Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[CH2:8][CH2:9][N:10]([CH3:38])[C:11]1[C:12]([NH2:37])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:39][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:38])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:37][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1cc(Nc2ncc(C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Acryloyl chloride (0.026 mL, 1M in THF, 0.32 mmol) was added dropwise to a mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 81, 147 mg, 0.32 mmol) and DIPEA (0.061 mL, 0.35 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). The resulting solution was washed with water and sat. brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methnaolic ammonia in CH2Cl2 gave a yellow dry film after concentrating the appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. This was concentrated in vacuo and dried to give the title compound (93 mg, 57%) as a beige solid; 1H NMR: 2.21 (6H, s), 2.28-2.34 (2H, m), 2.37 (3H, s), 2.73 (3H, s), 2.89 (2H, t), 3.81 (3H, s), 3.89 (3H, s), 5.72 (1H, dd), 6.19 (1H, dd), 6.38 (1H, dd), 7.02 (1H, d), 7.06 (1H, d), 7.18-7.23 (1H, m), 7.48 (1H, d), 7.91 (1H, s), 8.06 (1H, s), 8.22 (1H, s), 8.36 (1H, d), 8.75 (1H, s), 10.11 (1H, s); m/z: ES+ MH+ 514.36.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].[C:16]([O:20][C:21](=[O:28])[NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:25]2[CH2:26][CH2:27][C@H:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[CH2:24]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 74.5 %

Procedure:
A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L., Priebe S. R., Sesnie J. A., Trehan A. K., J. Med. Chem., 1992; 35(10):1764-1773), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under a nitrogen atmosphere for 4.5 hours. The yellow solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue is then purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (5.24 g). 1H NMR (CDCl3): δ 7.35 (ddd, 1H), 4.70-4.65 (bs, 1H), 4.42-4.20 (m, 3H), 3.90-3.62 (m, 3H), 3.58-3.42 (m, 1H), 2.28-2.03 (m, 1H), 1.99-1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]=[CH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 16 h

Procedure:
A solution containing 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (500 mg, 2.34 mmol), 2-amino-N-(5-chloropyridin-2-yl)benzamide (580 mg, 0.23 mmol), and pyridinium p-toluenesulfonate (58 mg, 0.23 mmol) in benzene (250 mL) was heated at reflux with azeotropic removal of water. After 16 h, the mixture was concentrated and the residue partitioned between EtOAc (300 mL) and water (150 mL). The organic phase was separated and washed again with water (150 mL), brine (150 mL); then dried with MgSO4, filtered and concentrated to afford, after purification by column chromatography (SiO2: 0 to 10% EtOAc:methylene chloride), 750 mg (72%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.[ClH:26].[C:27](O)(=[O:29])[CH3:28]>>[ClH:26].[C:27]([O:1][CH:2]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)(=[O:29])[CH3:28]
Reactant: C[C@H](CCc1ccc(C(N)=O)cc1)NCC(O)COc1ccccc1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)OC(CN[C@H](C)CCc1ccc(C(N)=O)cc1)COc1ccccc1

Procedure:
0.5 g of p-[(R)-3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]butyl]benzamide was warmed to 40° for 24 hours in 25 ml of acetic acid saturated with hydrochloric acid gas. Thereupon, the solvent was removed in vacuo and the crystalline residue was recrystallized from acetonitrile, and there was obtained p-[(R)-3-[[(RS)-2-acetoxy-3-phenoxypropyl]amino]butyl]-benzamide hydrochloride of m.p. 83°-85°, [α]D20 =+10° (c=0.6 in methanol), ε222 =15020, ε234 =13590.
Reaction SMILES: COC(=O)C[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:16]([CH3:17])=[C:15]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)[C:14](=[O:31])[N:13]([CH3:32])[C:12]2=[O:33])[CH:6]=1.[OH-:35].[Na+].[O:37]1[CH2:41]CCC1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:22]2[C:18]([C:15]3[C:14](=[O:31])[N:13]([CH3:32])[C:12](=[O:33])[N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:41]([OH:37])=[O:35])[C:16]=3[CH3:17])=[CH:19][CH:20]=[N:21]2)=[CH:24][CH:25]=1)#[N:30]
Reactant: COC(=O)Cc1cccc(-n2c(C)c(-c3ccnn3-c3ccc(C#N)cc3)c(=O)n(C)c2=O)c1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
To a solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]phenylacetic acid methyl ester (prepared in Example 32) (239.6 mg) in tetrahydrofuran (2.0 ml) was added under ice-cooling sodium hydroxide (5M aqueous solution, 108 μl) and the resulting mixture was stirred at room temperature for twenty hours. The reaction mixture was washed with dietylether (15 ml), and the aqueous layer was acidified (pH=3) with potassium hydrogen sulfate and then extracted with ethyl acetate (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)benzoic acid (67.2 mg).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@H:23]([NH:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[CH2:27]2)[CH3:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:37][C:34]1[CH:33]=[CH:32][C:31]([C@@H:28]2[CH2:29][CH2:30][C@H:26]([NH:25][C@@H:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH3:24])[CH2:27]2)=[CH:36][CH:35]=1)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (5 mL) and ethyl bromoacetate (0.13 mL, 1.2 mmol) were added to 4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenol (331 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. After the extracted solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (NH silica; ethyl acetate/hexane: 5/95-8/92) to give the title compound (298 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][CH2:13][CH2:12][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(CCCO)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
tert-Butyl(3-hydroxypropyl)(isobutyl)carbamate (0.73 g, 3.15), triethylamine (0.64 g, 6.30 mmol) and CH2Cl2 (30 mL) were added to a round-bottom flask. To the solution was added methanesulfonyl chloride (0.54 g, 4.72 mmol) and the reaction mixture was stirred for 5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (hexanes/EtOAC) to afford the desired product (0.63 g, 64%) as a yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:33]=1[OH:34]>ClCCl.O>[OH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Nc1c(O)cccc1O
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2c(O)cccc2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (2.49 g) and 1,1′-carbonyl diimidazole (2.31 g) in dichloromethane (10 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred suspension of 2-aminoresorcinol (1.62 g) in dichloromethane (15 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1 N HCl (100 ml) and brine (100 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (2.122 g, 60%) as a beige solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.ClC1N=CN=C([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)=O)C=1.C(N(CC)CC)C.CNC1CCCCC1>C1COCC1>[CH:29]1([N:28]([CH3:26])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[O:9])[CH:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cc(C(=O)Nc2ccc(O)cc2)ncn1)C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (75.0 mg; 0.30 mmol) in THF (4 mL) was treated with triethylamine (42 μl; 0.30 mmol) and N-methylcyclohexylamine (Aldrich, 43 μl; 0.33 mmol). The reaction mixture was stirred for 24 h. The solvents were removed in vacuo, then the crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][NH2:25])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>CN(C=O)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][NH:25][C:35]5[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: CC(C)Cc1nc(-c2ccc(OCCN)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(-c2ccc(OCCNc3ccncc3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine, the product of Example 512, was treated with 4-chloropyridine in DMF and was heated at 100° C. Aqueous workup and chromatography on silica gel afforded Example 519. (Yield: 80 mg)
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29].C[N:34]([CH3:37])C=O>O.ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[C:15]([C:28]([C:27]4[CH:31]=[C:23]([N:34]5[CH:37]=[CH:9][C:8]([CH3:15])=[N:7]5)[CH:24]=[CH:25][C:26]=4[CH3:32])=[O:29])=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CN(C)C=O
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccn(-c2ccc(C)c(C(=O)c3cccc4c3Nc3ncccc3CN4)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (2.0 g, 10.1 mmol) in dimethylformamide (15 mL) under nitrogen was added potassium carbonate (4.1 g, 29.7 mmol). The mixture was treated dropwise with a solution of crude 5-fluoro-2-methyl benzoyl chloride of Step A (15.0 mmol) in dimethylformamide (10 mL). After stirring at room temperature for 15 minutes, the mixture was diluted with water and stirred to give a solid mass which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give a purple oil. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided 1.88 g (55.8%) of the title product as a foam which was crystallized by sonication from ethanol-hexane, m.p. 138-140° C.
Reaction SMILES: CS(O)(=O)=O.[O:6]=[C:7]([N:21]1[CH2:26][CH2:25][N:24]2[C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=[C:23]2[CH2:22]1)[CH:8]=[C:9]([NH2:20])[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19].CC(O)C.N>C1COCC1.O>[O:6]=[C:7]([N:21]1[CH2:26][CH2:25][N:24]2[C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=[C:23]2[CH2:22]1)[CH2:8][CH:9]([NH2:20])[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 4 h

Procedure:
In a 50 mL round bottom flask dry THF (17 mL) was taken. It was cooled to −10° C. and 2.0 M Borane methyl sulfide complex solutions in THF (7.41 mL) were added. After that methanesulfonic acid (2.4 mL) was added dropwise at −10° C. over a period of 15-30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (2.0 g) is mixed in a solvent mixture of THF (5.0 mL) and IPA (5.0 mL) and added into the reaction mixture, keeping the temperature between −10 to −5. It was stirred for 4 h at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected, was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-2.0 g, % Y-100%, % H2O-5.18%, % Purity by HPLC-96.6%). XRD-amorphous-FIG. 1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O:38]CC)=[O:37].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)c(Cl)c5)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cccc(-c2ccc(Cl)c(Cl)c2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(3,4-dichlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.051 g, 0.085 mmol) in 3:1 v/v THF/ethanol (1 ml) was added 1M sodium hydroxide (0.20 ml, 0.20 mmol), and the reaction was stirred for 16 hours. The reaction was concentrated, taken up in water, and acidified with 1M hydrochloric acid. The reaction was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel preparative thin-layer chromatography, eluting with 95:5:1 DCM/MeOH/glacial acetic acid to yield the desired compound (0.032 g, 0.056 mmol, 66% yield). MS (apci) m/z=569.0 (M+H).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:6].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.C(Cl)Cl>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][C:5]([OH:13])=[O:6]
Reactant: OCCC(F)(Cl)C(F)(F)Br
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(O)CC(F)(Cl)C(F)(F)Br
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of 4-bromo-3-chloro-3,4,4-trifluorobutanol (IX) (2.41 g, 10 mmol) in acetone (35 mL) was treated with Jones reagent (7.5 mL) in 10 min with stirring and cooling (ice-water bath). The mixture was then stirred at room temperature for 30 min and 0.5 mL of i-propanol was then added. The precipitated salts were removed by filtration, washed with acetone. The residue obtained after concentration of the filtrate was dissolved in methylene chloride (100 mL), washed with 1N HCl (50 mL), brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 2.17 g (85%) of 4bromo-3-chloro-3,4,4trifluorobutanoic acid (VIII) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:16])([F:15])[C:10](OCC)=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].Cl.O>C(O)C>[Cl:1][C:2]1[C:3]([C:9]([F:15])([F:16])[CH2:10][OH:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC(F)(F)c1ncc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a solution of 10 g (37 mmol) of ethyl (3,5-dichloropyridin-2-yl)(difluoro)acetate (Int-7) in 60 mL of ethanol, were added portionwise at 0° C., 1.05 g (27.7 mmol) of sodium borohydride. The reaction mixture was stirred below 10° C. for 2 hours. 30 mL of 1 N HCl were then slowly added followed by 500 mL of water. The aequeous phase was extracted three times by 300 mL of ethyl acetate and the organic phase was successively washed with brine, water and dried over magnesium sulfate. After evaporation of the solvent under vacuum 8.5 g of yellow oil were obtained. After trituration in diisopropyl ether and filtration 6.8 g (80%) of 2-(3,5-dichloropyridin-2-yl)-2,2-difluoroethanol (Int-9) were obtained as a white solid. Mp (melting point)=56° C. (M+1)=228. 19F-NMR (235 MHz, CDCl3) δ (ppm): −105.85 (CF2).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.O[C@H]1CCNC1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([C:24]([NH:26][CH2:27][C@:28]3([OH:35])[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]3)=[O:25])=[C:19]([Cl:36])[CH:18]=[CH:17][C:16]=2[N:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:36][C:19]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)[CH:23]=[CH:22][C:21]=2[C:20]=1[C:24]([NH:26][CH2:27][C@:28]1([OH:35])[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]1)=[O:25]
Reactant: O[C@@H]1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Agent: O[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](O)C4)ccc23)C1

Procedure:
The title compound was prepared by the method of Example 1, step e) by reacting (R)-3-hydroxypyrrolidine (80 mg) (instead of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.2 g) and diisopropylethylamine (300 μl) in acetonitrile (3 ml) to afford the title compound as a cream solid (190 mg). m.p. 222-223° C. (acetonitrile).
Reaction SMILES: [OH-:1].[K+].[OH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#N)[CH:26]=4)[N:22](S(C4C=CC=CC=4)(=O)=O)[C:19]3=[N:20][CH:21]=2)[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1.Cl>C1COCC1>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([O:5][CH3:4])[CH:11]=1)[CH2:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([OH:3])=[O:1])[CH:26]=3)[NH:22][C:19]2=[N:20][CH:21]=1
Reactant: [OH-]
Reactant: COc1cc(CCc2cnc3c(cc(-c4ccnc(C#N)c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)O)c4)cc3n2)cc(OC)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
6.0 M Potassium hydroxide in water (0.2 mL, 1 mmol) was added to a solution of 4-[2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl]pyridine-2-carbonitrile (50.0 mg, 0.0951 mmol) in THF (0.5 mL) and then the reaction was stirred at 90° C. for 5 hours. The mixture was then acidified to pH=2 by adding conc. HCl and then the solvent was removed to provide the desired crude product which was used in the next step directly. LCMS calculated for C22H21N4O4(M+H)+: m/z=405.2. Found 405.2.