Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:24])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: COc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)cc(F)c4C)ccc32)cc1

Procedure:
Example 134 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 4-methoxybenzylamine to give the title compound (0.012 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Cl)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Cl)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one 170 (100 mg, 0.510 mmol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (98.4 mg, 0.561 mmol). PTSA (175.9 mg, 1.2 mmol) was added to the reaction mass, which was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude (E)-5-chloro-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one (171), which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 22% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][C:2](OC(=O)C)([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O.[NH2:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>O>[CH3:1][C:2]([O:22][C:21](=[O:23])[C@H:15]([CH2:16][CH2:17][C:18]([O:20][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:19])[NH2:14])([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Yield: 40.7 %

Procedure:
Acetic acid 1,1-dimethylethyl ester (1742 g; 2 L; 15 mol) (commercial product), 70% aq. perchloric acid (51 mL; 0.59 mol) and L-glutamic acid (78.8 g; 0.54 mol) (commercial product) were stirred at 25° C. over 5 days. After addition of a solution of K2CO3 (41.46 g, 0.3 mol) in H2O (140 mL) to the reaction mixture, the organic phase was separated, washed with water (2×500 mL), dried (NaSO4) and concentrated to dryness. The residue (27.2 g) was dissolved in Et2O (200 mL) and extracted with 1N HCl (2×70 mL), the combined aqueous phase was washed with Et2O (40 mL) and collected with the aqueous phases previously obtained from the first neutralization and successive washings. Addition of 10 N NaOH up to pH 8.8 led to an emulsion which was extracted with Et2O (2×600 mL). The combined organic phases were washed with H2O (250 mL), dried and evaporated to give the desired compound (57.7 g; 0.22 mol). Yield 41%.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)=[O:11])(=O)OC.[CH3:19][O:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@@H:29]1[CH:34]=O>COCCOC>[CH3:19][O:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@@H:29]1/[CH:34]=[CH:9]/[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)=[O:11]
Reactant: COC(=O)CCCCCCN1C(=O)CC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)c1cccc(Br)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of NaH (0.14 g, 1 eq) in 30 mL of ethylene glycol dimethyl ether stirred at 0° C. under nitrogen was added [2-(3-bromo-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (1.82 g, 1.05 eq). After 1 hour at 0° C., 7-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid methyl ester (1.44 g, 5.64 mmol) in 2 mL of DME was added slowly. The ice bath was removed and then the mixture was stirred for an additional 3 hours at room temperature. Saturated ammonium chloride solution was added and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by chromatography. EtOAc(1):Hexane(1)followed by EtOAc(5):Hexane(1) to yield 1.6 g of 7-{(R)-2-[(E)-3-(3-bromo-phenyl)-3-oxo-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16]C1C=CC(N)=CC=1.C(O)(=O)CC(O)=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([O:16][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: COc1ccc(N)cc1
Agent: C[O-]
Agent: O=C(O)CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(Cl)cc(OC)c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloro-6-methoxyquinoline (0.97 g) synthesized from p-anisidine and malonic acid according to the method of WO200226713 in methanol (20 mL) was added sodium methoxide (1.37 g), and the mixture was stirred at 70° C. for 3 h. The reaction solution was added dropwise to ice water, and the resulting solids were collected by filtration. The resulting solids were purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to obtain 2-chloro-4,6-dimethoxyquinoline (0.61 g) as white solids.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4]1.[C:16]([N:23]1[CH2:26][CH2:25][C:24]1=O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:19]([O:18][C:16]([N:23]1[CH2:26][CH:25]([N:2]([C@H:3]2[CH2:7][CH2:6][N:5]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:4]2)[CH3:1])[CH2:24]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC1=O
Reactant: CN[C@H]1CCN(C(=O)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C1CN(C(=O)OC(C)(C)C)C1)[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of compound 4d (TFA salt, 124 mg, 0.39 mmol) and compound 1e (94 mg, 0.55 mmol) in 1,2-DCE (2 mL) was added acetic acid (0.1 mL). To this mixture was added Na(OAc)3BH (132 mg, 0.624 mmol). The reaction was stirred at room temperature for 4 h. To the reaction mixture was added aq. NaHCO3, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5% TEA) gave compound 4e (0.11 g). MS m/z (M+H+) 360.5.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Yield: 462.5 %

Procedure:
A suspension of (4′-biphenyl)acetic acid (6.4 g) in 60 ml of ethanol is added with 1.1 g of para-toluensulfonic acid, then the reaction mixture is refluxed for 4 hours 30 minutes. The solvent is evaporated off, the residue is dissolved in diethyl ether and the resulting organic phase is washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with brine. The organic phase is then dried over sodium sulfate and the solvent is evaporated off to give 7.1 g of the product as a yellow oil.
Reaction SMILES: [CH:1]([N:3]1[C:8]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2].[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12>>[CH:1]([N:3]1[C:8]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:22][S:23][C@H:18]23)=[O:12])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: CON=C(C(=O)O)C1=CSCCN1C=O
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCN1C=O

Procedure:
2-(4-Formyl-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 2.3 g.) was allowed to react with 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.3 g.) in a similar manner to that of Example 1 to give the captioned compound (2.5 g.), pale yellow powder, mp. 150° to 155° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (170 mg, 1.114 mmol) was dissolved in tetrahydrofuran (2 mL) under nitrogen atmosphere. After cooling to 0° C., 40% NaH (30 mg, 1.224 mmol) was added. The resulting reaction mixture was stirred for 15 minutes and then heated at 80° C. for 3 hours after adding SEM-Cl (185 mg, 1.114 mmol). The heated reaction mixture was cooled to room temperature and then extracted with dichloromethane and water. The organic layer was separated and washed with sodium chloride aqueous solution. The organic layer was dried with magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1) to give the target compound as a yellow oil (235 mg, 0.83 mmol, 74% yield).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1>CN1C(=O)CCC1>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:25][CH:26]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccc(CC(N)=O)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN(c1ccc(CC(N)=O)cc1)c1cc(-c2cccc(Cl)c2)nc2c1CCC2
Yield: 15.3 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.060 g, 0.20 mmol) and 2-(4-(methylamino)phenyl)acetamide (0.066 g, 0.40 mmol) in NMP (3 mL) was microwaved for 3 h at 140° C. After this time, the mixture was purified by silica gel chromatography followed by preparative HPLC to afford the title compound (0.012 g, 15%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.18 (br s, 1H), 8.10 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.55 (br s, 7.37-7.27 (m, 5H), 6.92 (br s, 1H), 3.57 (s, 3H), 3.01 (t, J=7.1 Hz, 2H), 1.96-1.85 (m, 4H); ESI MS m/z 392 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:29][NH2:30]>O>[CH3:29][NH:30][C:19](=[O:21])[CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)NC
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.24 g, 16.5 mmol, prepared in Parts A and B of Example 16), THF (15 mL), and methylamine (available as a 40% solution in water, 8 mL) was scaled in a high-pressure vessel, heated at 80° C. overnight, and concentrated under reduced pressure to provide 4.7 g of N-methyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24](F)=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC1C=CC(F)=CC=1C(Cl)=O>>[F:29][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[C:13]1[C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=2[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:31])([CH3:30])[CH3:1])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: O=C(Cl)c1cc(F)ccc1F
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)ccc2F)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 64 was prepared according to the procedure described for the synthesis of compound 37 by replacing 2,4,5-trifluorobenzoyl chloride with 2,5-difluorobenzoyl chloride in the synthesis of intermediate 19. LCMS (+ESI) m/z=420.2 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:10])[CH2:7][CH:8]=[CH2:9].C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]([NH:10][CH2:6][CH2:7][CH:8]=[CH2:9])=[O:4]
Reactant: C=CCCN
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCNC(=O)CBr
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
A solution of bromoacetyl bromide (5.21 g, 25.8 mmol) in dichloromethane (5 ml) was added dropwise at −78° C. to a solution of 3-butene-1-amine (2.00 g, 25.8 mmol) and triethylamine (2.56 g, 25.8 mmol) in dichloromethane (20 ml). After 10 min at −78° C., the reaction mixture was allowed to reach room temperature over 2 h, then washed with water. The organic layer was washed with brine, dried (MgSO4), and evaporated to produce the title compound (4.59 g, 94%). Yellow liquid, 1H-NMR (300 MHz, CDCl3): 6.53 (br. s, 1H), 5.85-5.7 (m, 1H), 5.2-5.1 (m, 2H), 3.89 (s, 2H), 3.38 (q, J=6.3, 2H), 2.31 (q, J=6.3, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:16][C:4]1[S:3][C:2]2=[N:1][C:21]([CH3:22])=[C:20]([C:19](=[O:24])[C:18]([F:26])([F:25])[F:17])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)=[C:6]2[CH:5]=1
Reactant: Nc1sc(Cl)cc1C(=O)c1ccc(F)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(Cl)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-5-chloro-thiophen-3-yl)-(4-fluoro-phenyl)-methanone in 2 ml acetic acid was added 0.025 ml (0.19 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 70° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 8 mg (11%) 1-[2-chloro-4-(4-fluoro-phenyl)-6-methyl-thieno[2,3-b]pyridin-5-yl)-2,2,2-trifluoro-ethanone as an orange oil. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCN(c2cc(Cc3ccccc3)c(Br)cn2)CC1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CCN(c2cc(Cc3ccccc3)c(C#CC3(O)CN4CCC3CC4)cn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of 270 mg of 4-benzyl-5-bromo-2-(4-hydroxypiperidino)pyridine, 130 mg of 3-ethynyl-3-quinuclidinol, 50 mg of tetrakis(triphenylphosphine)palladium(0), 2 mg of cuprous iodide, 0.35 ml of triethylamine and 2 ml of N,N-dimethylformamide was stirred at 100° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the reaction solution was extracted with ethyl acetate-aqueous dilute ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 5% methanol/ethyl acetate, to give 120 mg of the target compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20]Br>C1COCC1>[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][N:11]1[CH:12]=[CH:13][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:10]1
Reactant: CSc1nccc(-c2cc[nH]c2)n1
Reactant: COC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCn1ccc(-c2ccnc(SC)n2)c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
2-Methylsulfanyl-4-(1H-pyrrol-3-yl)-pyrimidine (260 mg, 1.36 mmol) was added to a suspension of fat free sodium hydride (39 mg, 1.63 mmol) in 5 ml of THF. The mixture was heated to 50° C. for 20 minutes. Then, 3-bromo-propionic acid methyl ester (0.156 ml, 1.36 mmol) was added and the temperature was increased to 80° C. After 14 hours, the mixture was cooled, quenched with water and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The crude product was used without further purification. Yield: 302 mg (80%).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][CH:10]=2)(=O)=O.[CH3:24][S:25]([C:28]1[C:36]2[C:31](=[CH:32][N:33]=[CH:34][CH:35]=2)[NH:30][N:29]=1)(=[O:27])=[O:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:7]([CH2:6][N:30]1[C:31]3=[CH:32][N:33]=[CH:34][CH:35]=[C:36]3[C:28]([S:25]([CH3:24])(=[O:26])=[O:27])=[N:29]1)=[CH:15]2
Reactant: CS(=O)(=O)CCCn1c(COS(C)(=O)=O)cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
To a solution of {5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl methanesulfonate (363 mg, 1.0 mmol), 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine (197 mg, 1.0 mmol) and PPh3 (786 mg, 3.0 mmol) in 50 mL of THF was added DIAD (606 mg, 3.0 mmol) dropwise via an additional funnel in an ice-water bath under N2 protection. The mixture was then stirred at RT overnight and then concentrated in vacuo. The residue was purified by preparative-HPLC to give the title product (13.592 mg, yield: 19.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].O>CN(C)C=O>[CH3:16][C:15]1[C:10]2[N:11]([CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Temperature: 0 °C

Procedure:
To a suspension of the product of Example 27 Step B (195 mg) in N,N-dimethylformamide (2 mL) was added triethylamine (0.12 mL) and the mixture cooled to 0° C. 3-chloropropanesulfonyl chloride (0.11 mL) was added dropwise and the mixture stirred for 1.5 hours before the addition of H2O (2 mL). The reaction mixture was partitioned between H2O (15 mL) and ethyl acetate (15 mL). The aqueous layer was brought to pH=9–10 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, decanted, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (210 mg).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:31])[C:6](=[O:30])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[CH:11][C:10]([O:26][CH3:27])=[C:9]([O:28][CH3:29])[CH:8]=2)(O)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:57][CH2:58][CH2:59][C:60]1[N:61]=[CH:62][NH:63][CH:64]=1>C(OCC)(=O)C.O.C(N(CC)CC)C.CN(C)C=O.C(Cl)Cl>[CH3:27][O:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:28][CH3:29])[C:6](=[O:30])[N:5]([CH3:31])[C:4]([C:1]([NH:57][CH2:58][CH2:59][C:60]1[N:61]=[CH:62][NH:63][CH:64]=1)=[O:2])=[C:13]2[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: NCCc1c[nH]cn1
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)n(C)c(=O)c2cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)NCCc3c[nH]cn3)n(C)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a mixture of methylene chloride (10 ml) and dimethylformamide (5 ml) are added the compound obtained in Example 128 (1.66 g), 1,3-dicyclohexyl carbodiimide (960 mg) and 1-hydroxybenzotriazole (710 mg), and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added a solution of 4-(2-aminoethyl)imidazole (850 mg) and triethylamine (1.28 ml) in dimethylfomamide (5 ml), and the mixture is stirred for three hours, and then further stirred at 50° C. for 7 hours. To the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:hexane=30:1) to give 6,7-dimethoxy-3-[2-(4-imidazolyl)ethylaminocarbonyl]-2-methyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (1.0 g) as listed in Table 12.