Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])=[N:6][CH:5]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COC(=O)c1ccc(N)nc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccccc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 6-aminonicotinic acid methyl ester (4 g) in pyridine (40 ml) is added with stirring 2-methylbenzoyl chloride (6.73 g) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dried to give 6-(2-methylbenzoylamino)nicotinic acid methyl ester (5.7 g) as white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37])[NH:32][CH2:31][CH2:30]2>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:15][C:16]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([O:26][CH3:25])=[C:35]([C:36]([F:38])([F:39])[F:37])[CH:34]=3)[CH2:30][CH2:31]2)=[O:24])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2cccnc2)c1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)N2CCc3cc(OC)c(C(F)(F)F)cc32)cc(-c2cccnc2)c1
Yield: 41.9 %

Procedure:
The title compound (0.15 g, 40%) was prepared as a tan powder using the methodology of Example 28 from phenyl N-(3-ethyl-5-(pyrid-3-yl)phenyl carbamate (D30) (0.26 g, 0.81 mmol) and 5-methoxy-6-trifluoromethyl indoline (D11) (0.177 g, 0.81 mmol) in DMF (10 ml). Melting point: 205° C.-207° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:1]([NH:8][C:10](=[O:11])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)Oc1ccccc1
Reaction time: 72 h

Procedure:
Benzylamine (53.5 g.) is added during 30 minutes to a stirred suspension of phenyl chloroformate (78.3 g.) and anhydrous potassium carbonate (151.8 g.) in dioxan (500 ml.) and the mixture is stirred at laboratory temperature for 72 hours and then poured into water. The mixture is extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is stirred with petroleum ether (b.p. 60°-80° C.) and the mixture is filtered. There is thus obtained as solid residue phenyl N-benzylcarbamate, which is used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (43 mg, 51%), MS (ISP) m/z=338.5 [(M+H)+], mp 303° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH2:7]([OH:9])[CH3:8].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[ClH:11].[CH2:7]([O:9][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])(=[O:19])=[O:20])=[CH:14][CH:13]=1)[CH3:8]
Reactant: CCO
Reactant: CC(C)NCCS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(S(=O)(=O)CCNC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6.6 g of a 60% dispersion of sodium hydride in oil (0.165 mole) in 300 mole of dimethyl sulfoxide was added 7.5 g (0.163 mole) of absolute ethanol. The mixture was stirred at room temperature for 0.5 hr, and 20.8 g (0.080 mole) of N-[2-(4-chlorophenylsulfonyl)ethyl]-2-propanamine hydrochloride was added as a solid. The mixture was heated at 120°-140° C. for 1 hr, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, an excess of ethereal hydrogen chloride was added, and ether was added. A white solid precipitated in amount of 14.92 g (69.2%), m.p. 168°-170° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[C:4]2[CH2:3]1.[Cl:21][CH2:22][C:23](OC(=O)CCl)=O>CN(C)C=O>[Cl:21][CH2:22][C:23]1[O:18][C:17]([C:16]2[N:15]=[CH:14][N:5]3[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=23)=[N:19][N:20]=1
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
9.4 g (34.7 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide were stirred at room temperature for 3 hours in 75 ml of N,N-dimethyl- formamide with 27.1 g (41.5 mmol) of chloroacetic anhydride. After evaporating the solvent the residue was stirred at room temperature overnight with 75 ml of a 10% solution of phosphorus pentoxide in methanesulphonic acid. The reaction mixture was treated with ice, made alkaline with conc. sodium hydroxide solution and extracted four times with methylene chloride. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 6.9 g (61%) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 221°-222°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:41])[CH2:20][N:21]2[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:24]3[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=3[C:22]2=[O:40])[CH2:14][CH2:13]1.[ClH:42]>C(O)(=O)C.O1CCOCC1>[ClH:42].[C:29]([CH2:28][CH:25]1[C:24]2[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=2[C:22](=[O:40])[N:21]([CH2:20][C:19]([NH:18][CH:15]2[CH2:14][CH2:13][CH:12]([CH2:11][NH:10][C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:17][CH2:16]2)=[O:41])[CH2:27][CH2:26]1)([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)NC2CCC(CNc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CC1CCN(CC(=O)NC2CCC(CNc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21

Procedure:
Analogously to Example II, the t-butyl ester (Example V) in glacial acetic acid was cleaved using 4N HCl in dioxane. After freeze-drying, 0.45 g of white amorphous hydrochloride remained; ESI-MS [M+H+]: 504.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[N:24]=[N:25][C:26]([N:29]([CH3:31])[NH2:30])=[CH:27][CH:28]=1>>[Cl:22][C:23]1[N:24]=[N:25][C:26]([N:29]([CH3:31])[NH:30][C:19]([C:9]2[CH:10]=[N:11][C:12]([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:21])=[CH:27][CH:28]=1
Reactant: CN(N)c1ccc(Cl)nn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 3-chloro-6-(1-methylhydrazinyl)-pyridazine (CAN 76953-33-8) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 444.1408 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12]C(=O)C)[C:9](=O)[CH3:10].[C:16](#[N:20])[CH2:17][C:18]#[N:19].[OH-].[K+].O>CO>[NH2:19][C:18]1[NH:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:9]([CH3:10])[C:17]=1[C:16]#[N:20]
Reactant: CC(=O)NC(C(C)=O)c1ccccc1F
Reactant: N#CCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N
Yield: 22.4 %

Procedure:
1-(2-Fluorophenyl)-1-acetamido-2-propanone (3.13 g) and malononitrile (1.49 g) were dissolved in methanol (15 ml) and the solution was stirred under ice-cooling. Then, 55% aqueous solution of potassium hydroxide was added to the above solution to adjust to pH 10. The reaction mixture was then warmed and stirred at 55-60° C. for 0.5 hour. After cooling, the reaction mixture was poured into iced water and the resulting crystals were collected by filtration. This crude crystalline product was recrystallized from methanol-water and, further, from benzene to provide the title compound as colorless crystals (0.72 g). m.p. 117-118° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1>O1CCOCC1.O.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>[CH3:16][N:17]1[C:21]([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=2)=[CH:20][CH:19]=[N:18]1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1csc(C(=O)O)c1
Temperature: 85 °C

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (3.91 g, 18.9 mmol) in dioxane/H2O (4:1, 100 mL) was added Cs2CO3 (21.7 g, 66.6 mmol), tetrakistriphenylphosphine Pd(0) (1.1 g, 0.95 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.94 g, 18.94 mmol) [prepared according to the procedure of Preparation 7]. The reaction mixture was heated to 85° C. in a sealed tube for 12 hours and partitioned between H2O and CHCl3. The pH of the aqueous phase was adjusted to ˜3 with 6N HCl and washed several times with CHCl3. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (2.84 g, 13.64 mmol, 72%): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5]([CH3:8])[CH2:4][S:3]1.OO.[CH3:11][OH:12]>>[CH3:1][C:2]1([O:12][CH3:11])[C:6](=[O:7])[CH:5]([CH3:8])[CH2:4][S:3]1
Reactant: CO
Reactant: CC1CSC(C)C1=O
Agent: OO
Product: COC1(C)SCC(C)C1=O

Procedure:
To a solution of 411 g (3.16 mol) of 2,4-dimethyl-tetrahydro-thiophen-3-one in 3000 ml of methanol are added dropwise, at an internal temperature of 63°-65° and over a period of one hour, 256.4 g (2.70 mol) of 35.8% hydrogen peroxide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].[F:15][CH:16](F)[CH2:17]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCl>[F:15][CH2:16][CH2:17][O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCC(F)F
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2cc(OCCF)cnc12
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (500 mg, 2.63 mmol), methanesulphonic acid 2,2-difluoro-ethyl ester (463 mg, 2.9 mmol), ad potassium carbonate (810 mg, 5.86 mmol) in dimethylformamide (7 ml) was heated at 100° C. for 16 hours. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=10:1 to 1:1 as the eluent yielding 150 mg (24%) of the 3-(2-fluoro-ethoxy)-8-nitro-quinoline as a yellow solid; (calculated) C11H9FN2O3 [236.2]; (found) [M+H]+=237.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25]Br)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([NH2:37])(=S)[CH3:35].O.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:37]/[C:34](/[CH3:35])=[CH:25]\[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:27]
Reactant: CC(N)=S
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
To a solution (44 ml) of 6-bromo-3-(2-bromoacetyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (4.41 g) in DMF was added thioacetamide (1.1 g) and the mixture was stirred at 70° C. for 24 hrs. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were washed with methanol and recrystallized (ethyl acetate) to give the title compound (1.31 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[CH2:13][C:12]=2[CH:28]=1.CN([CH:32]=[O:33])C>>[CH:32]([C:9]1[C:8]([O:7][CH3:6])=[CH:28][C:12]2[CH2:13][C:14]3[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=3[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:11]=2[CH:10]=1)=[O:33]
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CC1Cc2cc(C=O)c(OC)cc2Cc2ccccc21
Temperature: 90 °C
Yield: 21 %

Procedure:
POCl3 (17 mL) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (1.0 g, 3 mmol) in dry DMF (40 mL) at RT under argon, and the dark solution was heated at 90° C. for 48 hr. The reaction was concentrated on the rotavap and the residue was partitioned between H2O and EtOAc. The organic layer was separated, dried (MgSO4), and concentrated on the rotavap. The residue was reconcentrated from xylenes (to remove any remaining DMF) then was chromatographed on silica gel (7% EtOAc in hexanes) to afford the title compound (230 mg, 21%) as a colorless oil: MS (ES) m/e 339.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:20](=[O:21])[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[C:12]3=[O:13])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C)C=O.O>[CH2:30]([O:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:20](=[O:21])[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[C:12]3=[O:13])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc2onc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1noc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc12

Procedure:
A mixture of N-(3-hydroxy-1,2-benzisoxazol-5-yl)-1-cyclohexene-1,2-dicarboximide (0.75 g, 2.64 mmol), potassium carbonate (0.6 g, 4.35 mmol) and allyl bromide (1 g, 8.3 mmol) in N,N-dimethylformamide is heated at 60°-70° C. for 2 hours and diluted with water. The aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and ether/hexanes solutions yields a gum. A solution of the gum in an ether/hexanes mixture is passed through a plug of silica gel and crystallized to give the title product as a pale yellow solid, mp 88°-89° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[C:20]([F:21])=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(F)ccc(F)c2o1
Reactant: Brc1ccccn1
Product: Fc1ccc(F)c2oc(CCC#Cc3ccccn3)nc12
Yield: 14.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (69 mg, 0.43 mmol) and 2-(but-3-ynyl)-4,7-difluoro-benzo[d]oxazole (90 mg, 0.43 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 17 mg (61 μmol, 14%) of 4,7-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[CH2:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH2:18][CH2:17][CH2:16]1)[CH3:14]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:19]2[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: CCN1CCCNc2ccccc21
Product: CCN1CCCN(C(=O)c2ccc(C#N)c(C)c2)c2ccccc21

Procedure:
The carboxylic acid from Example C (0.53 g, 3.29 mmol) was reacted with 1-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 23B (0.514 g, 2.92 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield 0.55 g (59%).
Reaction SMILES: [I-:1].O.[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[O:12][C:11]2=[O:17])[CH:7]=[CH:8][CH:9]=1>[Ag+].FC(F)(F)C([O-])=O>[I:1][C:9]1[CH:8]=[CH:7][C:6]([N:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[O:12][C:11]2=[O:17])=[CH:5][C:4]=1[F:3]
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reactant: [I-]
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[C:9]([N:13]1[CH:21]=[C:20]2[C:15]([C:16](=[O:40])[NH:17][C:18]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:38]=[C:37]5[C:32]([CH:33]=[CH:34][C:35](Cl)=[N:36]5)=[CH:31][CH:30]=4)=[O:28])[CH2:23][CH2:22]3)[CH2:19]2)=[N:14]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]1[CH:21]=[C:20]2[C:15]([C:16](=[O:40])[NH:17][C:18]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:38]=[C:37]5[C:32]([CH:33]=[CH:34][C:35]([N:2]([CH3:3])[CH3:1])=[N:36]5)=[CH:31][CH:30]=4)=[O:28])[CH2:23][CH2:22]3)[CH2:19]2)=[N:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccc(Cl)nc4c3)CC1)C2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1ccc2ccc(C(=O)N3CCC4(CC3)Cc3cn(C(C)(C)C)nc3C(=O)N4)cc2n1
Temperature: 70 °C
Yield: 25 %

Procedure:
A solution of dimethylamine in tetrahydrofuran (2.2 mL, 4.4 mmol, 2.0 M) was added to 2′-tert-butyl-1-(2-chloroquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (100 mg, 0.2 mmol). The reaction vessel was sealed and the mixture was heated to 70° C. for 15 hours. The reaction was cooled to room temperature and concentrated. Purification by reversed-phase HPLC gave the title compound (25 mg, 25%). +ESI (M+H) 461.2; HPLC retention time 1.96 minutes (Method A).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:2]2[CH2:3][CH2:4][C:5]3[NH:6][C:7]4[CH:8]=[CH:9][C:10]([C:14]([NH:16][CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[O:15])=[CH:11][C:12]=4[C:13]=3[CH2:1]2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CNCC4)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(F)(F)F)cc2)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (11.63 g, 29.2 mmol) and 4-(trifluoromethyl)benzaldehyde (4.8 mL, 6.12 g, 35.1 mmol) in DCM (200 mL), sodium triacetoxyborohydride (12.4 g, 8.5 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and then poured into saturated sodium bicarbonate solution (300 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated to give an off-white solid. Trituration with ethyl ether provided tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (9 in Scheme 1(c)) as a white solid (13.60 g, 84%). 1H NMR (DMSO-d6, 300 MHZ) 11.03 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 4.22-3.83 (m, 5H), 3.62 (s, 2H), 2.90-2.77 (br s, 6H), 1.82-1.70 (m, 2H), 1.55-1.30 (m, 11H) ppm; MS (ES) 557 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH:16]=[N:17][NH2:18].CCN(CC)CC>C1COCC1>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH:16]=[N:17][NH:18][C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: NN=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
To a stirred solution of 2-chloro-nicotinoyl chloride (1.75 g, 10 mmol) in 40 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (1.88 g, 10 mmol) in 20 mL THF at 0° C., followed by 1.5 mL Et3N. The solution was stirred at room temperature overnight and precipitate was observed. It was filtered and the solid was washed with MeOH, dried to yield the title compound (3.63 g, 90%). 1H NMR (acetone-d6): 11.08 (s, 1H), 8.53 (d, J=4.5 Hz, 2H), 8.27 (s, 1H), 7.72 (m, 3H), 7.57 (m, 2H).