C. for 24 h to give title compound as a white solid: ESIMS: 504; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 10.00 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.24 (m, 1H), 6.30 (t, 1H), 4.56 (d, 1H), 4.44 (d, 1H), 4.12 (m, 1H), 3.90 (m, 1H), 2.55 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].[ClH:33]>C(Cl)Cl>[Cl:33][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17][CH2:31]1
Reactant: Cl
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenylazetidine-1-acetate (0.12 g) was dissolved in dry methylene chloride (5 ml). To this solution was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methyl 3-chloro-3 -methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.07 g). Infrared Absorption Spectrum (Chloroform)
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N+:10]2[O-].C(OC(=O)C)(=[O:25])C.N>>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:25])[NH:10]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(ccc[n+]2[O-])c1Oc1ccc(F)cc1F
Agent: N
Product: COc1ccc2[nH]c(=O)ccc2c1Oc1ccc(F)cc1F
Temperature: 75 °C
Reaction time: 22 h
Yield: 22.2 %

Procedure:
5-(2,4-Difluoro-phenoxy)-6-methoxy-quinoline N-oxide (1.35 g, 4.5 mmol) was mixed with 5 mL of acetic anhydride and stirred at 75° C. for 22 hours. The reaction mixture was poured on ice, neutralized with aqueous ammonia, and the resultant precipitate was filtered and washed with water. The aqueous layer was extracted with dichloromethane and the organic extract was dried over MgSO4. The solvent was removed under vacuum. The dry residue, combined with the filtered precipitate, was dissolved in a minimum amount of CH2Cl2 and purified using a Biotage system, eluting with 10–30% EtOAc/hexane to give 0.3 g (22.2%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-1H-quinolin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: Clc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(Cl)cn2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.5 g, 2.02 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 2,5-dichloro-pyridine (0.4 g, 2.79 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 80° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 40% ethyl acetate in hexane to provide (5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 360 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.01 (d, 1H), 7.49 (dd, 1H), 7.36-7.27 (m, 5H), 7.26 (m, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 3.82 (m, 2H), 3.21 (m, 2H), 2.15 (m, 2H), 1.58 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[OH:16][C@@H:3]1[C:4]([CH3:14])([CH3:15])[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:25]([NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)c2ccc([N+](=O)[O-])cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CC1(C)c2ccc([N+](=O)[O-])cc2[C@@H](NC(=O)NCc2ccccc2)[C@@H]1O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of trans-3-amino-1,1-dimethyl-2-hydroxy-5-nitro indane (0.75 g, 3.37 mmoles, as prepared in part H of Example 1) and benzyl isocyanate (0.45 g, 3.37 mmoles) in ethanol (6 ml) was heated at reflux for three hours and cooled to room temperature. The reaction product, which had precipitated from solution was collected by suction filtration and dried under vacuum to afford 1.13 g of the title compound as a pure white solid, m.p. 202°-204° C. 1H NMR (DMSO-d6) δ 8.14 (dd, J=2.34 and 8.21 Hz, 1H), 7.91 (s, 1H), 7.50 (d, J=8.21 Hz, 1H), 7.39-7.25 (m, 5H), 6.61 (m, 1H), 5.63 (d, J=5.28 Hz, 1H), 4.93 (dd, J=8.21 and 8.79 Hz, 1H), 4.34 (d, J=5.68 Hz, 2H), 3.79 (dd, J=5.87 and 8.79 Hz, 1H), 1.32 (s, 3H), 1.06 (s, 3H). 13H NMR (DMSO-d6) δ 158.63, 156.50, 146.85, 142.88, 140.81, 128.25, 127.01, 126.61, 123.87, 123.33, 118.66, 84.74, 57.93, 44.05, 44.07, 25.04, 22.42.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][N+:21]([O-])=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C.CCOCC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:26]#[N:27])[CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CN(C)C(=O)Cl
Reactant: CC(c1cc[n+]([O-])cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: CCOCC
Product: CC(c1ccnc(C#N)c1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.6 %

Procedure:
A mixture of the product of part (i) (20.0 g) and N,N-dimethylcarbamoyl chloride (6.80 g) in dichloromethane (250 ml) was stirred at room temperature for 2.5 days, giving a clear solution. Trimethylsilyl cyanide (6.35 g) was added and stirring was continued for a further 48 hours. Additional quantities of N,N-dimethylcarbamoyl chloride (1.30 g) and trimethylsilyl cyanide (1.30 g) were then added and the solution was stirred for a further 36 hours. The reaction was then washed successively with 10% potassium carbonate solution, brine and then dried (MgSO4). Evaporation of the solvent gave a solid which was stirred with ether and filtered to give the title compound, (19.2 g), m.p. 188°-189°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[C:40](O)(=[O:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[N:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)=[N:28][CH:29]=2)=[CH:38][CH:37]=1)(=[O:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Oc1ccc(-c2cnc(-c3ccc(CCCCC)cc3)nc2)cc1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
0.8 g of N,N'-dicyclohexylcarbodiimide is added within 5 minutes while stirring to a solution of 1.0 g of 4-(2-[4-pentylphenyl]-5pyrimidinyl)phenol, 0.4 g of caproic acid and 0.05 g of 4-(dimethylamino)pyridine in 30 ml of dichloro-methane. The reaction mixture is stirred overnight, then filtered, the filtrate is washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 4:1) and two-fold recrystallization of the fractions which are pure according to thin-layer chromatography give 1.0g of 4-(2-[4-pentylphenyl]-5-pyrimidinyl)phenyl hexanoate; m.p. (C-SC) 124° C., phase transition (SC -SA) 185° C., cl.p. (SA -I) 224° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7](=[O:16])[N:8]([CH3:15])[CH2:9][C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.47 g (11 mmol) of N-chlorosuccinimide are heated to 100° for 30 minutes in dimethylformamide. Subsequently, the mixture is poured into water and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate and yields 3-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 217°-218°.
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.[O:30]([CH2:34][CH2:35][NH2:36])[CH2:31][CH2:32][NH2:33].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>[NH2:33][CH2:32][CH2:31][O:30][CH2:34][CH2:35][NH:36][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]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCOCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

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 (86.2 mg, 0.20 mmol), 2,2′-oxybis(ethylamine) (31.3 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. 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 purified by reverse phase chromatography (20-95% of ACN/water) 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 [2-(2-amino-ethoxy)-ethyl]-amide (20.3 mg, 19.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H34Cl2N4O2S+H [(M+H)+]: 517.2132. found: 517.2133.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:10]([NH:18][C:19]([NH:8][C:6]1[CH:5]=[C:4]([Br:9])[N:3]=[C:2]([Br:1])[CH:7]=1)=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)nc(Br)c1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1cc(Br)nc(Br)c1)c1ccccc1
Temperature: 65 °C
Yield: 91.2 %

Procedure:
To a solution of 2,6-dibromo-pyridin-4-ylamine (0.80 g, 3.17 mmol) in THF (50 mL) was added benzoylisothiocyanate (0.47 mL, 3.49 mmol). The reaction mixture was heated to 65° C. overnight. After completion of reaction (TLC monitoring), THF was distilled off and the crude solid was filtered and washed with hexane (2×50 mL) to get the desired product as a pale-yellow solid (1.20 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])[CH2:12][CH2:11]2)=[C:6]([Cl:28])[N:5]=[C:4]([CH3:29])[N:3]=1.O1CCOCC1.Cl>CO>[ClH:28].[NH2:19][C@@H:17]([CH3:18])[C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][C:7]2[C:2]([NH2:1])=[N:3][C:4]([CH3:29])=[N:5][C:6]=2[Cl:28])[CH2:11][CH2:12]1)=[O:27]
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(Cl)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)N)CC2)c(Cl)n1
Reaction time: 0.17 h

Procedure:
Add tert-butyl N-[(1S)-2-[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate (28.75 g, 67.49 mmol) to 1,4-dioxane (143.7 mL). Then add 4M hydrogen chloride in 1,4-dioxane (168.7 mL, 674.9 mmol) and stir for 10 min. Add MeOH (20 mL) and stir the mixture for 3 h with vigorous stirring. Concentrate the mixture under reduced pressure, dilute the solids with diethyl ether (200 mL), and stir overnight. Filter the material, rinsing with diethyl ether (2×25 mL). Dry the material via suction for 15 min, then place under vacuum for 1 h at 45° C. to obtain the title compound as a crude white powder (27.7 g). LC-ES/MS m/z (35Cl/37Cl) 326.1/328.2 (M+1).