Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24](=[O:26])[CH:25]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 32 %

Procedure:
Further, in a nitrogen atmosphere, 3′,5′-bis(trifluoromethyl)-2-aminobenzophenone (1.1 g, 3.3 mmol) was dissolved in toluene (13 mL), and acetic anhydride (0.62 mL, 6.5 mL) was added to the solution at room temperature, followed by stirring while heating and refluxing. The mixture was cooled to room temperature and then concentrated using a rotary evaporator. The residue was dissolved in ethylene glycol dimethyl ether (13 mL), and potassium tert-butoxide (1.5 mL, 13 mmol) was added to the solution at room temperature, followed by stirring for 2 hours. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was dried and then concentrated using a rotary evaporator. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). Thus, 4-{3,5-bis(trifluoromethyl)phenyl}-2-quinolinone (372 mg, 1.04 mmol) was obtained in a yield of 32%.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH:16][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC2CCC(C1)N2Cc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)NC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of amine 100 (2.70 g, 12.48 mmol) in CH2Cl2 (13 mL), was added 1M Na2CO3 (19 mL, 18.72 mmol, 1.5 equiv). The mixture was cooled to 0° C. and isobutyryl chloride (1.6 mL, 14.98 mmol, 1.2 equiv) was added dropwise with stirring over 30 min. The resulting mixture was warmed to room temperature and allowed to stir for 2 h after which time the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with 1N NaOH (2×20 mL), then with H2O (2×20 mL), then dried over MgSO4, filtered, and concentrated in vacuo to yield amide 101 (3.3 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccn(CCCO)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (56 mg, 57%) as a colorless oil: [α]30589=−20.0° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.34-1.80 (m, 8H, 4×CH2), 1.79-1.91 (m, 2H, CH2), 2.03-2.21 (m, 1H, CH), 3.29-3.38 (m, 2H, OCH2), 3.84-3.93 (m, 1H, ArCH), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.55 (t, J=5.0 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.74 (m, 4H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]3)=[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:3]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCc2c(cc(NS(=O)(=O)c3ccc(Cl)cc3)cc2-c2ccccc2Cl)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (80 mgs, 0.2 mmoles) was stirred in dichloromethane (12 mls) and triethylamine (80 ul, 0.58 mmoles) was added, followed by 4-chlorobenzenesulphonyl chloride (75 mgs, 0.36 mmoles). The reaction was flushed with nitrogen and left stirring at room temperature overnight. The reaction was purified by semi-preparative C18 HPLC (47 mgs, 44% yield, 100% pure, CO-AAW00034).
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1.N1CC[O:22]CC1.[F:25][C:26]([F:30])=[C:27](F)F.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:25][CH:26]([F:30])[C:27]([N:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1)=[O:22]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)F
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride (1.47 g, 5.0 mmol) and morpholine (1.57 g, 18.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.7 liter/hr), with vigorous stirring at 60° C. for 2 hours. After cooling to an ambient temperature, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution (100 ml), and extracted twice with toluene (100 ml×2). The toluene layer was washed twice with 5% hydrochloric acid (50 ml×2) and water (70 ml) and then brine (70 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.47 g, 4.4 mmol, yield 87%).
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH2:3][CH2:4][N:5]([C:13](=[O:30])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:16][CH:15]=1)[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12.Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C>CO>[CH3:32][N:33]([CH3:34])[C@@H:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:30])[C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][CH:19]=2)[CH2:4][CH2:3][C@H:2]1[OH:1]
Reactant: CNC
Reactant: O=C(Nc1ccc(C(=O)N2CCC3OC3c3ccccc32)cc1)c1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)[C@@H]1c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)CC[C@H]1O
Yield: 68.6 %

Procedure:
A mixture of 4,5-epoxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g), dimethylamine hydrochloride (2.6 g), triethylamine (4.5 g) and methanol (15 ml) is refluxed for 19 hours. After completion of the reaction, the solvent is distilled off and the resulting residue is dissolved in dichloromethane. The mixture is washed successively with water and saturated saline solution. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from ethanol/diethyl ether to give trans-5-dimethylamino-4-hydroxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless needles, m.p. 180°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:13]([O:14][CH2:15][CH2:16][O:17]C2CCCCO2)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:24]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:24][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:14][CH2:15][CH2:16][OH:17])[C:6]=1[O:5][C:4]1[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=1[O:2][CH3:1])[C:10]#[N:11]
Reactant: COc1ccccc1Oc1c(OCCOC2CCCCO2)cc(C#N)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccccc1Oc1c(N)cc(C#N)cc1OCCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.5 g of 4-(2-methoxy-phenoxy)-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzonitrile were dissolved in ethanol (100 ml), a solution of tin dichloride dihydrate (7.6 g) in 37% HCl (17 ml) was added dropwise thereto at room temperature and the mixture was subsequently stirred at room temperature for 12 hours. The mixture was poured on to ice-water, adjusted to pH 7 and the product was extracted with ethyl acetate. After usual processing of the organic phase there was obtained 3-amino-5-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-benzonitrile as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:18](OCC)=[O:19])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1.[AlH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:18][OH:19])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of ethyl 6-chloro-1-(3-fluorophenyl)-1H-indole-2-carboxylate (0.60 g, 1.9 mmol) in tetrahydrofuran (10 mL) was cooled at −78° C. Lithium tetrahydroaluminate (1 M) in tetrahydrofuran (6.0 mL, 6.0 mmol) was added dropwise and the resulting mixture was stirred at this temperature for 1 hour. The reaction was quenched by the addition of water (0.12 mL) and stirred for 10 minutes, warmed up to room temperature, followed by the addition of 5% aqueous NaOH solution (0.12 mL) with stirring for 10 minutes. Then additional water (0.36 mL) was added and stirring was continued for 10 minutes. The mixture was filtered, dried over MgSO4 and concentrated to give the crude product (0.53 g). The residue was used in the next step directly. LCMS calculated for C15H12ClFNO(M+H)+: m/z=276.1. Found: 276.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.CCCCC>[Cl:1][C:2]1[C:11]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1c(Cl)ccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: CCCCC
Product: O=S(=O)(Nc1c(Cl)ccc2cccnc12)c1ccccc1
Yield: 61.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-chloroquinolin-8-amine (Intermediate 52) (100 mg, 0.56 mmol), benzenesulfonyl chloride (110 mg, 0.67 mmol) and DMAP (cat.) gave the title compound (110 mg, 56%) after trituration from n-pentane.
Reaction SMILES: [NH2:1][C:2]1[C:11]([SH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:3]=1[F:21].[CH3:22]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:21][C:3]1[C:2]2[N:1]=[CH:22][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F
Solvent: O
Solvent: COC(OC)OC
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate in trimethyl orthoformate (50 mL) was added p-TsOH (0.61 g, 3.17 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (pale yellow solid, 8.64 g, 85.1% yield for two steps). 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.92 (s, 2H), 3.97 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[CH2:8])[C:6]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:5][C:4]1=[O:14])[CH3:2].C(N(CC)CC)C.[I-].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>C(C(C)=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:32][CH2:33][CH2:34][N:11]2[CH2:12][CH2:13][C:6]3([O:5][C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:7]3=[CH2:8])[CH2:9][CH2:10]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Reactant: C=C1N(CC)C(=O)OC12CCNCC2
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: C=C1N(CC)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 15 h
Yield: 68.7 %

Procedure:
A mixture containing 7.8 g of 3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 8.5 ml of anhydrous triethylamine, 80 ml of anhydrous methyl ethyl ketone, 3.0 g of potassium iodide and 16.7 g of 4,4-bis(4-fluorophenyl)-3-butenyl chloride is refluxed under nitrogen while stirring for 15 hours, then the solvent is distilled off under reduced pressure. After adding benzene and water to the residue, the benzene layer is washed with water to neutral, dried over anhydrous magnesium sulfate, filtered through an aluminum oxide bed and evaporated under reduced pressure. After recrystallizing the residue from ethanol, the title product is obtained in 68.7% yield, m.p.: 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19](OCC)=[O:20])=[C:5]2[OH:24].C(N(C(C)C)C(C)C)C.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:18])[C:6]([C:19]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:20])=[C:5]2[OH:24]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
Ethyl 6,7-dichloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (550 mg, 1482 μmol) was dissolved in 1,4-dioxane (1482 μL), and N-ethyl-N-isopropylpropan-2-amine (774 μL, 4445 μmol). tert-Butyl 2-aminoacetate hydrochloride (373 mg, 2222 μmol) was added to the reaction, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (350 mg) as a white solid after flash chromatography. MS (m/z)=456 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:17][C:18]3[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO.C[O-].[Na+:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([S:17][C:18]3[N:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[N:23]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+:32]
Reactant: COc1cc(OC)nc(Sc2nccc(-c3ccc(Cl)cc3)c2C(=O)O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1cc(OC)nc(Sc2nccc(-c3ccc(Cl)cc3)c2C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 0.50 g (0.0012 mol) of 4-(4-chlorophenyl)-2-(4,6-dimethoxylpyrimidin-2ylthio)nicotinic acid in 7 ml of ethanol was added 0.30 g (0.0016 mol) of methanol solution of 28% sodium methylate at room temperature. After addition, the mixture was further stirred at room temperature for 20 minutes. The crystal thus precipitated was filtrated, and washed with ethanol and dried to obtain 0.46 g of a white powder of the aimed product.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]([N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:7][CH2:8][CH2:9]2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1cccc(Cl)c1)N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
Pyridine (25 ml) was added to a mixture of 3,4-dihydro-2H-1,4-benzoxazine (17.8 g) in DCM (200 ml). The mixture was cooled on an ice bath and poured out into a mixture of m-chloro-cinnamoyl chloride (33 g) in DCM (100 ml). The mixture was stirred at room temperature overnight. Water was added and the mixture was decanted. The organic layer was dried, filtered and the solvent was evaporated till dryness, to give a residue which was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate 80/20) and recrystallisation from ACN/diethyl ether, yielding 26 g (65.8%) of 4-[3-(3-chlorophenyl)-1-oxo-2-propen-1-yl]-2,3-dihydro-4H-1,4-benzoxazine (interm. 51).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.024 g, 24%). MP: 69-79° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.50 (s, 1H), 8.55 (d, 1H, J=8.3 Hz), 8.15 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H, J=7.8 Hz), 7.63-7.57 (m, 1H), 7.50 (s, 1H), 7.29-7.23 (m, 1H), 6.64 (s, 1H), 3.87 (s, 3H), 3.31-3.20 (m, 1H), 2.90-2.68 (m, 10H), 1.69 (t, 3H, J=18.7 Hz), 1.32 (d, 6H, J=6.8 Hz). MS: 580.48 (MH)+.
Reaction SMILES: [C:1]1([N:7]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[C:14]([CH3:26])=[CH:13]3)=[O:9])[CH:6]=CC=[CH:3][CH:2]=1.BrN1C(=O)C[CH2:36][C:35]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[NH2:53][C:54]1[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=1>C(Cl)(Cl)(Cl)Cl>[C:1]1([N:7]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH2:26][NH:53][C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)=[CH:13]3)=[O:9])[CH:2]=[CH:3][CH:36]=[CH:35][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCN(C(=O)c1ccc2[nH]c(CNc3ccc(C#N)cc3)cc2c1)c1ccccc1

Procedure:
3.5 g (8 mmol) of 1-tert.butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were dissolved in 80 ml of carbon tetrachloride, mixed with 1.5 g (8.4 mmol) of N-bromo-succinimide and 20 mg of azobisisobutyronitrile and refluxed for 2.5 hours. Then the still warm solution was filtered, the filtrate obtained was washed with saturated sodium hydrogen carbonate solution and dried with sodium sulphate. After distillation of the solvent the crude product was dissolved in 30 ml of N-ethyl-diisopropylamine, mixed with 1.0 g (8 mmol) of 4-aminobenzonitrile and refluxed for 2.5 hours. The solvent was distilled off in vacuo and the residue obtained was purified by chromatography (silica gel; ethyl acetate/petroleum ether=1:4 to 1:1). Yield: 1.1 g (30% of theory), Rf value: 0.21 (silica gel; ethyl acetate/petroleum ether=1:1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[C:11]([CH2:16][OH:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:4][CH:3]=1.P(=O)(O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:16][O:17]2)=[CH:6][CH:7]=1
Reactant: OCc1ccccc1C(O)c1ccc(F)cc1
Agent: O=P(O)(O)O
Product: Fc1ccc(C2OCc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 200 parts of α-(4-fluorophenyl)-1,2-benzenedimethanol and 2295 parts of phosphoric acid 60% was stirred for 3 hours at 100° C. Stirring was continued overnight at room temperature. The reaction mixture was poured onto water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, with a 10% sodium carbonate solution and again with water, dried, filtered and evaporated. The residue was distilled, yielding 57 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; bp. 108° C. at 0.2 mm. pressure (intermediate 92).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]OC(OC)N(C)C>CC#N>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CNC(=N)NC(=O)Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CC#N
Product: CNc1ncn(-c2c(Cl)cccc2Cl)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred suspension of 11.88 g (40 mmol) of 1-(2,6-dichlorophenyl)-3-methylamidinourea hydrochloride in 30 ml of CH3CN was added 9.52 g (80 mmol) of N,N-dimethylformamide dimethylacetal in 20 ml of CH3CN. The solid material began to dissolve immediately but in a few minutes, before the starting material had dissolved, another fine white solid began to precipitate out. The reaction mixture was stirred at ambient temperature for one hour then heated to reflux for two hours. After two hours, the reaction mixture was allowed to come to ambient temperature and the white solid precipitate filtered out to yield the desired product, melting point 270° C.; TLC (EtoAc 9:1); one major spot, one minor spot at origin. A small sample recrystallized from CH3OH/EtOAc gave one spot on TLC. (9.6 g, 89%) was crystallized from MeOH to yield 1-(2,6-dichlorophenyl)-4-methylaminodihydro-s-triazin-2-one.