Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[C:7](OCC)[CH2:8][CH3:9])[C:4]([NH2:6])=[O:5])#[N:2].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][NH2:23].O>CO>[NH2:2][C:1]1[N:22]([C:15]2[C:14]([Cl:13])=[CH:19][C:18]([Cl:20])=[CH:17][C:16]=2[Cl:21])[N:23]=[C:7]([CH2:8][CH3:9])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(CC)=C(C#N)C(N)=O
Solvent: O
Solvent: CO
Product: CCc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Part A: To a stirred solution of 320 mg (1.9 mmol) of 2-cyano-3-ethoxypentenamide in 7 mL of MeOH was added 465 mg (2.2 mmol) of 2,4,6-trichlorophenylhydrazine. The solution was stirred 3 h at reflux, treated with 2 mL of water, and allowed to stir an additional 1 h, cooling to RT. The white solid which precipitated was filtered, washed with 2:1 MeOH-water, and air-dried to afford 520 mg (82%) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide, mp 186-188° C., Mass Spec (CI+): 331.9989 (M)+.
Reaction SMILES: [C:1]([C:4]1([CH2:17][C:18]([OH:20])=O)[CH2:16][CH2:15][N:7]2[C:8]3[C:13]([CH:14]=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)(O)=[O:2].C(=O)([O-])[O-].[NH4+:25].[NH4+]>ClCCl.CO>[NH:25]1[C:18](=[O:20])[CH2:17][C:4]2([CH2:16][CH2:15][N:7]3[C:8]4[C:13]([CH:14]=[C:6]3[CH2:5]2)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:1]1=[O:2]
Reactant: O=C(O)CC1(C(=O)O)CCn2c(cc3ccccc32)C1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: O=C1CC2(CCn3c(cc4ccccc43)C2)C(=O)N1
Temperature: 200 °C
Yield: 68.8 %

Procedure:
A mixture of 100 mg of 8-carboxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-acetic acid and 69 mg of ammonium carbonate was heated at 200° C. for 1 hour. After cooling and chromatography on silica gel using dichloromethane/methanol (9:1) for the elution there were obtained 64 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[CH2:16](OCC)C>C[Li]>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:16])=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12
Reactant: CCOCC
Reactant: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Agent: [Li]C
Product: CC(=O)c1sc(C)c2c1CCC(C)(C)C2
Temperature: 26 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (4.10 g, 18.28 mmol) in diethyl ether (300 mL), methyllithium (23 mL, 1.6 M solution in diethyl ether) is slowly added at rt. The reaction mixture becomes clear, yellow and slightly warm (26° C.), and is stirred for 15 min before it is quenched with water. The organic layer is separated, washed once more with water, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (2.80 g) as a pale yellow crystalline solid; LC-MS: tR=1.06 min, [M+1]=223.17; 1H NMR (CDCl3): δ 3.00 (t, J=7.0 Hz, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.26 (s, 2H), 1.51 (t, J=7.0 Hz, 2H), 0.95 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O[CH:20]([NH:22]C(=O)C)[CH3:21])(C)C>FC(F)(F)C(O)=O>[NH2:22][CH:20]([C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[OH:15])[CH3:21]
Reactant: CC(=O)NC(C)OC(C)C
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.06 g (10.0 mmol) of 3,5-di-tert-butylphenol in 10 mL of trifluoroacetic acid was added 1.6 g (11.0 mmol) of N-(1-isopropoxyethyl)acetamide and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layers were separated and then extracted with EtOAc. The organic layers were combined, dried (Na2SO4), filtered and evaporated in vacuo. The product was purified on a silica gel flash chromatogrohy column eluted with 0-25% EtOAc in CH2Cl2. Evaporation of the purified fraction and drying in vacuo afforded the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:16][C@H:17]3[CH2:54][N:20]4[C:21](=[O:53])[C@@H:22]([NH:45]C(=O)OC(C)(C)C)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]5[CH2:35][C@@:31]5([C:36](=[O:44])[NH:37][S:38]([CH:41]5[CH2:43][CH2:42]5)(=[O:40])=[O:39])[NH:32][C:33](=[O:34])[C@@H:19]4[CH2:18]3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]2[CH:55]=[CH:56][CH:57]=[CH:58][C:2]1=2.[ClH:59]>C(OCC)(=O)C.O1CCOCC1>[ClH:59].[NH2:45][C@@H:22]1[C:21](=[O:53])[N:20]2[CH2:54][C@H:17]([O:16][C:7]3[C:6]([C:5]4[S:1][C:2]5[CH:58]=[CH:57][CH:56]=[CH:55][C:3]=5[CH:4]=4)=[N:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[CH2:18][C@H:19]2[C:33](=[O:34])[NH:32][C@:31]2([C:36]([NH:37][S:38]([CH:41]3[CH2:42][CH2:43]3)(=[O:39])=[O:40])=[O:44])[CH2:35][C@H:30]2[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Agent: Cl
Agent: N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 18 (0.296 g, 0.357 mmol) was dissolved in a mixture of ethyl acetate (1.7 mL) and 4 N HCl in dioxane (1.7 mL) and stirred at room temperature for one hour. The mixture was then evaporated under reduced pressure to provide the title compound (0.262 mg, 96% yield).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][C:25]([CH3:38])([CH2:36][CH3:37])[C:26](=[O:35])[C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][NH:30]1)=[O:28]>C(Cl)Cl>[C:1]([N:30]1[CH:29]([C:27](=[O:28])[C:26](=[O:35])[C:25]([CH3:38])([CH3:24])[CH2:36][CH3:37])[CH2:34][CH2:33][CH2:32][NH:31]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a solution of 5-hexynoic acid (0.467 g, 4 mmol) in 10 ml CH2Cl2 was added triethylamine (0.56 ml, 4 mmol), followed by isobutyl chloroformate (0.53 ml, 4 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinyl pentane-1,2-dione (0.424 g, 2 mmol) in 1 ml CH2Cl2 was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.385 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, 3H, J=7.0); 1.26 (s, 6H); 1.76(m, 8H); 2.28 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 3.60 (m, 1H); 4.50 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1)#[N:15]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1cncs1
Agent: [Pb]
Product: CNC(=NCCSCc1cncs1)NC#N

Procedure:
The reaction of N-methyl-N'-[2-(5-thiazolylmethylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 3(b) gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1ccccn1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccn1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-pyridyl)acetate hydrochloride (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=123-125° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[CH3:15][NH2:16]>CO.[OH-].[Na+].C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([NH:16][CH3:15])=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CNC(=C[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture comprising 7.0 g of (tetrahydro-3-furanyl)methylamine, 12.5 g of 1,1-bis(methylthio)-2-nitroethylene and 100 ml of acetonitrile was refluxed for 5 hours. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) to give 6.6 g of 1-[{tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene. Then, a mixture comprising 4.0 g of the 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene obtained above, 6.0 ml of 40% methylamine in methanol solution, 20 ml of 1N aqueous sodium hydroxide solution and 20 ml of ethanol was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/methanol=9/1) to obtain 3.2 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylamino-2-nitroethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1([CH2:12][O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: ClCn1nnc2ccccc21
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCn1nnc2ccccc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (8.45 g, 54 mmol) is dissolved in DMF (100 ml) and after addition of 1-(chlormethyl)-1H-benzotriazole (9.96 g, 59.4 mmol) and K2CO3 (9.7 g, 70.2 mmol) the mixture is stirred at 45° C. for 1 h (TLC control). Then the mixture is evaporated under high vacuum. The residue is diluted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation gave 3.9 g of a colorless solid. The product is used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:5]1[CH2:16][C:15]2[C:7](=[CH:8][C:9]3[O:13][CH2:12][O:11][C:10]=3[CH:14]=2)[C:6]1=[O:17])C.CC([O-])=O.[Na+]>C(Cl)Cl.O>[Br:1][C:14]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[C:7]2[C:15]=1[CH2:16][CH:5]([CH3:3])[C:6]2=[O:17]
Reactant: CCC1Cc2cc3c(cc2C1=O)OCO3
Reactant: BrBr
Agent: CC(=O)O[Na]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc3c(c2Br)OCO3)C1=O
Reaction time: 24 h
Yield: 58 %

Procedure:
Br2 (11.42 ml, 221.44 mmol) was added dropwise at 0° C. into well stirred mixture of 6-ethyl-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (40.01 g, 210.37 mmol) solution in CH2Cl2 (93 ml) and NaOAc (35.32 g, 430 6 mmol) solution in water (62 ml). After 20 h of stirring at room temperature, 11.5 g of AcONa and 3.42 ml of Br2 (30% of starting amount) were added. This procedure was repeated after 24 h, the resulting mixture was stirred for additional 48 h. The resulting mixture was diluted by CH2Cl2 (200 ml), the organic layer was separated, washed with water (350 ml), dried over MgSO4 and evaporated. The residue was recrystallized from hexane-benzene (3:1) yielding 32.83 g (58%) of white-yellow solid.
Reaction SMILES: C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([C:28]([CH3:37])([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH3:29])(=[O:27])=[O:26])=[C:9]12)C1C=CC=CC=1.C(O)C.[H][H]>C1COCC1.[Pd]>[CH3:20][C:11]1([CH3:21])[N:10]2[N:22]=[CH:23][C:24]([S:25]([C:28]([CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH3:37])(=[O:27])=[O:26])=[C:9]2[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)(C)S(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)S(=O)(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To 0.075 g (0.146 mmol) of 8 dissolved in 6 mL of 1:1 THF:ethanol was added 0.10 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 2 h at room temperature, the catalyst was removed via filtration and the filtrate concentrated to give 0.056 g (91%) of the title compound as a white solid. MS Calcd.: 423. Found: 424 (M+H).
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[NH2:6][C@H:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:8]([OH:10])=[O:9]>CO>[ClH:4].[CH3:1][O:9][C:8](=[O:10])[C@H:7]([NH2:6])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)Cl
Reactant: N[C@@H](C(=O)O)C1CCCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)C1CCCCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of acetyl chloride (0.5 mL, 7.04 mmol) in MeOH (10 mL) at 0° C. is added (R)-amino-cyclohexyl-acetic acid hydrochloride (1.0 g, 5.16 mmol). The mixture is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature and concentrated. The resulting residue is triturated with Et2O to afford the title compound (1.0 g, 93%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][C:22](=[O:38])[N:23]2[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37].CI.Cl[C:42]1C=CC=CC=1C1C=C(O)C=C2C=1C=CC(=O)N2C1C(Cl)=CC=CC=1Cl>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[CH2:20][CH:21]([CH3:42])[C:22](=[O:38])[N:23]2[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(O)cc2n1-c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)C(C)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 1 mL of THF at −78° C. was added 130 μL of a 1M solution of lithium bis(trimethylsilyl)amide in THF, then a solution of 50 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxyquinolin-2(1H)-one (INTERMEDIATE 6) in 2 mL of THF dropwise. The mixture was stirred for 30 min at −78° C.; then 57 mg of methyl iodide was added dropwise. The mixture was stirred 10 min at −78° C., then removed from the bath and allowed to warm to rt. The reaction was quenched by addition of 100 μL of MeOH, then poured into 10 mL of water and extracted with 2×10 mL of CH2Cl2. The combined organics were washed with 10 mL of brine, dried (MgSO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-acetone, to yield a 1:1.5 mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxyquinolin-2(1H)-one and the title compound. Mass spectrum (ESI) 446 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[CH:24]=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc2cc(N)ccc2n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2n1
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (119 mg, 0.528 mmol) in dichloromethane (3 mL) was added pyridine (100 μL, 1.26 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoxaline (80 mg, 0.50 mmol) was added. The resulting mixture was stirred for 5 h. at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (161 mg, 92%), single spot at Rf 0.67 (ethyl acetate). mp 158.7-159.3° C., HPLC purity 99+% (tR 2.23 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.66 (1H, s), 8.02 (1H, d, J=7.7 Hz), 7.89 (1H, d, J=8.9 Hz), 7.61 (1H, d, J=2.5 Hz), 7.55 (1H, d, J=8.2 Hz), 7.46 (11H, dd, J=8.9, 2.5 Hz), 7.23 (1H, t, J=7.9 Hz), 7.08 (1H, s, N—H), 2.76 (3H, s), 2.71 (3H, s). LCMS: 346.11 (M−). FAB-MS (MH+, C16H14ClN3O2S): calcd 348.0573, found 348.0589.
Reaction SMILES: CC1O[C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCOCC>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1ccc2nc(C)oc(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1) mixture (760 mL) at 0° C. was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 mL, 1M in Et2O, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1N HCl (200 mL). The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was then dissolved in EtOH (400 mL) and 6N HCl (160 mL) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1N NaOH. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88% yield);
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:28][C:29]1[C:30]([F:43])=[C:31]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:33][CH:34]=1.Cl.ClC1C=C(NC2C3C(=CC(OC4CCNCC4)=C(OC)C=3)N=CN=2)C=CC=1F>>[ClH:1].[Br:28][C:29]1[C:30]([F:43])=[C:31]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Agent: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Agent: Cl
Product: COc1cc2c(Nc3cccc(Br)c3F)ncnc2cc1OC1CCNCC1

Procedure:
tert-Butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with tert-butyl (3-bromo-2-fluorophenyl)carbamate using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.85-2.1 (m, 2H), 2.1-2.32 (m, 2H), 3.0-3.35 (m, 4H), 4.02 (s, 3H), 4.83-5.0 (m, 1H), 7.3 (dd, 1H), 7.5-7.65 (m, 2H), 7.75 (dd, 1H), 8.45 (s, 1H), 8.8(s, 1H), 9.15 (bs, 2H), 11.86 (s, 1H); Mass Spectrum: (M+H)+ 447.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=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>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([F:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(F)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(F)c2)ccn(CC2CC2)c1=O
Yield: 28.4 %

Procedure:
To a solution of intermediate 15 (0.8 g, 2.55 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.58 g, 2.31 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.26 mg, 0.23 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1 (0.241 g, 30%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH3:43])=[C:37]([F:44])[CH:36]=3)(=[O:34])=[O:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[F:44][C:37]1[CH:36]=[C:35]([S:32]([N:29]2[CH2:30][CH2:31][N:26]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:22][CH:21]=3)(=[O:25])=[O:24])[CH2:27][CH2:28]2)(=[O:33])=[O:34])[CH:40]=[CH:39][C:38]=1[CH2:41][CH2:42][CH3:43]
Reactant: CCCc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)cc1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: CCCc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1F

Procedure:
In the manner given in Example 1C, 4-chloro-7-(trifluoromethyl)quinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-[(3-fluoro-4-propylphenyl)-sulfonyl]piperazine to give 1-[(3-fluoro-4-propylphenyl)sulfonyl]-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.