Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[C:3]([CH3:39])[CH:4]=2)[CH3:15])=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NS(C)(=O)=O)c(C)c4)c3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methanesulfonyl chloride (0.03 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. Methanesulfonyl chloride (0.03 ml) and triethylamine (36 mg) were further added thereto, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and the residue was dissolved in methanol. To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 3 hours at ambient temperature and concentrated. To the residue were added dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-(4-methanesulfonamido-3-methylcinnamoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (185 mg) as an amorphous powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[C:13]=1[Cl:14]
Reactant: OCCCCBr
Reactant: Oc1cccc(Cl)c1Cl
Product: Clc1cccc(OCCCCBr)c1Cl

Procedure:
This example was prepared by substituting 3-bromopropanol with 4-bromobutanol and substituting 1-naphthol with 2,3-dichlorophenol in EXAMPLE 31A.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[ClH:24]>O>[ClH:24].[ClH:24].[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1
Reactant: NCCCCCO
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Agent: Cl
Solvent: O
Product: O=c1[nH]c(NCCCCCO)ncc1Cc1cccnc1

Procedure:
2-Methylthio-5-(3-pyridylmethyl)-4-pyrimidone (23.3 g) and 5-aminopentanol (24.5 g) were fused together at 170°-180° for 2 hours. Water was added to the cooled residue and the mixture was adjusted to pH7 with dilute hydrochloric acid. The solid (23.8 g) which crystallised out was recrystallised from 2-propanol containing hydrogen chloride to give 2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidone dihydrochloride, m.p. 203°-205°.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2]1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH:26]([CH2:29][OH:30])[O:27][CH3:28]>>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH:26]([O:27][CH3:28])[CH2:29][O:30][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCC1CO1
Reactant: COC(CO)COC1CCCCO1
Product: CCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Yield: 53.2 %

Procedure:
The epoxide (9) (4.8 g, 20 mmoles) as obtained in Example 4-1 was reacted with 7.6 g (40 mmoles) of 2-methylglycerol monotetrahydropyranyl ether in the same manner as Example 1-2 to give 4.58 g (53.2%) of the desired compound (10).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:16]I.O>CO>[CH3:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccccc2)cc1

Procedure:
To a solution of 4-hydroxy-1,1'-biphenyl (34 g, 0.2 mol) and potassium hydroxide (20 g, 0.36 mol) in methanol (400 ml) and H20 (200 ml), methyl iodide (28.4 g, 0.2 mol) was added, and the resultant mixture was stirred for 4 hours under reflux. After cooling, the mixture was poured into H2O (1 l), the resultant precipitate was filtered, washed with H20 and recrystallized from ethanol to give the title compound as white crystals; yield;: 26.5 g; mp. 87.3°-87.7° C. ##STR41##
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=[O:40])[N:15]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=1)C.Cl.O>CO.[OH-].[Na+]>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:27])([F:28])[F:26])[CH:19]=2)[C:14]([C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40])=[CH:35][CH:34]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(OC(F)(F)F)c1)Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2cc(Cl)ccc2NCC(=O)O)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 33 mg of (2-{(4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-carbamoyl}-4-chloro-phenylamino)-acetic acid ethyl ester (0.06 mmol) in 0.5 ml methanol and 0.11 ml 1N aqueous NaOH was heated for 2 hours to 50° C. After cooling down to RT the mixture was neutralized with 0.11 ml 1N aqueous HCl, treated with a small amount of water, and extracted twice with ethylacetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 26 mg (79%) of the title compound as an off-white solid. MS (ISP) 563.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[ClH:19]>>[Cl:19][CH2:3][CH2:2][CH2:1][C:4](=[O:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(C1CC1)C(c1ccccc1)c1ccccc1
Reactant: Cl
Product: O=C(CCCCl)C(c1ccccc1)c1ccccc1

Procedure:
A mixture of 16 parts of 1-cyclopropyl-2,2-diphenylethanone and 300 parts of hydrochloric acid were stirred and refluxed for 4 hours. The reaction mixture was cooled and extracted with 2,2'-oxybispropane. The extract was washed with water and with a diluted sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 17 parts of 5-chloro-1,1-diphenyl-2-pentanone as a residue. (intermediate 3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([CH2:16][C:17]1[S:25][C:24]2[C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:22][C:21]([Cl:32])=[N:20][C:19]=2[CH:18]=1)[CH3:15])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:32].[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[S:25][C:17]([CH2:16][N:14]([CH3:15])[CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:18][C:19]=2[N:20]=1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 182.4 %

Procedure:
To a solution of 2-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg) in dichloromethane (10 mL) was added hydrogen chloride (3 mL of a 2.0 M solution in diethyl ether). The mixture was stirred at room temperature for 16 h and then reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrrolidin-2-ylmethyl-amine hydrochloride salt as a yellow solid (380 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:29])[CH:21]=1>>[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[C:22]([CH3:29])[CH:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(C)c(N)cc1OC
Product: COc1cc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar to Example 117 and isolated as a red solid (8 mg, 11%). 1H NMR (CDCl3): 9.69 (s, 1H), 8.74–8.68 (m, 2H), 7.56 (s, 1H), 7.43–7.39 (m, 1H), 6.84 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[CH2:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCc1ccc2nc(N)c3ccccc3c2c1
Reaction time: 18 h
Yield: 65.6 %

Procedure:
20.0 g (87.7 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 13.7 g (73.1 mmol) 2-bromo-4-butylaniline, 1.70 g (1.46 mmol) tetrakis(triphenylphosphine)palladium(0), and 27.2 g (198 mmol) potassium carbonate where refluxed in 400 mL toluene and 200 mL ethanol under N2 atmosphere for 20 h. HPLC and TLC revealed almost complete consumption of the aniline. An additional 1.8 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile was added and refluxed continued for an additional 18 h. The reaction mixture was cooled and passed through a filter. The solids were washed with ethyl acetate to remove organics from the collected base. The filtrate was then evaporated down and dried on silica. The sample was purified using silica gel chromatography with 100% ethyl acetate as the eluent. The product fractions were then evaporated down to a minimal amount and the product recrystallized from EtOAc/hexanes to give 12.0 g of the title compound as light yellow solids (65.9% yield, GC-MS confirmed).
Reaction SMILES: Br[C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:28])[N:13]([C:16]4[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=4[CH:25]([CH3:27])[CH3:26])[C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2.[Cu][C:30]#[N:31].O>CN1CCCC1=O>[C:30]([C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:28])[N:13]([C:16]4[C:17]([CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=[CH:20][C:21]=4[CH:22]([CH3:24])[CH3:23])[C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2)#[N:31]
Reactant: N#C[Cu]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(C#N)ccc(c23)C1=O
Yield: 71.8 %

Procedure:
24.8 g of 4-bromo-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide and 7.5 g of copper(I) cyanide in 150 ml of N-methylpyrrolidone were heated at 210° C. for 4 hours. After cooling, water was added to the reaction mixture, producing a precipitate. The precipitate was filtered off, washed and dried. Column chromatography of the precipitate on silica gel (eluent: dichloromethane) gave 15.6 g of 4-cyano-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide having a melting point of 291° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:21]([O-:24])(=[O:23])=O)[C:5]2[C:10]([C:11]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH+:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:26]([N:25]([CH2:30][CH3:29])[S:21]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]2[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:1][C:2]=2[CH:3]=1)(=[O:24])=[O:23])[CH3:27]
Reactant: O=C(Nc1c(O)cc(S(=O)(=O)[O-])c2ccccc12)c1ccccc1
Reactant: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1cc2oc(-c3ccccc3)nc2c2ccccc12
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A mixture of 3.43 g pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate and 10 ml thionyl chloride was refluxed for 3.5 hours. Toluene (20 ml) was added and the excess thionyl chloride was distilled off with toluene under reduced pressure. The solid residue was dissolved in 50 ml methylene chloride and 10 ml diethylamine was added portionwise while stirring. After 30 min, the reaction mixture was poured into 100 ml ice-water and extracted with 100 ml dichloromethane. The organic phase was separated, washed with water, and dried over sodium sulfate. Evaporation of the solvent gave 2.52 g N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide of high purity by NMR. Recrystallization from 95% ethanol gave an analytical sample, m.p. 157° C.
Reaction SMILES: CO.[Na].[CH3:4][SH:5].Br[C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]>O>[CH3:4][S:5][C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]
Reactant: CC(C)C(=O)C(C)(C)Br
Reactant: CS
Agent: [Na]
Solvent: CO
Solvent: O
Product: CSC(C)(C)C(=O)C(C)C

Procedure:
A solution of 200 ml. of methanol containing 9.2 g. (0.40 mole) sodium metal was cooled in an ice-bath and saturated with gaseous methyl mercaptan. To this was added 77.2 g. (0.40 mole) of 2-bromo-2,4-dimethylpentan-3-one at room temperature and the resulting mixture stirred for two hours. The reaction mixture was diluted with water, extracted with ethyl ether, the extracts washed with water, brine and dried over anhydrous sodium sulfate. The ether was evaporated and the residue distilled in vacuo to afford 50.4 g. of product, B.P. 76° (20 mm.).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[CH:15][C:12]=1[C:13]#[N:14].C(OCC)(=O)C.[ClH:28]>C(O)(=O)C>[Cl:28][C:11]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cl
Reactant: Cc1c(N)c(C#N)cc(F)c1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc(C#N)c1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (5.6 g) is added to conc. sulfuric acid (59 ml) at below 70° C. The mixture is heated at 70° C. for 10 minutes and then cooled, and thereto is added dropwise a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123 ml) at below 40° C. The mixture is stirred at the same temperature for 30 minutes and then added in portions to a solution of cuprous chloride (20 g) in conc. hydrochloric acid (200 ml), and thereafter is heated at 80° C. for 30 minutes. After cooling, to the reaction mixture is added ice water, and ethyl acetate is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=1:1) to give 2-chloro-4,5-difluoro-3-methylbenzonitrile (8.0 g), as a white crystal, m.p. 59°-61° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 197.8 %

Procedure:
(3,5-dihydroxy-phenyl)-acetic acid methyl ester (5 g, 27.4 mmol) in anhydrous DMF (20 mL) was treated with K2CO3 (11.4 g, 82.5 mmol) and benzyl bromide (6.5 mL, 55 mmol). The resultant mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the aqueous layer extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a brown solid (9.82 g, 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:27][C:23]1[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][CH:24]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Cc1cccc(O)c1
Product: COc1ccc2c(Oc3cccc(C)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methyl-phenol to give (6-methoxy-1-m-tolyloxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
6-Chloro-N4-(4-chlorophenyl)-pyrimidine-4,5-diamine I-(1A-1)a (34 g, 134 mmol) in pyridine (150 ml) was cooled to 0° C. and to it was added 2,4-dichlorobenzoyl chloride (25 ml, 178 mmol). The reaction was allowed to warm to ambient temperature overnight. The solid precipitate was collected by vacuum filtration and dried under high vacuum to yield the title compound I-(1A-1)b as a colorless solid (14 g, 25%). The pyridine solution was concentrated under reduced pressure and then triturated with methanol (500 ml) to provide additional material (35 g, 60%): +ESI MS (M+1) 427.4; 1H NMR: (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.16 (s, 1H), 8.38 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.75 (d, J=2.0 Hz, 2H), 7.64–7.60 (m, 3H), 7.40 (d, J=8.7 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CNC
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=O)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 4-fluoro-2-trifluoromethylbenzaldehyde (500 mg, 2.60 mmol), dimethylamine (5.5 mol/L in ethanol, 0.95 mL, 5.2 mmol), potassium carbonate (360 mg, 2.6 mmol) in 5.2 mL of N,N-dimethylformamide was stirred at 110° C. overnight in a sealed tube. After the reaction mixture was diluted with water, the solution was extracted with ether. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) to obtain the title compound as a pale yellow powder (393 mg, 70%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[S:28][C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]=3[S:19][C:11]=2[C:10]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:8]>>[CH3:5][O:6][C:7]([C:9]1[S:28][C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([N:20]([C:1](=[O:3])[CH3:2])[CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]=3[S:19][C:11]=2[C:10]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:8]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NCC3CCCCC3)cccc12
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N(CC3CCCCC3)C(C)=O)cccc12
Yield: 58 %

Procedure:
Step B Amide Formation: Addition of acetyl chloride (0.05 mL, 0.65 mmol) to 7-(Cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (60 mg, 0.13 mmol) was carried out following a procedure similar to that delineated in Step B, Example 27, affording 38 mg of 7-(Acetyl-cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as a yellow solid. (58% yield).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].[CH3:15][O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20].C[O-].[Na+]>CO>[CH3:15][O:16][C:17]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([F:13])([F:12])[F:11])=[N:2][O:1][C:19]=1[NH2:20])=[O:21]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1ccccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2C(F)(F)F)noc1N
Yield: 85.1 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-2-(trifluoromethyl)benzimidoyl chloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.14 g, 41.74 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (8.13 g, 28.42 mmol, 85%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH2:13])[CH2:7]2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=O>C(O)C.[Pd]>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][NH:13][CH:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)[CH3:20]
Reactant: CCOC(=O)C=O
Reactant: NC1CCc2c(F)cc(F)cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNC1CCc2c(F)cc(F)cc2C1
Yield: 85.1 %

Procedure:
A mixture of 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (6.0 g, 32.8 mmol), prepared as in Example 8, and ethyl glyoxylate (4.6 g, 36.0 mmol) in 300 mL of ethanol was hydrogenated over 10% palladium on carbon (0.75 g) for 10 hours. The mixture was filtered and concentrated by evaporation. Purification of the residue by column chromatography on silica gel (elution: 30% ethyl acetate/hexane) gave ethyl[(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]acetate (7.5 g, 27.9 mmol) as an oil.