Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH3:15])=[CH:10][CH:9]=1)[CH3:2].[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)C(N)(CO)CO.CS(Cl)(=O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([N:16]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[S:31]([CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:33])=[O:32])[CH3:15])=[CH:12][CH:13]=1)[CH3:23]
Reactant: CCN(CC)CCCOc1ccc(C(C)NCCN(C)C)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(C(C)N(CCN(C)C)S(=O)(=O)Cc2ccccc2)cc1
Reaction time: 4 h

Procedure:
To a 4 ml vial was placed N-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N′,N′-dimethyl-ethane-1,2-diamine (22 mg, 0.07 mmol), phenyl-methanesulfonyl chloride (27 mg, 0.14 mmol), PS-DMAP (93 mg, 1.48 mmol/g), and CH2Cl2 (1.5 ml). The vial was agitated by means of a lab quake shaker for 4 h. To the solution was added PS-Trisamine (100 mg, 3.3 mmol, 3.0 mmol/g) and the reaction was allowed to agitate overnight to scavenge excess methansulfonyl chloride. Filtration, washing with CH2Cl2 and concentrating afforded N-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N-(2-dimethylamino-ethyl)-C-phenyl-methanesulfonamide. Mass spec hit M+1, 476: LCMS>93% @ 230 nm and ELSD.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[C:3]=1[OH:9].CCO[C:13]([S-])=[S:14].[K+]>CCO>[Br:8][C:4]1[C:3]2[O:9][C:13]([SH:14])=[N:1][C:2]=2[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(Br)c1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Sc1nc2ccnc(Br)c2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.34 g (7.09 mmol) 4-amino-2-bromo-pyridin-3-ol are dissolved in 13 ml EtOH and 1.86 g (11.3 mmol) potassium ethyl xanthogenate are added. This mixture is stirred for 18 h at reflux temperature. After cooling to room temperature, the reaction mixture is concentrated in vacuo and 5 ml water are added. With the addition of acetic acid, a pH of 5 is adjusted. The product starts to crystallize and is filtered off, washed 2× with water and dried to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[CH2:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH3:17]>C1COCC1>[CH2:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH:27]([O:30][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH3:17]
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Reactant: CCC1CCC(C2CCC(O)CC2)CC1
Solvent: C1CCOC1
Product: CCC1CCC(C2CCC(OC(=O)C(F)(F)F)CC2)CC1

Procedure:
Trifluoroacetylbenzotriazole in an amount of 4.0 g (18.6 mmol) was dissolved in 50 ml of THF, 2.3 g (10.9 mmol) of 4-(4-ethylcyclohexyl)cyclohexanol was added thereto, they were subjected to a reflux for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=8/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 1.8 g (5.9 mmol) of trifluoroacetic acid 4-(4-ethylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-ethylcyclohexyl)cyclohexanol was 54%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH2:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[C:35]2[C:39]1[CH2:40][CH2:41]NCC=1)[CH3:29]>CS(C)=O>[CH2:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[C:35]2[CH2:39][CH:40]1[CH2:41][CH2:23][N:22]([CH2:12][CH:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)[CH2:21][CH2:20]1)[CH3:29]
Reactant: CCc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: CCc1cccc2c(CC3CCN(CC4COc5ccc6nc(C)ccc6c5O4)CC3)c[nH]c12
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.60 g, 1.6 mmole) and 7-ethyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.4 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform. The product fractions were concentrated in vacuum and the residue triturated with ether to give 0.16 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 85-90° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:36]([C:28]2[NH:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCNC(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure G: A mixture of N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1-isoquinolin-1-ylmethyl-butane-1,4-diamine (121 mg, 0.35 mmol), 1H-benzimidazole-2-carboxylic acid (70%, 97 mg, 0.42 mmol) (Eur. J. Med. Chem. 1993, 28, 71), HOBT (61 mg, 0.46 mmol), EDCI (91 mg, 0.46 mmol), and DIPEA (90 μL, 0.53 mmol) in DMF (5 mL) was stirred at room temperature overnight. Workup and purification gave the product as a pale yellow oil. (71 mg, 41%). 1H NMR (CDCl3) δ 1.40-1.47 (m, 2H), 1.56-1.63 (m, 2H), 2.06 (s, 3H), 2.25 (s, 3H), 2.62 (t, 2H, J=7.5 Hz), 3.30 (q, 2H, J=6.0 Hz), 3.81 (s, 2H), 4.18 (s, 2H), 7.21 (s, 1H), 7.30-7.33 (m, 2H), 7.49-7.55 (m, 3H), 7.70-7.75 (m, 3H), 7.99 (d, 1H, J=6.0 Hz), 8.21 (s, 1H), 8.40 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.32, 23.96, 27.56, 39.69, 53.84, 54.24, 59.72, 59.87, 112.7, 120.80, 120.88, 123.66, 125.22, 126.83, 127.24, 128.12, 130.18, 132.31, 133.15, 134.62, 136.64, 139.13, 141.77, 143.22, 145.43, 146.90, 154.28, 159.30, 159.68. ES-MS m/z 515 [M+H]+. Anal. Calcd. for C30H32N6O.1.6CH2Cl2: C, 60.39; H, 5.64; N, 13.37. Found: C, 60.20; H, 5.52; N, 13.54.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].[OH-].[Na+].O>CCOCC>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoroaniline (11.1 g, 100.0 mmol) in 100 ml of dry ether cooled in an ice bath is added ethyl chloroformate (7.1 ml, 8.1 g, 75.0 mmol). After addition, the mixture is allowed to warm to RT and is stirred at RT for 3 hours. Then a 10% sodium hydroxide solution (54 ml, 2.8M, 150.0 mmol) is added, followed by another 7.1 ml of ethyl chloroformate. The mixture is stirred at RT for 3 hours, and is then poured into water and ether. The organic layer is separated, washed with 5% HCl and with brine, and dried. The solvent is removed to give ethyl N-(2-fluorophenyl)carbamate.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:36]>O1CCOCC1>[ClH:36].[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(-c3cccc(C(F)(F)F)c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(-c3cccc(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a cooled solution of tert-butyl (S)-1-(2-((trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-ylcarbamate (400 mg) in dioxane (5 mL) at 0° C., HCl in 1,4 dioxane (5 mL) was added and stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated, residue was triturated with Et2O to get (S)-1-(2-((trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine hydrochloride (250 mg, 62%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([CH2:25]Cl)[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].O.O.[Na+].[CH3:33][N:34]([CH3:38])[C:35](=[S:37])[S-:36]>C(#N)C.O>[CH3:1][N:2]([CH3:29])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([CH2:25][S:37][C:35](=[S:36])[N:34]([CH3:38])[CH3:33])[N:24]=1)=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: COc1cc(CCl)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(CSC(=S)N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1

Procedure:
A mixture of 9.3 g of N-(2-dimethylsulfamoylphenylsulfonyl)-N'-(4-chloromethyl-6-methoxy-pyrimidin-2-yl)-urea and 3.7 g of dimethyldithiocarbamic acid sodium salt dihydrate is stirred in 100 ml of acetonitrile at 20°-25° C. for 3 hours. In further processing, the reaction mixture is diluted with 1 liter of water, and the precipitated product is separated. The yield is 10.0 g (91% of theory) of N-(2-dimethylsulfamoylphenyl-sulfonyl)-N'-(4-methoxy-6-dimethylthiocarbamoylthiomethyl-pyrimidin-2-yl)-urea m.p. 181°-183° C. (decomp.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20]>>[CH3:14][O:15][C:16](=[O:22])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCC(=O)CC(=O)OC
Product: CCC(=O)C(Cc1ccc(S(=O)(=O)CC)cc1)C(=O)OC

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-ethanesulfonylbenzene and 3-oxopentanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH:32]([C:42]#[CH:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][CH:34]=1.[OH-].[K+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH:32]([C:42]#[CH:43])[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][O:40][CH3:41])=[CH:37][CH:38]=1
Reactant: C#CC(c1ccc(COC)cc1)c1cc([C@@]2(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#CC(c1ccc(COC)cc1)c1cc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.11 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos1-yl)-2-(4-methoxymethylethynyl-benzyl)-benzene in 2 mL methanol is added 0.85 mL of 1 M aqueous potassium hydroxide solution. The solution is stirred for 1 h at ambient temperature and then diluted with ethyl acetate. The resulting solution is washed with brine and dried over sodium sulfate. The solvent is evaporated and the residue is filtered through silica gel (dichloromethane/methanol 9:1->2:1).
Reaction SMILES: [C:1](=[N:23]O)([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:21]O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:21][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:1]([NH2:23])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ON=C(c1ccccc1)c1ccc(C(=NO)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(C(N)c2ccccc2)cc1

Procedure:
The dioxime from Step 2 (30 g) is dissolved in ethyl alcohol (300 ml), saturated with ammonia gas and Raney nickel catalyst W-6 (2 g) added. The mixture is subjected to 700 psi hydrogen pressure and heated at 70° for three hours. The catalyst is removed by filtration and 220 ml of ethanol is removed by distillation. The pale yellow precipitate is filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH:8]=1)[CH3:2].[CH2:33]([SH:37])[CH2:34][CH2:35][SH:36].B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=3)[S:37][CH2:33][CH2:34][CH2:35][S:36]2)[CH:8]=1)[CH3:2]
Reactant: SCCCS
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1cccc(C2(c3cccc(CC(C)(C)C(=O)OCC)c3)SCCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (6.2 g, 14 mmol) in dichloromethane (100 mL) was added 1,3-propanedithiol (1.9 g, 17.5 mmol) and borontrifluoride etherate (0.52 mL) solution was stirred at room temperature overnight and 5% sodium hydroxide solution (17.5 mL) was added. The organic layer was separated, washed with water (50 mL), dried over sodium sulfate, and evaporated to afford 3-(3-{2-[3-(2-ethoxycarbonyl-2-methyl-propyl)-phenyl]-[1,3]dithian-2-yl}-phenyl)-2,2-dimethyl-propanoic acid ethyl ester (6.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3): δ (ppm): 7.58-6.96 (m, 8H), 4.10 (q, J=7.2 Hz, 4H), 2.85 (s, 4H), 2.76 (t, J=5.6 Hz, 4H), 1.98 (m, 2H), 1.25-1.14 (m, 18H). 13C NMR (75 MHz, CDCl3): δ (ppm): 177.2, 142.2, 138.1, 131.1, 129.3, 127.8, 127.3, 60.4, 46.2, 43.5, 29.4, 24.9, 24.5, 14.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:13]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]([CH2:36][C:37]([F:40])([F:39])[F:38])C(=O)OC(C)(C)C)[CH:23]=4)[O:20][CH:21]=3)=[O:16])=[CH:12][N:11]([CH3:41])[N:10]=2)[C:5]1=[O:42].Cl>C(OCC)(=O)C.CO>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:13]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:36][C:37]([F:38])([F:40])[F:39])[CH:23]=4)[O:20][CH:21]=3)=[O:16])=[CH:12][N:11]([CH3:41])[N:10]=2)[C:5]1=[O:42]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCN(CCO)C2=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2CCN(CCO)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of tert-butyl (4-(4-((3-(3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (1.00 g) and 3M hydrogen chloride in a mixed solvent (10 mL) of ethyl acetate/methanol (1:1) was stirred overnight at room temperature. The precipitate was collected by filtration, and the obtained solid was washed with ethyl acetate/methanol (9:1), and dried under reduced pressure. To the obtained solid were added 1N aqueous sodium hydroxide solution (2.39 ml) and water (4 ml), and the mixture was stirred at room temperature for 30 min, and then at 0° C. for 30 min. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (531 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13](=[O:16])[O:14][CH2:15][CH:8]1[CH2:7][CH2:6]2.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13](=[O:16])[O:14][CH2:15][CH:8]1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC1COC(=O)N21
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: O=C1OCC2CCc3cc(O)ccc3N12
Reaction time: 1 h

Procedure:
To a solution of 4.6 g (21 mmol) of 7-methoxy-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 50 ml of dichloromethane are added dropwise, at 0° C., 4.0 ml (42 mmol) of boron tribromide. After one hour, the medium is hydrolyzed by addition of aqueous ammonia to the point of neutrality. The precipitate formed is then filtered off and dried under vacuum.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH3:22]OC(=O)OC.CN(C)C=O>O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH3:22])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 76.3 %

Procedure:
A mixture of 0.5 g 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 0.8 g of dimethylcarbonate and 10 ml of dimethylformamide was reacted at 160° - 170° C in sealed-tube for 20 hours. After the reaction was finished, the solvent was distilled off from the mixture to leave a residue, to which was added water. This residue was extracted with ether and then dehydrated. The ether solution was applied on a column of alumina, and then eluted with ether. The ether was evaporated from the eluate and left to give 0.4 g of 1-(m-trifluoromethylphenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 122° - 124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[C:14]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2
Reactant: COc1cccc(OC)c1CCC#N
Reactant: Nc1ccc(F)cc1C=O
Product: COc1cccc(OC)c1Cc1cc2cc(F)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-fluorobenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: NCc1ccccc1Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CSc1nc(NCc2ccccc2Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
2-Chloro-5-nitro-4-thiocyanatopyrimidine (100 mg, 0.46 mmol) was suspended in 1 mL absolute EtOH. o-Bromobenzylamine hydrochloride (103 mg, 0.46 mmol) was dissolved in 1 mL absolute EtOH and added to the reaction quickly at ambient temperature. Then triethylamine (129 μL, 0.92 mmol) was added dropwise via syringe. The reaction was stirred 16 h at ambient temperature. The resulting precipitate was filtered providing 136 mg of the desired (2-bromo-benzyl)-(5-nitro-4-thiocyanato-pyrimidin-2-yl)-amine as a white solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].Cl.[CH3:21]O>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O:19][CH3:21])=[O:18]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc2c(c1)CCc1ccccc1S2

Procedure:
A solution of 950 mg. of 10,11-dihydrodibenzo[b.f]thiepin-2-acetic acid in 50 ml. of methanol is saturated with hydrogen chloride. After 2 hours the reaction mixture is evaporated under reduced pressure and the residue is chromatographed on silica gel using ethyl acetate:hexane (1:7) as eluant to yield methyl 10,11-dihydrodibenzo[b.f]-thiepin-2-acetate (XII, R1 = Me), which is dissolved in 10 ml. of benzene and treated with 900 mg. of 85% m-chloroperbenzoic acid dissolved in 10 ml. of dimethoxyethane. After 5 minutes, 3 ml. of saturated aqueous sodium sulfite is added, followed by 1 ml. of saturated aqueous potassium carbonate. The organic layer is separated, dried with anhydrous magnesium sulfate and filtered through a column of 20 g. of silica gel, eluting with benzene. Evaporation of the eluate under reduced pressure yields a residue which upon recrystallization from chloroform:hexane (1:1) yields 900 mg. of methyl 10,11-dihydrodibenzo[b.f]thiepin-2-acetate-S,S-dioxide (XV, R1 = Me), having a melting point of 103°-105° C.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:3]1[C:2]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Reactant: Cc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc(-c2cnc(Nc3ccccc3C)c(Cl)c2C#N)c1
Temperature: 180 °C

Procedure:
A mixture of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (50 mg, 0.179 mmol, from Step 3 of Example 128) and o-toluidine (384 mg, 3.58 mmol) in DMSO (1 mL) was heated to 180° C. under microwave for 1 h. LCMS and HPLC analysis indicated that the reaction was ˜25% complete. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with 1 N HCl (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Purification by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave 3-chloro-5-(3-methoxyphenyl)-2-(o-tolylamino)isonicotinonitrile as yellow solid, assumed as TFA salt (7 mg, 8% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1H, s), 7.38-7.54 (2H, m), 7.28-735 (1H, m), 7.15-7.27 (2H, m), 7.07-7.14 (2H, m), 6.97-7.05 (1H, m), 3.87 (3H, s), 2.27 (3H, s); MS (ES+) m/z: 350 (M+H); LC retention time: 3.848 min (analytical HPLC Method A).