Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2([CH2:21][C:22]([O-:24])=O)[N:18]=[C:19]=[S:20].[CH3:25][NH2:26]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:21][C:22](=[O:24])[N:26]([CH3:25])[C:19](=[S:20])[NH:18]3)[CH2:6][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: O=C([O-])CC1(N=C=S)CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1C(=O)CC2(CC(c3ccccc3)Oc3ccc(Br)cc32)NC1=S
Reaction time: 1 h

Procedure:
To a solution of 2-(6-bromo-4-isothiocyanato-2-phenylchroman-4-yl)acetate (192 mg, 0.46 mmol) in DCM (5 mL) is added a solution of 2 M MeNH2 in THF (1.3 mL), and stirred for 1 h. The solvent is removed under reduced pressure and the residue is dissolved in DCM (2 mL) and hexane (2 mL) and evaporated to afford 6-bromo-1′-methyl-2-phenyl-2′-thioxo-2′,3′-dihydro-1′H-spiro[chroman-4,4′-pyrimidin]-6′(5′H)-one as a white foam (209 mg), which is used for the next step without further purification. MS ESI +ve m/z 417 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:37][C:36]5[CH:39]=[CH:40][C:33]([O:32][C:31]([F:30])([F:41])[F:42])=[CH:34][CH:35]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (45 mg, 0.139 mmol, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.5 mL) in a 4-mL scintillation vial. Triethylamine (28.0 mg, 0.277 mmol) was added followed by the addition of 4-(trifluoromethoxy)benzaldehyde (34.2 mg, 0.180 mmol) as a solution in dichloromethane (0.2 mL). The resulting solution was stirred at room temperature for 15 minutes, at which point sodium triacetoxyborohydride (70.5 mg, 0.333 mmol) was added as a neat solid in one portion, and the resulting suspension was stirred at room temperature for an additional 4 hours. The suspension was loaded directly onto a 4 g silica column and eluted with ethyl acetate (flow rate=18 mL/minute) over 15 minutes to give the title compound as a colorless oil (34 mg, 53%). 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=1.2 Hz, 1H), 7.92 (d, J=1.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.41 (t, J=3.9 Hz, 1H), 4.18 (dd, J=16.4, 9.4 Hz, 1H), 4.02 (dd, J=13.7, 2.0 Hz, 1H), 3.69-3.45 (m, 3H), 2.94 (d, J=12.5 Hz, 2H), 2.81 (d, J=12.0 Hz, 1H), 2.60 (dd, J=14.8, 6.9 Hz, 1H), 2.50-2.34 (m, 2H), 2.15 (dd, J=12.8, 9.3 Hz, 1H), 1.98 (tt, J=7.9, 5.1 Hz, 1H), 1.86 (ddd, J=14.4, 10.4, 4.4 Hz, 1H), 1.02-0.79 (m, 4H); MS (ESI+) m/z 463.1 (M+H)+; [α]D24.1=−0.04 (c=0.23, CH3OH).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([CH2:15][O:16][CH3:17])=[CH:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:21][O:20][C:18]([C:10]1[C:9]([NH2:8])=[CH:14][CH:13]=[C:12]([CH2:15][O:16][CH3:17])[N:11]=1)=[O:19]
Reactant: COCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OC)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1ccc(N)c(C(=O)OC)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 3-(tert-butoxycarbonylamino)-6-(methoxymethyl)picolinate (695 mg, 2.35 mmol) at r.t. in dichloromethane (10 ml) under an argon atmosphere was added 2,2,2-trifluoroacetic acid (903 μl, 11.7 mmol) in one portion. The mixture was stirred at 50° C. overnight, then cooled to r.t. and treated carefully with 10% aq. Na2CO3 (10 ml). The aqueous solution was extracted with CH2Cl2 (10 ml). The combined organics were washed with brine (10 ml), dried over MgSO4, filtered and concentrated to leave the product as a light brown solid (424 mg, 92%) which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]2[CH3:26].[S:27](Cl)(=[O:30])(=[O:29])[NH2:28].O>CC(N(C)C)=O>[S:27](=[O:30])(=[O:29])([O:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([N:6]2[C@@H:5]([CH3:26])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:18])=[O:17])=[CH:24][CH:23]=1)[NH2:28]
Reactant: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OS(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a stirred solution of 4-{[(6S)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol (1.11 g, 3.0 mmol) in dimethyacetamide (10 mL), cooled to 0° C., was added sulfamoyl chloride (1.39 g, 12.0 mmol). The mixture was allowed to warm to room temperature and stirring continued for 16 hours. Water (100 mL) was added and a white precipitate deposited on the inside of the reaction vessel. The water was removed and the flask was washed with additional water. The white solid was dissolved in dichloromethane and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30% -50% methyl tert-butyl ether in hexane, to afford the title compound (1.16 g, 87% ) as a white solid, m.p.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.[Pd]>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:10])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (0.63 g, 2.5 mmol) and triethylamine (0.65 mL, 5 mmol) in methanol (15 mL) was added Pd/C (0.1 g), and the mixture was hydrogenated under 30 psi pressure at rt overnight. The mixture was filtered and the filtrate was concentrated to give tert-butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44 g, 70%). 1H NMR (400 MHz, CDCl3): 4.48 (brs, 1H), 3.78 (m, 2H), 2.30 (brs, 1H), 1.82 (m, 1H), 1.66 (m, 4H), 1.45 (s, 9H), 1.40-1.00 (m, 6H), 1.10 (d, J=6.4 Hz, 3H), 1.00-0.70 (m, 2H); MS (E/Z): 272 (M+H+).
Reaction SMILES: COC1C=CC=CC=1C1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH:25]=O>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cc(OC)cc(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 84 %

Procedure:
According to the preparation of 42, 3,5-dimethoxybenzaldehyde (40) (1.2 g, 7.3 mmol) was used to afford 49 (1.7 g, 84.0%) as pale yellow needles.
Reaction SMILES: [H][H].[NH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]([F:27])[CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:3][C:4]1[C:9]([NH2:10])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[C:16]([F:27])[CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Method D2 (using hydrogen). N-(4-(2-amino-3-nitropyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (540 mg, 1.5 mmol) was dissolved in ethanol (15 mL) and AcOEt (5 mL). Palladium 10% on activated carbon (150 mg) was added and the reaction mixture was stirred for 2 hours under hydrogen atmosphere. The catalyst was filtered off and the filtrate evaporated to afford the title compound (490 mg, 100%). 1H-NMR (δ, ppm, DMSO-d6): 4.65 (s, 2H, NH2,Py3), 5.86 (s, 2H, NH2,Py2), 6.23 (d, 1H, HPy,6, J=5.71 Hz), 6.85 (d, 1H, Harom,Ph, J=8.80 Hz), 7.01 (d, 1H, Harom,Ph, J=11.51 Hz), 7.32 (d, 1H, HPy,5, J=5.71 Hz), 7.45 (t, 1H, Harom,Ph, J=8.76 hz), 11.37 (s, 1H, NHCOCF3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:32][CH3:33])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC=CC=4)=[CH:16][CH:15]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:12]3[CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=[C:11]3[CH2:32][CH3:33])=[CH:19][CH:18]=2)=[O:24])(=[O:42])=[O:43])=[CH:39][CH:40]=1
Reactant: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-(4-cyanophenyl)-2-ethyl-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 534 [M+H]+, 532 [M−H]−, 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.7 Hz), 2.92 (2H, t, J=7.1 Hz), 3.47-3.55 (2H, m), 6.61 (1H, br), 7.27-7.37 (4H, m), 7.50 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.6 Hz), 7.77 (2H, d, J=8.6 Hz), 7.89 (2H, d, J=8.6 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([F:17])=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15]C)[CH:11]=[CH:10]2)=[CH2:4].[I-].[Na+]>CC(C)=O.C(OCC)(=O)C>[F:17][C:6]1[CH:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12](=[O:15])[N:13]3[CH2:2][C:3](=[CH2:4])[C:5]=1[C:14]=23
Reactant: C=C(CCl)c1c(F)cnc2ccc(OC)nc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=C1Cn2c(=O)ccc3ncc(F)c1c32
Yield: 35.5 %

Procedure:
A mixture of 8-[1-(chloromethyl)ethenyl]-7-fluoro-2-(methyloxy)-1,5-naphthyridine (4.9 g, 19.5 mmol) and sodium iodide (29 g, 195 mmol) in acetone (100 ml) was heated to reflux for 18 hours. The mixture was evaporated and the residue partitioned between water (200 ml) and dichloromethane (200 ml). The aqueous phase was further extracted with dichloromethane (2×200 ml) and the combined dichloromethane extracts washed with water (2×200 ml) dried over magnesium sulphate and evaporated. The resulting solid was triturated with ethyl acetate (50 ml) and filtered and washed with ethyl acetate (20 ml) affording a brown solid. This material was then dissolved in ethyl acetate and filtered through a plug of silica. Evaporation afforded a solid (1.4 g, 36%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:29][CH3:30])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][NH:21]2)=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[C:31]1([O:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:30][O:29][CH:13]([O:12][CH3:11])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:38]([O:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2C(=O)Oc1ccccc1
Temperature: -25 °C
Reaction time: 1.42 h

Procedure:
A solution of LHMDS in THF (1M, 500 μL, 0.500 mmol) was added drop wise to a solution of 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 321, 130 mg, 0.474 mmol) and diphenylcarbonate (105 mg, 0.490 mmol) in THF (2.2 ml) at −25° C. The reaction mixture was stirred for 85 minutes at −25° C., then warmed to room temperature and stirred for 45 min, placed in a fridge and stored over the weekend at 4° C. The reaction mixture was then cooled to −65° C. and further LHMDS (500 μl, 0.500 mmol) was added and it was allowed to warm to −45° C. to −35° C. and stirred for 80 min. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and water. Phases were separated and the water phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.78 min; ESI-MS 395.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.44-7.34 (m, 3H), 7.25-7.15 (m, 5H), 5.11 (s, 1H), 4.04-3.96 (m, 2H), 3.34 (s, 6H), 2.90 (t, 2H), 2.15-2.04 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.C1N=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1.CNC>C(#N)C>[CH3:24][N:25]([CH3:26])[C:28]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1)=[O:29]
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (10 g, 59 mmol), DBU (18 mL, 0.12 mol) and CDI (24 g, 0.15 mol) in 400 mL acetonitrile is stirred for 5 h at 100° C. Then dimethylamine (150 mL, 2M in THF) is added and the reaction mixture is stirred overnight at 100° C. The reaction mixture is concentrated under reduced pressure and the residue is poured in water. The mixture is acidified to pH 5 with 6 M HCl in water and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is triturated with diethyl ether. Yield: 9.1 g.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([O:18]C)[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].Cl.CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To a solution of 38.5 g (0.13 m) of 2,3-dichloro-4-methoxy-2'-fluorobenzophenone of Example 2A in 250 ml of dry benzene, 34.67 g (0.26 m) of AlCl3 is added. The mixture is refluxed 5 hours, poured over 100 ml concentrated HCl and 100 ml ice. The mixture is extracted with ethyl acetate, dried (Na2SO4) and evaporated to give 35 g. Trituration with hexane gives 32.8 g (89%) of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone. Analytical sample is recrystallized from ether-hexane, m.p. 128°-131° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-amino-1benzyl-4-ethoxycarbonylpyrazole (0.5 g) in DMF (10 ml), was added 60% NaH (0.082 g). After stirring for 5 min at room temperature, benzyl bromide (0.307 ml) was added, and the mixture was stirred for 1 h at room temperature. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene/ ethyl acetate=50/1) to give 3-benzylamino-1-benzyl-4-ethoxycarbonylpyrazole (0.3 g). This intermediate was derived to the title compound by the similar method to Reference Example 1 (yield 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCOc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
(3-Aminophenoxy)-acetonitrile (3.0 g) was dissolved in 12 ml of pyridine, cooled in an ice bath, treated with 3.47 g of methanesulfonyl chloride, and stirred at room temperature for 3 hours. The mixture was poured into ethyl acetate, washed with hydrochloric acid, then with water, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (3:7) giving 3.0 g of N-(3-cyanomethoxyphenyl)-methanesulfonamide. An aliquot of this product was crystallized from ethyl acetate:hexane (3:7) to give a solid, mp 91-92° C. ##STR66##
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([S:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)CCS
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(SCCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 3-mercaptopropionic acid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:40][CH2:24][C:21]2[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[O:23][N:22]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: NC1CCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCC2)no1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclobutylamine (250 μl, 2.96 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([N:38]=[C:39]=[O:40])[CH:37]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:39]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=2)=[O:40])[CH:25]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)Nc3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that describe in Example 37, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 5-methylphenyl isocyanate were coupled. Purification of the crude reaction product gave the title compound as a white foam (78.8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:26][O:27][CH2:28][CH:29]=[CH:30]B(O)O.C([O-])([O-])=O.[K+].[K+]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:30]=[CH:29][CH2:28][O:27][CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: COCC=CB(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CCOC)Cc2ccccc2C1

Procedure:
To a solution of 2-(2-Iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.89 mmol) and 3-methoxy-1-propenylboronic acid (206 mg, 1.78 mmol) in 10 mL EtOH/10 mL dioxane is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 195 mg, 0.089 mmol) and 2M aqueous solution of K2SO4 (1.78 mL, 3.56 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 4 h. After concentration in vacuo, the residue is purified by HPLC to give the product (220) as pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[C:24]1([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1C#Cc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and ethynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (60 mg, 50%); 1H NMR δ (CDCl3): 8.39 (d, J=8.55 Hz, 1H), 7.9 (br s, 1H), 7.59-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.41-7.35 (m, 3H), 7.02 (t, J=7.22 Hz, 1H), 2.21 (s, 3H); LCMS m/z: 235.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].O.[NH2:30][NH2:31]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:31][NH:30][C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Product: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 90.1) and hydrazine hydrate. The crude material was purified by silica gel column chromatography (7.5% MeOH/CH2Cl2) and triturated in Et2O. tR: 0.75 min (LC-MS 2); ESI-MS: 393 [M+H]+ (LC-MS 2); Rf=0.23 (7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H) 2.46 (s, 3H) 2.64 (s, 3H) 6.48 (s, 1H) 7.19-7.46 (m, 5H) 8.47 (s, 1H) 13.49 (br. s., 1H).