Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]([NH:13][C:14]3[S:15][C:16]([C:20]([NH:22][C@@H:23]([CH2:27][NH:28][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[C:17]([CH3:19])[N:18]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:36]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>C1COCC1.C(OCC)(=O)C.C1COCC1.O.[Cl-].[Na+].O.OS([O-])(=O)=O.[K+]>[N:36]1([CH2:42][CH2:43][O:25][C:24](=[O:26])[C@@H:23]([NH:22][C:20]([C:16]2[S:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:18][C:17]=2[CH3:19])=[O:21])[CH2:27][NH:28][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[O:30])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: OCCN1CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OCCN1CCOCC1
Yield: 18.2 %

Procedure:
A mixture of (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (50 mg, 0.0975 mmol), 4-morpholineethanol (1.06 mL, 8.751 mmol) and 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in ethyl acetate (0.4 mL, 0.672 mmol) in THF (2 mL) was heated at 600C for 25 h. The reaction mixture was cooled, diluted with 2/1 ethyl acetate/THF (100 mL), water (10 mL), brine (10 mL) and aqueous 1N KHSO4 (10 mL), mixed and separated the layers. The aqueous layer was extracted with 2/1 ethyl acetate/THF (2×50 mL). The organic layers were combined, washed with aqueous saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (ethyl acetate to 10% methanol/ethyl acetate) followed by an ether trituration to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 2-morpholin-4-yl-ethyl ester (11.1 mg, 18.2%) as a white solid. MS m/e 626.7 (M+H+).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:18][C@@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.Cl.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To a suspension of Boc-Leu-OH.H2O (0.997 g) and DTrp-OMe.HCl (1.021 g) in dichloromethane (10 ml) were added TEA (0.6 ml) and HOBT.H2O (0.615 g) under argon. EDCI.HCl (0.769 g) was added to the mixture at 0°-5° C. The resulting reaction mixture was stirred at room temperature for 16 h, washed successively with water, 10% aq. citric acid, sat. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was triturated with hexane to give the product (1.665 g). FAB-MS(m/e,(C23H33N3O5 +H)+):432
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2(O)[CH:22]=[CH:21][NH:20][C:19](=[O:23])[NH:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Cl>C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2(O)C=CNC(=O)N2)cc1OC1CC2CCC1C2
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc[nH]c(=O)n2)cc1OC1CC2CCC1C2
Temperature: 25 °C
Yield: 31.5 %

Procedure:
The hydroxypyrimidinone of Example 60 (0.2 g, 0.61 mmol) is dissolved in 5 ml ethanol, treated with 2.5 ml 1N HCl and refluxed for 6 hours. The reaction is cooled to room temperature, quenched with water and the product extracted 3× ethyl acetate. The organics are washed, dried, filtered and concentrated in vacuo to yield a crude substance which is crystallized from ethyl acetate to give 60 mg (31.5%) of the pyrimidinone as a crystalline solid. This material is a 7:3 mixture of endo/exo bicycloalkyl isomers.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:12])=[O:13])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=3)[N:3]=2)[CH2:27][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCNCC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 116 °C
Reaction time: 20 h
Yield: 28.7 %

Procedure:
A mixture of tert-butyl 4-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (202 mg, 0.400 mmol), 4-aminobenzamide (82 mg, 0.60 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 116° C. in a sealed tube for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give 4-(4-(piperidin-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (58 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Br:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-bromoquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation D, 5 g, 13.1 mmol) and triethylamine (1.59 g, 15.7 mmol) in CH2Cl2 (120 mL) was added over 40 minutes to a solution of triphosgene (4.3 g, 14.4 mmol) in CH2Cl2 (80 mL) at 0° C. using ice-bath. The reaction mixture was stirred for 20 minutes at this temperature then was quenched with saturated aqueous NaHCO3, stirred for 5 minutes and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and solvent was evaporated to obtain the title compound. Yield: 3.2 g (60%); 1H NMR (DMSO-d6, 300 MHz): δ 11.835 (s, 1H), 8.783 (s, 1H), 7.908-7.938 (d, 1H, J=9 Hz), 7.810-7.838 (d, 2H, J=8.4 Hz), 7.665-7.694 (d, 2H, J=8.7 Hz), 7.613-7.650 (dd, 1H, J=9 Hz, 1.8 Hz), 6.949-6.955 (d, 1H, J=1.8 Hz), 1.609 (s, 6H); MS: m/z 406 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])([CH3:27])[CH3:26]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC(C)C)n(C)n1
Yield: 21 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using isopropylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (15 mg, 21%) which was obtained as a white solid. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=O)[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C@@H:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN[C@H](C(=O)N1CC[C@H](O)C1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN[C@H](CN1CC[C@H](O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a stirred solution of 2-allylamino-1-(3-(S)-hydroxy-pyrrolidin-1-yl)-2-(S)-phenyl-ethanone (5.65 g, 15.1 mmol) in anhydrous tetrahydrofuran (60 cm3) cooled to 0° C. in an ice bath was added a 1 M solution of lithium aluminum hydride (22.6 cm3, 22.7 mmol) over 20 minutes. The solution was allowed to warm and stir at ambient temperature for 16 hours. The reaction was cooled to 0° C. in an ice bath and quenched with water (0.860 cm3), 15% sodium hydroxide (0.860 cm3) and water (2.60 cm3) to form a white flocculate precipitate. The mixture was vacuum filtered, the precipitate washed with tetrahydrofuran (5×30 cm3) and the filtrate volatile fractions removed in vacuo to afford a crude yellow oil. The crude product was purified by column chromatography (silica, eluting with dichloromethane-methanol-ammonium hydroxide 97:3:0 to 90:10:1) to afford the title compound as a yellow viscous oil (2.54 g, 68.3%) with a positive ion ESI (M+H)+247.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.[CH:18](=[O:20])[CH3:19].Cl>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:18]([OH:20])[CH3:19])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC=O
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (3.50 g, 15.4 mmol) in dry THF (20 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 23.1 mmol, 14.4 mL). The mixture was stirred for 2 hours then acetaldehyde (0.95 mL) was added and the mixture was slowly warmed up to room temperature and stirred overnight at room temperature. 1N HCl was added and the solution extracted with ethyl acetate and the organic extract was dried (MgSO4), filtered and evaporated to give 3.3 g of 1-(3,3-dimethyl-2,3-dihydro-benzofuran5-yl)-ethanol. 1H NMR (300 MHz; CDCl3): δ 1.35 (s, 6H), 1.49 (d, J=6.5 Hz, 3H), 4.24 (s, 2H), 4.86 (q, J=6.5 Hz, 1H), 6.75 (d, J=8.2 Hz, 3H), 7.10–7.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)ccc21

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (34 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (44 mgs) was converted to the title compound (40 mgs as a white solid). 1H-NMR (CDCl3): δ 10.29 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.74-7.72 (m, 1H), 7.41-7.35 (m, 2H), 7.22 t, J=7.8 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.97 (s, 1H), 6.54 (s, 1H), 3.31 (s, 3H), 2.33-2.31 (m, 2H), 2.06-2.04 (m, 2H), 1.30 (s, 6H). LC/MS: found (M+H)+=488.22; MP: 136-138° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CCCOCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 50 °C

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.0 g (11.5 mmol.) of imidazole (101e), followed by addition of 5 ml of water and 1.84 g (46 mmol) of sodium hydroxide, and then, 250 mg (0.8 mmol) of n-tetrabutylammonium bromide and 2.3 g (14 mmol) of 4-chloromethylpyridine hydrochloride were further added. The mixture was stirred under heating at 50° C. for 8 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) to provide 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole (136c) as oil. To thus-obtained oil (136c) was added 27 ml of concentrated hydrochloric acid and the mixture was heated at 110° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 3.8 g (yield 76%) of 3-(5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-propan-1-ol (137c) as crystals. mp 106-107° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21].[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][OH:34].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][O:34][C:6]1[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=1
Reactant: Cc1nc(C)c(CNc2nc(S(C)(=O)=O)nc(Cl)c2C)s1
Reactant: OCCCc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CNc2nc(OCCCc3nc4ccccc4[nH]3)nc(Cl)c2C)s1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-methylsulfonyl-pyrimidin-4-amine F5 (480 mg, 1.384 mmol) and 3-(1H-benzimidazol-2-yl)propan-1-ol (244 mg, 1.38 mmol) were placed in a 20 mL vial and dissolved in THF (5 mL). A 1 M solution of NaHMDS in THF (1.38 mL, 1.38 mmol) was added, and the reaction was stirred overnight. Solvent was then removed, and the product was purified by silica gel flash column chromatography (EtOAc/hexanes gradient). 500 mg (82%) of F6 were isolated as an off-white foam. 1H NMR δ (300 MHz, DMSO-d6): 7.84-7.80 (1H, m), 7.76 (2H, dd, J=6.20, 3.18 Hz), 7.51 (2H, dd, J=6.28, 3.15 Hz), 4.46 (2H, d, J=5.76 Hz), 4.37-4.31 (2H, m), 2.54 (4H, s), 2.46 (3H, s), 2.29 (3H, s), 1.99 (3H, s). HRMS (Electrospray): m/z 443.1413 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]2=[O:23])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:24][C:25]1[CH:30]=[N:29][C:28](Cl)=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([N:20]2[CH2:21][CH2:22][CH:17]([N:14]3[CH2:15][CH2:16][C@H:12]([NH:11][C:8]4[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[C:13]3=[O:23])[CH2:18][CH2:19]2)=[N:29][CH:30]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
(S)-3-(6-(Methylsulfonyl)pyridin-3-ylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (0.076 g, 0.22 mmol) and 2,5-dichloropyrazine (0.054 g, 0.36 mmol) were dissolved in NMP (0.45 mL) and treated with DIEA (0.098 mL, 0.56 mmol). The mixture was stirred at 80° C. overnight and then cooled to ambient temperature. The reaction mixture was partitioned between EtOAc (40 mL) and H2O (20 mL). The mixture was filtered through a 0.45 μm nylon membrane and the solids were washed with EtOAc and then dried under high vacuum to provide (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(6-(methylsulfonyl)pyridin-3-ylamino)pyrrolidin-2-one (0.030 g, 0.067 mmol, 30%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[C:20]#[N:21])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[CH:11]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)C#N)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(C(C)(C)C#N)c1

Procedure:
Pd(OH)2/C (2.0 g) and compound 7 (20.0 g, 0.104 mol) were stirred in MeOH (150 mL) at room temperature under hydrogen at 10 psi pressure for 16-18 hours. The mixture was then filtered through a pad of Celite®, and the filtrate was concentrated to give compound 15, which was used in the next reaction without further purification. 1H NMR (DMSO-d6; 400 MHz) δ 9.83 (s), δ 7.24 (s), δ 7.18 (m), δ 6.80 (m), δ 1.71 (s), δ 1.24 (s).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCOCCO
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: OCCOCCNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared according to the method of Example 220 using the product of Example 219 (0.3 g) and 2-(2-aminoethoxy)ethanol.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si](Cl)(C)C>C1COCC1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C1C=CCCC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Into a 1 L round-bottom flask placed a solution of cyclohex-2-en-1-one (15.00 g, 156.04 mmol, 1.00 equiv) in anhydrous THF (300 mL) was added 1,3-diethyl 2-bromopropanedioate (56.00 g, 234.25 mmol, 1.50 equiv), In powder (18.00 g, 1.00 equiv) and TMSCl (87.00 g, 800.81 mmol, 5.00 equiv) under nitrogen. The resulting solution was stirred for 30 min at room temperature and quenched by the addition of 200 mL of saturated aqueous sodium carbonate, extracted with 3×300 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:5) to give 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g, 71%) as yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[C:18]1([C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:9]([C:10]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:26]2[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:25])=[O:12])=[CH:13][CH:14]=[C:15]([CH3:17])[N:16]=1
Reactant: Cc1ccc(C(=O)O)c(NCc2ccco2)n1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC[C@@H]2C(O)(c2ccccc2)c2ccccc2)c(NCc2ccco2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of 2-[(2-furylmethyl)amino]-6-methylnicotinic acid (13.9 mg) and diphenyl(pyrrolidin-2-yl)methanol (18.2 mg) in DMF (1.0 ml) was added a solution of HOBt (9.7 mg) and WSC.HCl (13.8 mg) in DMF (0.5 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2% aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was subjected to reversed-phase preparative HPLC, and the object fraction was passed through MP-CO3 resin (manufactured by Polymer Laboratories) to remove trifluoroacetic acid. The obtained solution was concentrated by a nitrogen gas blower to give the object compound (10.6 mg).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.B(F)(F)F.CCOCC.O>C1(C)C=CC=CC=1>[C:6]1([C:1]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:2][CH2:3][CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: CCCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCC=C(c1ccccc1)N1CCCC1
Yield: 77.3 %

Procedure:
In 50 ml of toluene, 4.44 g of n-butyrophenone, 6.40 g of pyrrolidine and 0.43 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 47 hours using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent under a reduced pressure, the residue was subjected to a distillation under a reduced pressure to obtain the desired enamine as a pale yellowish oil (yield: 4.66 g, 77%).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([O:19][CH2:20][CH2:21][NH:22][S:23]([CH2:26][CH:27]3[CH2:29][CH2:28]3)(=[O:25])=[O:24])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C([BH3-])#N.[Na+].[Cl-].[NH4+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:12]([CH:11]1[C:10]2[CH:9]=[C:8]([O:19][CH2:20][CH2:21][NH:22][S:23]([CH2:26][CH:27]3[CH2:29][CH2:28]3)(=[O:25])=[O:24])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH:1][CH:32]1[CH2:33][O:30][CH2:31]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: O=S(=O)(CC1CC1)NCCOc1ccc2c(c1)C(Cc1ccccc1)C(NC1COC1)CC2
Temperature: 40 °C

Procedure:
N-(2-(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-cyclopropylmethanesulfonamide (50 mg, 0.121 mmol) was dissolved in methanol. Oxetan-3-one (87 mg, 1.21 mmol), zinc chloride (66 mg, 0.482 mmol) and sodium cyanoborohydride (23 mg, 0.362 mmol) were added at 0° C. The reaction mixture was then heated to 40° C. for 5 h. Aqueous ammonium chloride solution was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 3 mg (6.4 μmol, 5%).