Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[C:60]([O:66][CH3:67])[C:20]=1[CH:21]=[CH:22][CH:23]([S:33]([CH:36]([CH:46]=[CH:47][C:48]1[C:53]([O:54][CH3:55])=[CH:52][C:51]([O:56][CH3:57])=[CH:50][C:49]=1[O:58][CH3:59])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([NH2:45])[CH:38]=1)(=[O:35])=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([NH2:32])[CH:25]=1>O1CCCC1>[CH3:67][O:66][C:60]1[CH:61]=[C:62]([O:64][CH3:65])[CH:63]=[C:19]([O:18][CH3:17])[C:20]=1/[CH:21]=[CH:22]/[CH:23]([S:33]([CH:36](/[CH:46]=[CH:47]/[C:48]1[C:49]([O:58][CH3:59])=[CH:50][C:51]([O:56][CH3:57])=[CH:52][C:53]=1[O:54][CH3:55])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([NH:45][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:16][CH:15]=2)[CH:38]=1)(=[O:35])=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([NH:32][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[CH:25]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)c2)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-methylpiperazin-1-yl)benzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) is added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution is stirred overnight and the reaction progress is monitored by TLC. The solvent is removed and the residue is taken up in dichloromethane and washed with water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give the desired amide product.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][OH:16].[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:5])[CH:3]=1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)CCO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
3-Fluoro-6-nitroaniline (0.7 g, 4.48 mmol) and N,N-dimethylethanolamine (1.34 mL, 13.45 mmol) were dissolved in toluene (5 mL). This solution was cooled at 0° C. and finely ground KOH (1.258 g, 22.4 mmol) was added to the stirring mixture. The reaction mixture was stirred for 16 hours at room temperature, diluted with H2O (30 mL) and then extracted with CHCl3 (3×25 mL). The combined organics were dried (Na2SO4), filtered and the solvent was removed in vacuo. Purification by SiO2 chromatography (0% to 10% 2.0M NH3 in MeOH/dichloromethane) gave 5-(2-dimethylamino-ethoxy)-2-nitro-phenylamine as a dark oil (0.665 g, 90%). MS(ESI) m/z 226.0 (M+H)+
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>[OH-].[Na+].C(Cl)Cl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH3:23]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A solution of 25 g (110 mmol) 4-benzoylbenzoic acid [611-95-0] and 20 mL SOCl2 was allowed to reflux for 2 h then allowed to cool. The excess SOCl2 was evaporated off and the resulting clear oil was dissolved in 10 mL CH2Cl2 then slowly added to 12 mL (116 mmol) diethylamine in a mixture of 10 mL 3N NaOH and 50 mL CH2Cl2. The mixture was allowed to stir for 30 min then partitioned between H2O and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered and concentrated. The product precipitated from EtOAc/hexane to give 29.6 g (105 mmol) white crystals. MS m/z (MH+) 282.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:5]2[CH:4]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:5]2[CH:4]=1
Reactant: CCOC(=O)c1cn2c(cc(OC)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2nc(C(=O)O)cn2c2ccccc12

Procedure:
250 mg of ethyl 5-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate in 20 ml of ethanol and 10 ml of water was hydrolyzed with 2 ml of N sodium hydroxide solution and was then acidified with 2.2 ml of N hydrochloric acid as in Example 36 to obtain 5-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid as colorless needles melting at 244°-247° C. The I.R. spectrum indicated that the compound existed entirely in the zwitterionic form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25]O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58].O>C(Cl)Cl>[Br:58][CH2:25][C:22]1[N:21]=[CH:20][C:19]([C:17]2[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14]([CH3:36])=[C:13]([CH:18]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:37])=[CH:24][CH:23]=1
Reactant: CCN(c1cc(-c2ccc(CO)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCN(c1cc(-c2ccc(CBr)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-(hydroxymethyl)pyridin-3-yl)-2-methylbenzamide (0.35 g, 0.694 mmol) in DCM (5 mL), triphenyl phosphine (0.361 g, 1.38 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (0.318 g, 1.38 mmol) was added portion wise to it and resulting solution was stirred at room temperature for 18 h. On completion, water was added to the reaction mass and extraction was carried out using DCM. Combined organic layers were dried over sodium sulphate, concentrated under reduced pressure to give crude material which then column purification gave desired compound (0.35 g, 89%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:16])[NH:10][CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:16])[C:8]=2[CH:7]=[N:6][C:5]=1[C:3]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)[nH]ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(=O)[nH]ccc2c1O
Yield: 89 %

Procedure:
A mixture of 4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.077 mmol), β-alanine (138 mg, 1.55 mmol) and NaOMe solution (2.3 mL, 1.16 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified with 4 M HCl to pH about 1, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 19 mg of the title compound as an off-white solid. MS: (+) m/z 278.21 (M+1).
Reaction SMILES: [NH2:1][C:2](=[S:18])[N:3]1[CH2:7][CH:6]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4]1.Cl[CH2:20][C:21]([C:23]1[CH2:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:25][N:24]=1)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH:26]1[O:25][N:24]=[C:23]([C:21]2[N:1]=[C:2]([N:3]3[CH2:7][CH:6]4[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:10][CH:5]4[CH2:4]3)[S:18][CH:20]=2)[CH2:27]1
Reactant: O=C(CCl)C1=NOC(c2c(F)cccc2F)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(N)=S)CC2C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2C1
Temperature: 90 °C

Procedure:
To a stirred solution of 1,1-dimethylethyl 5-(aminothioxomethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (i.e. the product of Step A) (0.5 g, 18.42 mmol) in chloroform (20 mL) was added 2-chloro-1-[5-(2,6difluorophenyl)-4,5-dihydroisoxazol-3-yl]ethanone (i.e. the product of Step B) (0.478 g, 18.42 mmol) and pyridine (0.29 g, 37.12 mmol) at room temperature. The reaction mixture was heated at 90° C. for 5 h, cooled to room temperature and concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL) and concentrated under reduced pressure. The resulting material was purified by column chromatography (1% methanol/chloroform as eluant) to provide the title product as white solid (0.7 g) melting at 78.9-80.2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][C:19]=1[O:28][C:29]([F:32])([F:31])[F:30].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])=[CH:20][C:19]=1[O:28][C:29]([F:30])([F:32])[F:31]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(OC(F)(F)F)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 4-chloro-3-(trifluoromethoxy)phenylacetic acid (0.025 g, 0.10 mmol) and Et3N (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.039 g, 85%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.44 (m, 3H), 7.12-7.22 (m, 4H), 3.90 (s, 2H), 3.76 (m, 2H), 2.80 (t, J=6.2 Hz, 2H), 2.02 (m, 2H); MS: (ES) m/z calculated for C21H16ClF4N3O2 [M+H]+ 454.1, found 454.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=2[F:17])=[C:5]([OH:20])[CH:4]=1)[CH3:2].[C:21]([NH:28][CH2:29][C:30](O)=[O:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:20][C:30](=[O:31])[CH2:29][NH:28][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[C:9]([F:17])[CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OC(=O)CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone (0.37 mmol; 100 mg) in dry THF (2 mL) cooled to 0° C. were added, N-Boc-glycine (0.37 mmol; 64 mg), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluoro phosphate (0.37 mmol; 190 mg) and triethylamine (1.09 mmol; 153 μL). The reaction was stirred at 0° C. for 3 hours and overnight at room temperature. The mixture was concentrated, treated with saturated NH4Cl and extracted with dichloromethane. Combined organic phases were washed with water, dried over Na2SO4 and concentrated in vacuo. The title compound (91 mg; 58%) was obtained as clear oil after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].N#N.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[C@@H:18]([CH3:24])OS(C)(=O)=O)=[O:15])([CH3:12])([CH3:11])[CH3:10]>O.ClCCCl>[C:9]([O:13][C:14]([NH:16][C@H:17]1[C@H:18]([CH3:24])[N:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]1=[O:26])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Yield: 60.5 %

Procedure:
Potassium carbonate (200g) was dissolved in 300ml of water, 1.5 liters of 1,2-dichloroethane was added, and the mixture was refluxed. A suspension of 178 g of N2 -(t-Butyloxycarbonyl)-O-(methylsulfonyl)-N-(phenylmethoxy)-L-threonineamide in 1.2-dichloroethane was added and the mixture was refluxed for 2 hours. The layers were cooled and the organic layer was evaporated, redissolved in ethyl acetate, washed twice with water, dried (MgSO4) and evaporated again. The oily residue crystallized on treatment with petroleum ether, yielding 76.7 g of the title compound, melting point 78° C.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[C:20]1([CH2:26][CH2:27][CH:28]=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:28]([OH:29])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Reactant: O=CCCc1ccccc1
Agent: [Li]CCCC
Product: N#Cc1ccc(C(C(O)CCc2ccccc2)n2cncn2)cc1

Procedure:
1-[1-(4-cyanophenyl)-2-hydroxy-4-phenylbutyl]-1,2,4-triazole is prepared by the method described in Example 1 starting from 1-(4-cyano-benzyl)-1,2,4-triazole (2.0 g, 0.0108 mol), n-BuLi (0.0108 mol) and 3-phenylpropionaldehyde (1.74 g, 0.013 mol). The product is purified by flash chromatography.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[Br:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[Br:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1Br

Procedure:
1-(2-Bromo-4-chlorobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2-bromo-4-chlorobenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:12][CH2:13][C:14]3([CH3:18])[CH2:17][O:16][CH2:15]3)=[CH:6][C:7](C#N)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+].[CH:21]([OH:23])=[O:22]>C(O)C>[CH:1]1([C:4]2[C:5]([O:12][CH2:13][C:14]3([CH3:18])[CH2:15][O:16][CH2:17]3)=[CH:6][C:7]([C:21]([OH:23])=[O:22])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(C#N)ncc2C2CC2)COC1
Reactant: O=CO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(COc2cc(C(=O)O)ncc2C2CC2)COC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinonitrile (1.73 g, 7.08 mmol) in ethanol (20 ml) in a microwave vial was added a 4.0M aqueous solution of potassium hydroxide (6.2 ml, 24.8 mmol). The vial was sealed and mixture was stirred at 85° C. overnight. The reaction was cooled down to 0° C. followed by addition of formic acid (1.14 g, 951 μl, 24.8 mmol) to acidify the reaction mixture. The crude solution was then evaporated to dryness and the crude material was directly purified by preparative HPLC to yield the title compound (1.34 g, 72%) as white solid. MS (ESI, m/z): 264.5 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[NH:11][CH2:10]1.Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10]1
Reactant: O=C1NCC(COc2cccc(Cl)c2)O1
Reactant: CCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 48 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 6.00 g of 5-(3-chlorophenoxymethyl)oxazolidin-2-one, 100 ml of anhydrous dimethylformamide and 6.48 g of ethyl 2-bromovalerate were used. The resulting crude product was applied to a silica gel chromatography column, and eluted, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give a polar diastereomer and a less polar diastereomer separately. From the polar diastereomer, 4.5 g of the title compound having an Rf value of 0.58 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) were obtained, and from the less polar diastereomer, 4.47 g of the title compound, melting at 43° C. to 49° C., were obtained.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[O:32][N:31]=[CH:30][C:29]=1[S:33](Cl)(=[O:35])=[O:34]>>[CH3:27][C:28]1[O:32][N:31]=[CH:30][C:29]=1[S:33]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)(=[O:35])=[O:34]
Reactant: Cc1oncc1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: Cc1oncc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 5-methyl-isoxazole-4-sulfonyl chloride. White solid. MS (ESI): 460.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[O:21])=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)N(C)C(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)N(C)C(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-1-isopropyl-1-methyl-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:14]=1[CH2:15][S:16][C:17]1[CH2:21][C:20]([CH2:23][CH3:24])([CH3:22])[O:19][N:18]=1.O>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:14]=1[CH2:15][S:16]([C:17]1[CH2:21][C:20]([CH2:23][CH3:24])([CH3:22])[O:19][N:18]=1)=[O:9]
Reactant: CCC1(C)CC(SCc2c(F)cccc2F)=NO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)CC(S(=O)Cc2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
4.6 g of m-chloroperbenzoic acid (purity: 70%, 18.8 mmoles) was added, with ice-cooling, to a solution of 4.1 g (15.0 mmoles) of 3-(2,6-difluorobenzylthio)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.5 g (yield: 34.8%) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 30° C. or less).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([CH3:20])[CH:13]=[CH:14][CH:15]=2)[NH:10]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([CH3:20])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc(C2NC(=O)c3cccc(C)c3N2)c(Cl)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: Cc1ccc(-c2nc3c(C)cccc3c(=O)[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Chloro-4-methylphenyl)-8-methyl-2,3-dihydroquinazolin-4(1H)-one (159 mg, 0.6 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (126 mg, 0.6 mmol) were dissolved in 5 ml of ethanol and then stirred at room temperature for 2 hours. The reaction mixture was filtered and the solid was washed with a little ethanol. This gave 108 mg (65.5% of theory) of 2-(2-chloro-4-methylphenyl)-8-methylquinazolin-4(3H)-one as a colorless said of melting point 234° C. 1H NMR (400 MHz, d6-DMSO δ, ppm) 12.54 (br. S, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.56 (d, 1H), 7.42 (m, 2H), 7.30 (d, 1H), 2.51 (s, 3H), 2.40 (s, 3H).