Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:39])=[C:34](\[CH3:38])/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:39])=[C:34](\[CH3:38])/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C/C(C(=O)O)=C(/C)c1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(C(=O)Nc1ccccc1OCCCC(=O)O)=C(/C)c1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
0.84 g of compound 29 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.13 g of ethyl 4-(2-aminophenoxy)butyrate and 0.78 g of 3-(1-benzylindol-5-yl)-2-methylisocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([NH:17]C(=O)OCC3C=CC=CC=3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[C:7]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]=3[NH:15]2)=[CH:10][CH:11]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Temperature: 25 °C

Procedure:
A mixture of benzyl 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-ylcarbamate (Example 50-1, 400 mg, 0.882 mmol), 10% palladium on charcoal (94 mg, 0.088 mmol) and ammonium formate (334 mg, 5.29 mmol) in methanol (20 mL) was heated at reflux for 1 h. The mixture was cooled to rt, diluted with methanol and filtered through a Celite pad. The filtrate was concentrated to give 7-amino-4-(2-fluorophenyl)-9H-carbazole-1-carboxamide in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H) 8.11 (br. s., 1H) 7.78 (d, J=7.78 Hz, 1H) 7.51 (d, J=2.01 Hz, 2H) 7.35-7.47 (m, 3H) 6.93 (d, J=7.78 Hz, 1H) 6.79-6.84 (m, 1H) 6.72 (d, J=8.03 Hz, 1H) 6.24 (dd, J=8.41, 1.88 Hz, 1H) 5.22 (s, 2H). Mass spectrum m/z 320.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (2.04 mmol) and Boc-p-amino-L-phenylalanine (1.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 4:1 dichloro-methaneldimethylformamide reaction solvent, washed with base only). The product was purified by chromatography on silica gel eluted with 50, 60, 70 and 100% ethyl acetate in hexanes. Yield 226 mg, 42%; HPLC (70/30) 2.45 minutes (100%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([O:20]CC)=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>C(O)C>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A 3.37 g amount of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester (prepared as described in Ex. 22) was added to a solution of 1.4 g of potassium hydroxide in 100 ml of ethanol. This mixture was heated at reflux for 5 hours, cooled to room temperature and evaporated to dryness in vacuo. The residue was dissolved in water and the solution was neutralized to pH 7.0 with concentrated hydrochloric acid. The white precipitate formed was collected by filtration, washed with water and dried in vacuo to give 2.5 g of the desired product as a whtie solid, mp 175°-177° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[CH:24]1([C:20]2[CH:21]=[C:22]([CH3:23])[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[CH:4]=[CH:3][C:2]([N:27]5[CH2:31][CH2:30][CH2:29][C:28]5=[O:32])=[N:7][C:6]=4[CH3:8])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2C)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)nc2C)CC1

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 249 and pyrrolidin-2-one (41 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (137 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]12[CH:12]3[CH2:13][CH2:14][C:15]4([CH3:25])[C:19]5([O:24][C:22](=[O:23])[CH2:21][CH2:20]5)[CH2:18][CH2:17][CH:16]4[CH:11]3[CH:10]=[CH:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.CN1CCCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:45]([OH:48])(=[S:47])[CH3:46]>O.C(O)(=O)C>[CH3:46][C:45]([S:47][C@H:10]1[C@H:11]2[C@H:16]3[C@:15]([CH3:25])([CH2:14][CH2:13][C@@H:12]2[C@:2]2([CH3:1])[C:8](=[CH:7][C:5]([CH2:4][CH2:3]2)=[O:6])[CH2:9]1)[C@@:19]1([O:24][C:22](=[O:23])[CH2:21][CH2:20]1)[CH2:18][CH2:17]3)=[O:48]
Reactant: CC12CCC(=O)C=C1C=CC1C2CCC2(C)C1CCC21CCC(=O)O1
Reactant: CC(O)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@H]12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 5.00 g of 17-hydroxy-3-oxo-17α-pregna-4,6-diene- 21-carboxylic acid γ-lactone (99.5% purity, 14.6 mmole), 15 ml of N-methyl-2-pyrrolidone and 228 mg of p-toluene-sulfonic acid monohydrate was heated to 80° C. in a nitrogen atmosphere. Then 3.0 ml of thioacetic acid was added and the mixture was stirred for 2 hours. At a temperature of 80° C., 5 ml of acetic acid was added followed by dropwise addition of 15 ml of water over 5 minutes. After completion of the dropwise addition, the resulting mixture was gradually cooled to 30° C. over an hour and twenty minutes. During the cooling, the acetylthio derivative was precipitated from the solution. Subsequently a mixture of 16.5 ml of methanol and 15 ml of water was added dropwise over 12 minutes. After completion of the dropwise addition, the mixture was stirred at 30° C. for another hour and filtered. The collected cyrstals were washed twice each with 25 ml of an equal volume mixture of methanol and water, and dried at a reduced pressure at 70° C. Thus, 4.7951 g of dried pure spironolactone was obtained as crystals, m.p. 204.4°-206.3° C.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[O:15][CH3:16]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[CH:9][C:8]=1[O:15][CH3:16]
Reactant: COc1cc(C=O)ccc1F
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(F)c(OC)c1
Temperature: -40 °C
Yield: 89.7 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (68.20 g, 0.191 mol) in anhydrous THF (400 mL) cooled to −40° C. was added n-butyllithium (2.5 M in hexanes, 71.2 mL, 0.178 mol) via syringe over 15 min, at which point the characteristic yellow color of the phosphorus ylide persisted. The reaction mixture was warmed to −10° C. over 1 h to complete the reaction. The mixture was subsequently cooled to −30° C. and a solution of 4-fluoro-3-methoxybenzaldehyde (10.00 g, 63.64 mmol) in anhydrous THF (40 mL) was added via a cannula over 10 min. The resultant mixture was warmed to ambient temperature over 16 h. The reaction was quenched by gradual addition of water (200 mL) and the aqueous extracted with diethyl ether (3×200 mL). The combined organic layers were washed with water (2×200 mL), brine (200 mL), dried (MgSO4) and concentrated under reduced pressure to give 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE II.1) (8.69 g, 57.1 mmol, 90%) as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=2[N+:13]([O-])=O)[CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([NH:4][C:5]2[C:6]([NH2:13])=[CH:7][C:8]([F:12])=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1NC1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the title compound from Step A (1.22 g, 5.69 mmol) were added 10% palladium on carbon (0.122 g, 1.15 mmol) and methanol (28.5 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was then filtered through CELITE® using dichloromethane, and the filtrate was concentrated. Purification by flash chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 6.83 (dd, J=12.4, 7.9 Hz, 1 H), 6.51 (dd, J=11.3, 7.8 Hz, 1 H), 3.82 (br s, 1 H), 3.15 (br s, 2 H), 2.40-2.37 (m, 1 H), 0.77-0.73 (m, 2 H), 0.52-0.50 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:3]=1.C(O)CCCCC.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>>[CH2:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1CNCCN1
Reactant: CCCCCCOc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCO
Product: CCCCCCOc1cncc(N2CCNCC2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-(n-hexyloxy)pyrazine (1.54 g, 7.17 mmol; obtained according to the procedure of example 50, step 1, starting from n-hexanol), piperazine (1.90 g, 22.1 mmol) and K2CO3 (0.99 g, 7.16 mmol). The yield of the title compound was 1.21 g (64%) which was obtained as a colorless oil. HRMS m/z calcd for C14H24N4O (M)+ 264.1950, found 264.1953. Anal. (C14H24N4O) C, H, N.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:29].C([O-])(O)=O.[Na+]>>[CH3:19][C:16]1([CH3:20])[O:15][CH:14]([CH2:13][N:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:29])[C:7]2=[O:12])[CH2:18][O:17]1
Reactant: I
Reactant: CC1(C)OCC(Cn2ccc3c(N)cccc3c2=O)O1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)OCC(Cn2ccc3c(I)cccc3c2=O)O1
Reaction time: 1 h

Procedure:
5-Amino-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)isoquinolin-1(2H)-one (4.2 g, 0.015 mol) was added to a solution of sodium nitrite (4 g, 0.06 mol) in dimethyl sulfoxide (80 mL, 1 mol) at 35° C. Aqueous hydrogen iodide (8 mL, 0.06 mol) in dimethyl sulfoxide (80 mL, 1 mol) was added, and the reaction mixture was stirred for 1 hour. The cooled reaction mixture was neutralized with sat. aq. NaHCO3 and extracted with methylene chloride (3×50 mL). The combined methylene chloride extracts were washed with brine, dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified via flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane) to give a light yellow solid. MS m/z (M+H) 385.6
Reaction SMILES: [C:1]([C:3]([CH3:16])([CH3:15])[C:4](=[O:14])[CH:5]([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:2].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[C:1]([C:3]([CH3:15])([CH3:16])[CH:4]([OH:14])[CH:5]([CH3:13])[C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])#[N:2]
Reactant: CC(C(=O)OC(C)(C)C)C(=O)C(C)(C)C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CC(C(=O)OC(C)(C)C)C(O)C(C)(C)C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-cyano-2,4-dimethyl-3-oxopentanoate (400 mg, 1.775 mmol) obtained in Example 12 was diluted with methanol (5 mL) and cooled to 0° C. Sodium borohydride (20 mg, 0.53 mmol) was added. The mixture was stirred at 0° C. for 10 min and 10% aqueous hydrochloric acid solution (0.5 mL) was added. The mixture was further stirred for 10 min. Aqueous saturated sodium hydrogencarbonate solution (2 mL) was added and the mixture was further stirred for 10 min.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(Br)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 0.61 ml of 3-bromoaniline in place of the 2-fluoroaniline. 105 mg of N-(3-bromophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:32])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:45][C:46]1[NH:50][N:49]=[N:48][N:47]=1>CN(C=O)C.C(#N)C>[Br:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:45][C:46]4[NH:50][N:49]=[N:48][N:47]=4)=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:32])[CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(C)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCC[C@H](c1ccc(C(=O)Nc2nnn[nH]2)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoic acid (25.0 mg, 0.047 mmol) and CDI (26 mg, 0.16 mmol) in DMF (1.0 mL) was stirred at RT for 30 minutes in a sealed tube, then 5-amino-1H-tetrazole (23.0 mg, 0.260 mmol) was added. The mixture was heated at 100° C. for 12 hours, allowed to cool to RT, then diluted with acetonitrile. The mixture was purified by preparative reverse phase HPLC eluting with 47-100% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.98 (br, 1H); 7.91 (d, J=8 Hz, 2H); 7.84 (br, 1H); 7.65 (d, J=8 Hz, 2H); 7.61 (d, J=8 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 7.35 (br, 1H); 4.88 (d, J=12 Hz, 1H); 3.79 (t, J=11 Hz, 1H); 2.41 (s, 3H); 1.50-1.52 (m, 1H); 1.23-1.30 (m, 1H); 0.92 (q, J=7 Hz, 2H); 0.68 (t, J=7 Hz, 3H). LC2: 2.70 min. (M+H)+ 594.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1C.[C:12]([Cl:16])(Cl)([Cl:14])[Cl:13]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([C:12]([Cl:16])([Cl:14])[Cl:13])=[C:2]([Cl:1])[CH:7]=1)([O-:10])=[O:9]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Product: O=[N+]([O-])c1ccc(C(Cl)(Cl)Cl)c(Cl)c1
Yield: 99.2 %

Procedure:
2-Chloro-4-nitrotoluene (2.19 g, 0.0128 mole) and dichloride monoxide (4.46 g, 0.0513 mole) in carbon tetrachloride (50 ml) were heated at 75°/18 hrs following the procedure described in Example 6. The product was dried and the solvent removed to give 1-nitro-3-chloro-4-trichloromethylbenzene (3.49 g, purity by HPLC 99.40%, yield 99.2%) as a pale yellow oil. The product was distikled in a short path still (bp 82-85/2μ) to give a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>CN(C=O)C.N1C=CC=CC=1>[NH2:24][C:25]1[C:26]([C:27](=[O:28])[NH2:29])=[CH:30][CH:31]=[CH:32][C:33]=1[NH:34][C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc(NC(=O)c2cc(Cl)nnc2Cl)c1N
Temperature: 50 °C

Procedure:
3,6-Dichloropyridazine-4-carboxylic acid (1.15 g, 5.96 mmol) and 1,1′-carbonyldiimidazole (CDI (0.97 g) in DMF (25 ml) were stirred at room temperature for 2 h. A solution of 2,3-diaminobenzamide (1.30 g, 5.96 mmol) in pyridine (25 ml) was added and the solution heated at 50° C. for 4 h. The cooled solution was concentrated and partitioned between ethyl acetate (EtOAc) and water, the organic layer separated, dried, filtered and concentrated to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (42 mg, 32%). MS (ISP) 517.0 [(M+H)+]; mp 231-232° C.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].F[C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C>CN(C=O)C>[CH:2]([S:4][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([CH3:3])[CH3:1]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Isopropylthiol (3.06 mL, 32.8 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid (5.06 g, 27.3 mmol) and triethylamine (8.4 mL, 60.3 mmol) in DMF (86 mL). The reaction mixture was stirred overnight at rt and then most of the DMF was removed in vacuo. The residual solution was poured into ice water (500 mL) and the resulting yellow solid was isolated by filtration to give 16A (6.5 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2I.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1
Reactant: Brc1ccc2nccc(I)c2c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1ccc2nccc(-c3cn[nH]c3)c2c1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of 6-bromo-4-iodoquinoline (1.37 g, 4 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (852 mg, 4 mmol), dichloro-[1,1′bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane adduct (162 mg, 0.2 mmol), 2 M potassium carbonate (6 mL), in dioxane (25 mL) was heated at 100° C. for 1.5 h and cooled to room temperature. The dioxane and water were separated and the dioxane evaporated to get the crude product which was purified on silica gel eluting with ethyl acetate/methanol, 0-3% methanol. A yield of the title compound (340 mg, 34%) was obtained. MS (ES)+ m/e 275 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][S:26][CH2:27]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:25][S:26][CH3:27])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSCCl
Reactant: O=C1Nc2c(Cl)ccc(O)c2C2(CCCCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCOc1ccc(Cl)c2c1C1(CCCCC1)NC(=O)N2
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 8′-chloro-5′-hydroxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one, which can be prepared according to processes disclosed in example 63 of PCT/EP02/03594 (6 g, 2.25 mmol) in dimethylformamide (6 mL) was added potassium carbonate (0.776 g, 5.6 mmol) and chloromethyl methyl sulfide (0.26 mL, 2.7 mmol). The mixture was stirred in a sealed tube at 100° C. for 3 days. Dimethylformamide was removed by evaporation in vacuo. Water was added to the residue and the aqueous layer was extracted twice with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:37]#[CH:38].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:38]#[C:37][C:31]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=3[Cl:29])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Reactant: C#Cc1cc(Cl)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4cc(Cl)ccc4Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 36 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 by using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.060 g, 0.10 mmol), 1,4-dichloro-2-ethynylbenzene (Intermediate-23, 0.026 g, 0.15 mmol), TBAF (0.064 g, 0.20 mmol), bis(triphenylphosphine)palladium(II) chloride (0.064 g, 0.20 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=5.7 Hz, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.57-7.69 (m, 5H), 7.86-7.94 (m, 2H), 8.68 (m, 1H), 12.45 (br s, 1H); MS (m/z): 557.05 (M+H+).