Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][NH:27][NH2:28])[CH3:23].C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:1].[N+:19]([C:5]1[CH:4]=[CH:3][C:2]2[N:27]([CH2:26][CH2:25][N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])[N:28]=[C:14]3[C:13]4[CH:12]=[CH:11][C:10]([O:17][CH3:18])=[CH:9][C:8]=4[O:7][C:6]=1[C:15]=23)([O-:21])=[O:20]
Reactant: CCN(CC)CCNN
Reactant: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3oc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Oc1cc(OC)ccc1-2
Product: Cl
Reaction time: 2 h

Procedure:
A mixture of 5.0 g of 1-chloro-6-methoxy-4-nitro-9H-xanthen-9-one, 2.58 g of [2-(diethylamino)ethyl]-hydrazine, and 3.43 ml of diisopropylethylamine in 100 ml of N,N-dimethylformamide was stirred for two hours. The mixture was evaporated to dryness and the residue was triturated with 2-propanol. The solid was collected, washed with diethylether, and dried at 60° C. in vacuo to afford the title compound, a salt with 1.0 equivalent of hydrogen chloride, mp 285°-288° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:22]([CH3:24])[CH3:23])=[N:5][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)#[CH:2].CC(N=NC(C#N)(C)C)(C#N)C.[I:37]I.CCOC(C)=O>C([SnH](CCCC)CCCC)CCC.CCOCC.CCCCCC>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:5]=[C:4]([CH:22]([CH3:24])[CH3:23])[C:3]=2/[CH:1]=[CH:2]/[I:37])=[CH:10][CH:11]=1
Reactant: II
Reactant: C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/I
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine (1.500 gm, 4.76 mmol) (The preparation of which is described in example 4) and 14 mg of AIBN in tri-n-butylstannyl hydride (Bu3SnH) (1.90 ml) was rapidly heated to 120° C. After 4 minutes of heating, the mixture was treated with additional Bu3SnH (0.4 ml) and the temperature of the reaction was raised to 130° C. Approximately 14 mg of AIBN was added to the reaction mixture 0.5, 1.5 and 2.5 hours after heating was initiated. After 4 hours, the mixture was cooled to room temperature, diluted with Et2O (40 ml) and treated with solid I2 (1.92 gm, 7.56 mmol). The dark reaction mixture was stirred for 1.5 hours, then quenched with 10% Na2SO3 in saturated NaHCO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2SO4), filtered and stripped to yield a yellow oil. Flash chromatography (Merck SiO2, 1% EtOAc in hexane followed by 1.5% EtOAc in hexane afforded (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridine as a solid. Recrystallization of the solid from hot hexane gave 1.438 gm (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridine. An additional 0.19 gm of compound was obtained from the mother liquor to give a total of 1.628 gm (77%) product.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].[Cl:21][C:22]1[N:31]=[C:30](Cl)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>O>[Cl:21][C:22]1[N:31]=[C:30]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2ccccc12
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of 2-(isopropylsulfonyl)aniline (450 mg) and N,N-dimethylformamide (10 mL), 55% sodium hydride in oil (200 mg) was added under ice cooling and stirred for 30 minutes, followed by addition of 2,4-dichloroquinazoline (500 mg). The reaction mixture was stirred for 30 minutes under ice cooling and further stirred overnight at room temperature. The reaction mixture was cooled on ice, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-[2-(isopropylsulfonyl)phenyl]quinazoline-4-amine (0.67 g) as a light-yellow solid.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=1[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C(O)C.C1(C)C=CC=CC=1>[CH2:29]([O:28][P:24]([CH2:23][C:22]1[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=1[CH2:20][CH2:19][CH2:18][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:25][CH2:26][CH3:27])=[O:31])[CH3:30]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOP(=O)(Cc1ccccc1CCCBr)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 42 %

Procedure:
To 0.48 g (21 mmol) of sodium in 50 mL of dry ethanol was added 4.56 g (21 mmol) of solid diethyl acetamidomalonate portionwise. This solution was stirred at reflux under nitrogen for 2 h. After cooling to room temperature the solvent was removed under reduced pressure yielding a tan solid. This solid was dried under vacuum about 2 h. The sodium salt of diethyl acetamidomalonate was then suspended in 50 mL of dry toluene and 9.0 g (21 mmol) of diethyl 2-(3-bromopropyl)benzylphosphonate in 25 mL of dry toluene was added dropwise. This solution was stirred at reflux under nitrogen for 20 h. After cooling to room temperature the solid which precipitated was removed by filtration and washed with toluene. The combined toluene solutions were concentrated under reduced pressure to yield a dark oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure yielding 4.2 g (42%) of the product as a yellow viscous oil which solidified upon standing, mp 76°-79° C. IR(neat) 1745.9, 1680 cm-1 (C=O). 1H NMR(CDCl3) δ 1.0-1.4 (m, 12H); 2.0 (s, 3H); 2.2-3.3 (m, 6H); 3.7-4.4 (m, 8H); 6.8 (5, 1H); 7.0-7.3 (m, 4H). Anal. Calcd. for C23H36NO8P: C, 56.90; H, 7.48; N, 2.89. Found: C, 56.27; H, 7.51; N, 2.86.
Reaction SMILES: [NH2:1][C@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[C:14]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])(=[O:37])=[O:38])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)NCC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(c1ccccc1)c1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
To a stirred solution of the product of step 1 (12.3 g, 35.6 mmol) in methylene chloride (200 mL) was added 2-nitrobenzenesulfonyl chloride (9.00 g, 40.6 mmol) followed by triethylamine (6.4 mL, 46 mmol). After 30 minutes the reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated. The resulting amber foam was purified by flash chromatography over silica (hexane/ethyl acetate) to afford 14.0 g (74%) of product as a colorless foam: 1H NMR (CDCl3) δ 7.95–7.87 (m, 1H), 7.76–7.62 (m, 3H), 7.35–7.15 (m, 10H), 7.06–6.94 (m, 3H), 6.90–6.83 (m, 2H), 6.42 (t, J=5.6, 1H), 5.80 (d, J=5.8, 1H), 4.12 (t, J=8.1, 1H), 4.01–3.82 (m, 3H), 3.18–3.08 (m, 1H), 2.68–3.57 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[S-:28][C:29]#[N:30].[K+].O.[NH3:33].O>O1CCCC1>[C:29]([NH:33][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23])(=[S:28])[NH2:30]
Reactant: N#C[S-]
Reactant: N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl)-2-methylbenzoyl chloride synthesized in Process 4 of Synthetic Example 1 in 20 mL of tetrahydrofuran, 245 mg of potassium thiocyanate was added and the resultant mixture was stirred at 40° C. for 1 hour. Next, the reaction mixture was left to be cooled to room temperature and 5 mL of concentrated ammonia water was added to the reaction mixture, followed by continuing the stirring of the mixture for another 30 minutes. After the completion of the reaction, 20 mL of water was added to the reaction mixture to dilute the mixture and the diluted reaction mixture was extracted with 40 mL of ethyl acetate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:1) to obtain 0.9 g of the objective substance as a colorless resin-state substance.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:19]([OH:21])[CH3:20])=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[N:6][CH:7]=1>CCCCCCC>[F:1][C:2]1[C:3]([C@@H:19]([OH:21])[CH3:20])=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[N:6][CH:7]=1.[F:1][C:2]1[C:3]([C@H:19]([OH:21])[CH3:20])=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1
Solvent: CCCCCCC
Product: C[C@@H](O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1
Product: C[C@H](O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1

Procedure:
The racemic mixture 7 (220 mg, 0.779 mmol) was separated by HPLC (ChiralPak AS-H, 21×250 mm, 90% heptane 10% ethanol, v/v) giving (S)-2-(5-fluoro-4-(1-hydroxyethyl)pyridin-3-yl)benzofuran-5-carbonitrile 7-(enantiomer-1) as white solid (72 mg) (retention time: 10.93 min) and (R)-2-(5-fluoro-4-(1-hydroxyethyl)pyridin-3-yl)benzofuran-5-carbonitrile 7-(enantiomer-2) as white solid (66 mg) (retention time: 12.57 min).
Reaction SMILES: C([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH2:21]1[O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:10]3[CH:11]=[CH:3][C:4]([C:5]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[O:7])=[CH:8][CH:9]=3)=[CH:15][C:16]=2[O:22]1
Reactant: CCc1cc(OCc2ccc3c(c2)OCO3)ccc1C(=O)O
Reactant: Nc1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1ccc(OCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 18-4 (0.545 g, 2 mmol) was added 4-aminopyridine 18-5 (0.235 g, 2.5 mmol), 1-hydroxy-benzotriazole hydrate (0.338 g, 2.5 mmol), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (0.479 g, 2.5 mmol) and dry DMF (5 ml) followed by triethylamine (0.35 ml, 2.5 mmol). The mixture was stirred at ambient temperature overnight. Then the DMF was removed under high vacuum. The residual oil was chromatographed on silica gel to obtain a white solid 18-6.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20]Cl)[S:15][C:16]=3[CH:17]=2)[N:10]=1)=[O:4].[CH2:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)[CH3:24]>O1CCOCC1>[CH2:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[N:18]([C:19](=[O:22])[CH3:20])[C:14]1[S:15][C:16]2[C:12](=[CH:11][C:9]3[N:10]=[C:6]([N:5]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]4[CH2:23][CH3:24])[C:3](=[O:4])[CH3:2])[S:7][C:8]=3[CH:17]=2)[N:13]=1)[CH3:24].[NH2:5][C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([N:18]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]4[CH2:23][CH3:24])[C:19](=[O:22])[CH3:20])[S:15][C:16]=3[CH:17]=2)[N:10]=1
Reactant: CCC1CCCCN1
Reactant: O=C(CCl)Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1
Solvent: C1COCCO1
Product: CCC1CCCCN1N(C(C)=O)c1nc2cc3nc(N(C(C)=O)N4CCCCC4CC)sc3cc2s1
Product: CCC1CCCCN1N(C(C)=O)c1nc2cc3nc(N)sc3cc2s1
Yield: 47 %
Yield: 37 %

Procedure:
A mixture of 8.0 gm of 2,6-bis-(chloroacetyl-amino)benzo[1,2-d:5,4-d']bisthiazole, 10.0 gm of 2-ethyl-piperidine and 100 ml of dioxane was refluxed for 2 hours. The reaction mixture was worked up as described in Example 16; the compounds (a) (47% of theory, from ethanol), M.P. 201°-203° C., and (b) (37% of theory, from ethanol), M.P. 223°-225° C. were isolated.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[C:14]([Cl:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:33][OH:34].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:33][OH:34])=[NH:20])=[C:14]([Cl:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC#N)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC(=N)NO)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
2.2 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-acetonitrile were dissolved in a mixture of 6 ml tetrahydrofuran and 12 ml methanol. 3.3 g hydroxylamine hydrochloride were added followed by the addition of 6.6 ml triethylamine. The reaction mixture was stirred at 60° C. for two hours. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with portions of 30 ml ethylacetate. The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to provide 2.3 g 2-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-N-hydroxy-acetamidine as crude material.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:28])=[CH:5][C:6]2[CH2:15][CH2:14][CH:13]([NH:16]C(C3C=CC=CC=3)C)[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=3[C:7]=2[C:25]=1[O:26][CH3:27].CO.C(O)(=O)C.C>[OH-].[Pd+2].[OH-].O>[NH2:16][CH:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]2[C:25]([O:26][CH3:27])=[C:3]([O:2][CH3:1])[C:4]([OH:28])=[CH:5][C:6]=2[CH2:15][CH2:14]1
Reactant: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(NC(C)c1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(N)CC2
Yield: 82.7 %

Procedure:
5 g of the product of Stage A, 50 ml of methanol, 25 ml of acetic acid and 150 ml of water were stirred for 30 hours at ambient temperature under a hydrogen atmosphere (400 mbar) in the presence of 2 g of 20% palladium hydroxide on wet activated charcoal (50% water). Filtration was carried out followed by washing with methanol, then concentrating to dryness under reduced pressure at 40° C. After crystallization from ethyl acetate, 3 g of the expected product were obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH:22]3[NH:29]C(=O)O)[CH2:20]1)[CH2:26]2)[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl.O1CCOCC1>[NH2:29][CH:22]1[CH:23]2[CH2:28][C:19]3([CH2:18][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:17])[CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:26][CH:25]([CH2:27][CH:21]1[CH2:20]3)[CH2:24]2
Reactant: O=C(O)NC1C2CC3CC1CC(CN(Cc1ccccc1)C(=O)Cc1ccccc1)(C3)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1C2CC3CC1CC(CN(Cc1ccccc1)C(=O)Cc1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a three-necked flask under nitrogen, 0.49 g of tert-butyl ester of {5-[(benzyl-phenylacetyl-amino)-methyl]adamantan-2-yl}-carbamic acid is dissolved in 1.7 ml of anhydrous dichloromethane. It is cooled to 0° C. and 3.64 ml of 4N solution of hydrochloric acid in dioxane is added. The reaction mixture is stirred for 1 h at room temperature and then concentrated to dryness. 20 ml of water is added, the reaction mixture is basified with potassium carbonate and it is extracted with dichloromethane until exhaustion of the aqueous phase. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. 0.35 g of N-(4-amino-adamantan-1-ylmethyl)-N-benzyl-2-phenyl-acetamide is obtained, and is used subsequently as it is.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][C:29](Cl)=[O:30].O>O1CCCC1>[Cl:20][C:10]1[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[N:12][C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)CCl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 2-amino-5-chloro-6-[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 1, METHOD A, Step 2, 5 g, 16.7 mmol) in tetrahydrofuran (150 mL) were added potassium carbonate (5.1 g, 36.6 mmol) and chloroacetyl chloride (2.7 mL, 33.3 mmol) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 h and at room temperature for 15 h. After addition of water, the mixture was extracted with ethyl acetate and washed with brine. The combined organic layer was dried over sodium sulfite and concentrated to give the title compound as a pale yellow solid.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=CC=2N=N1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[C:37]([S:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=O)=[C:38]([Cl:41])[CH:39]=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[C:37]([S:42][CH2:43][CH2:44][CH2:45][C:46](=[O:48])[NH:6][CH3:10])=[C:38]([Cl:41])[CH:39]=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCC(=O)O)c2CC1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
Add O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (123 mg, 0383 mmol) portion wise to a solution of 3-tert-butoxycarbonyl-7-chloro-6-(3-carboxy-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (146 mg, 0365 mmol) and methylamine (182 μL, 0.365 mmol) in anhydrous DMF (5 mL) under nitrogen at 0° C. Stir for 15 min then add diisopropylethylamine (127 μL, 0.73 mmol) in anhydrous DMF (1 mL) and continue to stir at, 0° C. for 1 h. Warm to room temperature and continue to stir overnight Pour into water (50 mL) and extract with EtOAc (3×20 mL). Wash the combined organic extracts with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Dry over MgSO4, filtrate and concentrate in vacuo to give a pale yellow oil (74 mg). MS (ES+) m/z: 398 (M+H)+. Purify using Mass-guided reverse phase HPLC [Supelco Discovery C18 column (21.2×100 mm, 5 μm packing), 25 mL/min flow rate, eluting with water/acetonitrile/acetic acid gradient over 12 min, fraction collection triggered by Electrospray MS]. Concentrate in vacuo to give the desired intermediate as a colourless oil (30 mg, 20%). MS (ES+) m/z: 435 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1)=[O:5]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.98 mL, 19.72 mmol) in dichloromethane (22.3 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (3.0 g, 19.72 mmol), pyridine (4.80 mL, 59.16 mmol) and dichloromethane (89.4 mL) at 0° C. The mixture was removed from the ice bath after 1.5 hours and was stirred at room temperature for 0.5 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration rinsing with hexanes to yield methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (5.16 g, 76%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.38 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (dd, J=6.1, 2.4 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.09-7.98 (m, 1H), 7.67 (t, J=9.2 Hz, 1H), 3.88 (s, 3H) ppm. ESI-MS m/z calc. 342.06. found 343.2 (M+1)+; Retention time: 1.54 minutes (3 minutes run).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:7][C@@H:8]([CH3:14])[C:9](OCC)=[O:10].C[O-].[Na+].O.O.O.C(O)(=O)C(O)=O>C(O)C>[OH:7][C@@H:8]([CH3:14])[C:9]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:10]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C1CNCCN1
Agent: C[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](O)C(=O)N1CCNCC1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
A flask charged with piperazine (10.0 g, 116 mmol) and (S)-ethyl 2-hydroxypropanoate 7 (17.84 g, 151 mmol, 1.30 equiv) was cooled to 10° C. Sodium methoxide (25 wt % in MeOH) (12.55 g, 58.1 mmol, 0.50 equiv) was slowly added while maintaining the temperature below 20° C. The cold water bath was removed and the reaction mixture was allowed to warm to ambient temperature and aged for 19 h. Water (6.23 g, 346 mmol, 3.0 equiv) was added and the mixture was aged for 16 h. The mixture was diluted with ethanol (40 mL) and concentrated under reduced pressure. The residue was diluted with ethanol (40 mL) and treated with a solution of oxalic acid dihydrate (6.58 g, 52.2 mmol) in ethanol (30 mL) to adjust the pH to 7.5. The suspension was cooled to <10° C., filtered through a pad of CELITE® and washed with ethanol (2×60 mL). The filtrate and washes were combined and concentrated to 50 mL. The solution was cooled to 10° C. and a solution of oxalic acid dihydrate (16.1 g, 128 mmol) in ethanol (60 mL) was slowly added. The suspension was allowed to warm to ambient temperature and stirred for 1 h. The suspension was cooled to 10° C. and the solid was collected by filtration, washed with cold ethanol (2×18 mL) and dried under reduced pressure at 50° C. for 24 h to afford the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V as a white solid (15.2 g, 53%). 1H NMR (300 MHz, D2O) δ 4.73-4.51 (m, 1H), 3.93-3.59 (m, 4H), 3.26 (dd, J=8.8, 4.0 Hz, 4H), 1.27 (d, J=6.7 Hz, 3H).