Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[C:29]([N:31]=[C:32]=[O:33])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:32](=[O:33])[NH:31][C:29]([C:28]2[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:27]=2[Cl:26])=[N:9]1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.19 (s, 9H), 4.48 (m, 2H), 6.09 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.32 (t, J=8.2 Hz, 2H), 7.40-7.45 (m, 2H), 10.66 (br s, 1H); MS (m/z): 455.21 (M+).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11]>>[CH:12]1([C:10](=[O:11])/[CH:9]=[CH:3]/[N:4]([CH3:5])[CH3:6])[CH2:14][CH2:13]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C1CC1
Product: CN(C)/C=C/C(=O)C1CC1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
To N,N-dimethylformamide dimethyl acetal (9.51 ml, 71.3 mmol) was added cyclopropyl methyl ketone (3.34 ml, 35.7 mmol) and the mixture was heated to 150° C. in a sealed vessel. After 16 hours, the reaction mixture was cooled and concentrated to afford (2E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one which was used without further purification.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([CH2:31][C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][CH:33]=3)([CH3:30])[C:19](=[O:29])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.CN(C=O)C>[NH2:17][C:18]([CH3:30])([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[C:19]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:29]
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(N)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-9H-Fluoren-9-ylmethyl[1-(1H-indol-3-yl-methyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (10 g, 18.4 mmol) was dissolved in a 20% piperidine in DMF solution (50 mL) and stirred for 12 hours at room temperature. The solvent was removed in vacuo and chromatographed over silica gel using CH2Cl2 then 5% MeOH:95% CH2Cl2 as eluants. The title compound was crystallized from ethyl acetate (4.73 g, 80%), mp 106°-110° C. (EtOAc); IR (film) 1646 cm-1 ; NMR (CDCl3) δ1.39 (3H, s), 2.56-2.74 (2H, m), 2.82 (1H, d, J 14 Hz), 3.28-3.40 (1H, m), 3.48 (1H, d, J 14 Hz), 3.44-3.53 (1H, m), 7.1-7.7 (11H, m), 8.3 (1H, s); Anal. (C20H23N3O) C, H, N.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C)C=O>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]1=[O:13])=[CH2:1]
Reactant: CCOC(=O)CCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCC(=O)OCC)c2ccccc21
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A solution of 19 g of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one [described in J. Chem. Soc. Perkins, 1982, p. 261] in 150 ml of dimethylformamide was added with stirring at 20° C.±2° C. to 5.75 g of sodium hydride as a 50% suspension in oil and 10 ml of dimethylformamide and the mixture was stirred for another 30 minutes. 23.4 g of ethyl 4-bromo-butyrate were added to the mixture over 15 minutes and the mixture was stirred at room temperature for 4 hours and was poured into 800 ml of iced water. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 33 g of ethyl 2,3-dihydro-3-(1-methyl-ethenyl)-2-oxo-1H-benzimidazol-1-butanoate.
Reaction SMILES: COCN[C:5]([C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[OH:17][C:16]1[C:7]([C:5](=[O:6])[CH3:18])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: C[Mg]Br
Reactant: COCNC(=O)c1cc2ccccc2cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc2ccccc2cc1O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid methoxymethylamide (600 mg) was dissolved in tetrahydrofuran (36 ml) to prepare a solution. A solution (9.8 ml) of 0.93 M methylmagnesium bromide in tetrahydrofuran was added thereto at −78° C., temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hr. A saturated aqueous ammonium chloride solution was added to stop the reaction, water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with an aqueous potassium carbonate solution, was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 1-(3-hydroxynaphthalen-2-yl)-ethanone (378 mg, yield 78%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]([OH:10])[CH2:8]Br)[O:4][N:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:8][CH:7]([C:5]2[O:4][N:3]=[C:2]([Br:1])[CH:6]=2)[OH:10])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: OC(CBr)c1cc(Br)no1
Solvent: CCO
Product: OC(CN1CCC(Cc2ccccc2)CC1)c1cc(Br)no1

Procedure:
A solution of 6.0 g of 1-(3-bromoisoxazol-5-yl)-2-bromoethanol and 11.7 ml of 4-benzylpiperidine in 150 ml of ethanol was refluxed for 2 hours.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43]C)=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>[OH-].[Na+].C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of compound 6 (37 g) in NaOH (1N, 150 ml), THF (500 ml) and water (500 ml) was stirred at room temperature overnight. The organic solvent was evaporated. The aqueous concentrate was washed with DCM and acidified with HCl (1N, 150 ml). The solvent was evaporated. The residue was stirred in water, filtered off and dried, yielding 32 g (84%) of 6,11-dihydro- 11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylic acid (compound 7, mp. 174.2° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH3:2].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:20][CH3:21])=[CH:23][CH:24]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(=O)CC2)ccc1OC
Reactant: CCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3ccc(CC)cc3)CC2)ccc1OC
Temperature: 85 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-one (94.8 mg, 0.36 mmol, 1.2 equiv; intermediate C1) and 4-ethyl-phenylamine (36.4 mg, 0.30 mmol, 1.0 equiv; commercially available) in ethanol (2 mL) and acetic acid (0.38 mL) was heated to 85° C. After 2 h, sodium cyanoborohydride (22.6 mg, 0.36 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 85° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.2 mg (16%) of the title compound. MS (ISP): 369.4 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].Cl>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:25]
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)CCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Yield: 12 %

Procedure:
The procedure of Example 5 was followed starting with (D) of Example 5 (2.5 g, 7.6 mmol) and using diethylamine in place of dibutylamine to produce 0.32 g (12% yield) of the named compound as the HCl salt, mp 219°-220° C. IR(KBr): 3400, 1600 cm−1. MS: 365(MH+). 1H NMR (CDCl3): δ 8.25-6.82 (m, 10H), 4.02 (t, J=5.4 Hz, 2H), 3.14 (m, 6H), 1.99 (m, 4H), 1.36 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2g, 0.008 mol), 4fluorophenyl isothiocyanate (1.45g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.31 g (71%), m.p. 146°-148 ° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=2)[N:11]=1.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[C:25]2[C:17]([C:12]3[N:11]=[C:10]([NH:9][CH2:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])[C:15]([F:16])=[CH:14][N:13]=3)=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled mixture of N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (0.060 g, 0.093 mmol) and iPr2NEt (0.057 mL, 0.330 mmol) in CH2Cl2 (2 mL) at 0° C., was added 2-methoxyacetyl chloride (0.010 g, 0.098 mmol). After 5 min, the solution was allowed to warm to room temperature. After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1 mL) and treated with LiOH (0.326 mL, 1.0 M solution) at 120° C. for 10 min. The resulting mixture was cooled to room temperature and partitioned and the aqueous layer extracted with EtOAc and the combined organics were concentrated in vacuo. Preparative HPLC provided the desired product, 556, as a racemic mixture of TFA salts (8.6 mg, 17% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:12][C@H:3]([CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][NH:1][CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccnc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
(2S)-1-Amino-3-(3-pyridinyloxy)-2-propanol (0.21 g, 1.25 mmol) (which was obtained in Example 124) and 5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) (0.413, 1.25 mmol) were mixed in N,N-dimethylformamide (12 mL) and then treated with sodium triacetoxyborohydride (0.56 g, 2.5 mmol) and acetic acid (0.26 mL). After stirring at room temperature under a nitrogen atmosphere for one day, the mixture was purified by column chromatography (dichloromethane/methyl alcohol 85/5) to give the title compound as a yellow solid (0.25 g, 56% yield); mp: 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.54 (m, 2H), 1.90-2.02 (m, 2H), 2.67 (t, 2H), 2.78-2.97 (m, 4H), 3.22-3.26 (m, 1 H), 3.35 (brs, 2H), 3.64-3.70 (d, 2H), 3.97-4.08 (m, 3H), 4.60-4.63 (m, 1H), 6.84-6.86 (m, 2 H), 7.03-7.05 (m, 2H), 730-7.36 (m, 1H), 7.38-7.40 (m, 1H), 8.16-8.17 (m, 1H), 8.8.29-8.30 (m, 1H); MS (ES) m/z: 457 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C@H:15]2[CH2:18][C@@H:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[C:13]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C@@H:17]1[CH2:18][C@H:15]([N:14]2[C:13]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of [(S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl]carbamic acid tert-butyl ester (570 mg, 1.3 mmol) in DCM (10 mL) was added TFA (4 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and loaded onto SCX-2 (20 g). The cartridge was washed with DCM then MeOH and then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow gum (320 mg, 73%). LCMS (Method J): RT 1.97 min [M+H]+ 340. 1H NMR (CDCl3, 400 MHz): δ 7.69-7.55 (2H, m), 7.44-7.24 (5H, m), 7.0 (1H, dt, J=11.8, 2.5 Hz), 4.81-4.66 (1H, m), 4.53 (2H, s), 4.32-4.21 (1H, m), 4.08-3.95 (1H, m), 3.02-2.75 (4H, m), 1.90 (2H, s, br), 1.50 (3H, d, J=7.0 Hz)-NMR: 328174
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[C:5]([C:14]([O:16]C)=[O:15])=[CH:4][C:3]=1[Cl:18].C(Cl)Cl>CO>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[C:5]([C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:18]
Reactant: COC(=O)c1cc(Cl)c(N)n2cc(C(C)C)nc12
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1cn2c(N)c(Cl)cc(C(=O)O)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 4 in EXAMPLE 1 (METHOD A) from methyl 5-amino-6-chloro-2-isopropylimidazo[1,2-a]pyridine-8-carboxylate (EXAMPLE 20, Step 1). Rf value: 0.33 (CH2Cl2:MeOH, 20:1, v/v)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:5]([F:16])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][C@@H:9]([NH:8][C:6]1[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:27])=[O:26]
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol, 14a, (1.95 g, 7.87 mmol) and triethylamine (1.37 mL, 9.84 mmol) in dichloromethane (25 mL) was added methanesulfonyl chloride (0.76 mL, 9.84 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (50 mL) were added. The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to afford 2.55 g of the desired product as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 326.99 (M+H) RT=2.96 minutes.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[CH2:29][O:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[C@H:30]([CH2:32][OH:33])[CH2:29][O:28][C:27]5=[O:26])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)nc2)CC1
Yield: 63.3 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 106 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (426 mg), the title compound (345 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCl.CC(=O)OCC>[Br:16][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(C(=O)OC)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Yield: 72.6 %

Procedure:
To a solution of dimethyl 4-methylisophthlate (Chemical Formula 4) (4 g, 19.2 mmol) in distilled dichloromethane were added N-bromosuccinimide (NBS, 4.8 g, 26.9 mmol) and benzoic peroxyanhydride (0.47 g, 19.2 mmol), followed by reaction at 80° C. for 24 hours in a pressure vessel with constant stirring. The reaction progress was monitored by TLC [Hex:EA=3:1]. When the reaction was detected to have reached completion, saturated NaHCO3 was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer thus formed was dried over anhydrous MgSO4, filtered and concentrated in a vacuum. The purification of the concentrate through column chromatography [Hexane: EtOAc=20:1] produced 4 g of dimethyl 4-(bromomethyl)isophthalate (Chemical Formula 5) (70%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[CH2:7]([SH:9])[CH3:8].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:7]([S:9][CH:5]1[O:1][C:2](=[O:6])[NH:3][CH2:4]1)[CH3:8]
Reactant: O=c1[nH]cco1
Reactant: CCS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCSC1CNC(=O)O1

Procedure:
A solution mixture comprising 3 g of 2-oxazolone, 25 ml of ethyl mercaptan and 600 mg of azobisisobutyronitrile, was reacted at 100° C. for 8 hours in an autoclave. After the completion of the reaction, excess ethyl mercaptan was distilled off, and the residue was purified by silica gel chromatography to obtain 1.6 g of 5-ethylthiooxazolidin-2-one having a melting point of from 82° to 86° C.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(B(CC)CC)C.O>C1C=CC=CC=1>[C:1]([C:9]1[NH:10][C:11]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: CCB(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 2-benzoylpyrrole (171mg, 1 mmol) and diethyl bromomalonate (1185 mg, 5 mmol) in benzene (20 mL) was added triethylborane (1.0 M in hexane, 5 mL, 5 mmol). The reaction mixture was stirred for 1 hour in an open vessel. Additional triethylborane (1 mL, 1 mmol) was added and the reaction was stirred for an additional hour. The mixture was poured into water and extracted with diethyl ether. The ethereal extract was washed with saturated aqueous sodium chloride, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica eluting with hexane/ethyl acetate (87:13) to provide 284 mg (86%) of diethyl (5-benzoylpyrrol-2-yl)methane-dicarboxylate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>ClCCl.CCOCC>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C@@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)=[O:29])=[CH:23][CH:22]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (0.050 g, 0.184 mmol) in dichloromethane (0.1 mL) was added 1-fluoro-4-isocyanatobenzene (0.025 mL, 0.221 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was diluted with ether and sonicated, then filtered and washed with ether to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.45 (s, 1H), 7.63 (dd, J=9.1, 4.9, 2H), 7.46 (t, J=7.9, 1H), 7.00 (t, J=8.8, 2H), 6.93 (d, J=8.8, 1H), 6.51 (d, J=7.7, 1H), 6.21 (d, J=6.7, 1H), 4.27-4.12 (m, 1H), 3.73-3.44 (m, 3H), 3.28 (dd, J=11.0, 4.0, 1H), 2.77-2.57 (m, 2H), 2.12 (td, J=12.7, 6.8, 1H), 1.87 (td, J=13.3, 7.9, 1H), 1.57 (dq, J=12.8, 7.8, 1H), 1.37 (dtd, J=13.2, 7.8, 5.3, 1H); MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8](Br)[CH:9]=[CH2:10]>C(N(CC)CC)C>[CH2:10]([S:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: Sc1cnccn1
Solvent: CCN(CC)CC
Product: C=CCSc1cnccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
6.57 g of 2-mercaptopyrazine prepared in Reference Example 1 was dissolved in 80 ml of dimethylformaind and 8.6 ml of triethylamine was added thereto. 6.84 ml of allyl bromide was added to the solution and the mixture was stirred at 50° C. for 2 hours. 500 ml of ice water was added to the reaction solution and the resulting mixture was extracted with diethylether and concentrated. The residues were distilled under vacuum to give 7.85 g(85%) of oily pale yellow liquid.