Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[C:3]=1[Cl:12].[C:13]([NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([NH:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:32])[CH2:31][CH2:30]2)=[O:8])=[C:4]([F:11])[C:3]=1[Cl:12]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)c(F)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3F)CC2)c1
Reaction time: 2 h
Yield: 46 %

Procedure:
To 4-amino-3-chloro-2-fluorobenzoic acid (0.754 mmol, 143 mg), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (0.754 mmol, 208 mg) and triethylamine (3.02 mmol, 0.421 ml, 305 mg) in dichloromethane (8 mL) was added 1-propanephosphonic acid cyclic anhydride (1.886 mmol, 1.117 mL, 1200 mg, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added. The organic solution was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography to yield the title compound (155 mg).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC(C)=CC=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([CH3:24])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Product: Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 68 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (80 mg, 0.34 mmol), triethyl orthoformate (0.65 ml), p-toluidine (67.5 mg, 0.63 mmol), and acetic acid (0.08 ml) were used to give 73.8 mg (0.23 mmol, 68% yield) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][NH:37][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCN(C(=O)OC(C)(C)C)CC4)ncc3C)sc2c1
Temperature: 95 °C
Yield: 43.2 %

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (400 mg, 1.20 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (688 mg, 3.01 mmol) and diisopropylethylamine (467 mg, 3.61 mmol) in 1,4-dioxane (4 mL) is heated at 95° C. under nitrogen for 3 days. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-35%, to give 4-{2-[5-methyl-4-(6-methylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid (264 mg, 43% yield). The intermediate is subjected to deprotection by dissolving this material (264 mg, 0.518 mmol) in MeOH (12 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (246 mg, 98% yield). ES+(m/z) 410 [M(free base)+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:25][N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][N:28]=[CH:27]1.Cl.CN(C)CCCN=C=NCC.SC1SC2C=CC=CC=2N=1.C(N(CC)CC)C>C(#N)C>[C:12]1([S:9]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2[CH:3]=[C:2]([NH:1][C:31]([C:30]3[N:26]([CH3:25])[CH:27]=[N:28][CH:29]=3)=[O:32])[CH:7]=[CH:6][CH:5]=2)(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Reactant: Cn1cncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Sc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cncc1C(=O)Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1

Procedure:
A solution of N-(3-amino-phenyl)-N-benzyl-benzene sulfonamide (25 mg, 0.07 mmol), 3-methyl-3H-imidazole-4-carboxylic acid (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol), mercaptobenzothiazole (2 mg, 0.007 mmol) and triethylamine (25 μl, 0.18 mmol) in dry acetonitrile (1 ml) were stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (10 ml), extracted with dichloromethane (3×7 ml) and the combined organics concentrated in vacuo. The crude residue was purified by preparative TLC (SiO2) eluting with ethyl acetate/dichloromethane (1:1) to afford the title compound as an off white solid (2.8 mg, 8%). HPLC retention time 5.6 min. Mass spectrum (ES+) m/z 447 (M+H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Br:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>CCOCC>[Br-:28].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of triphenylphosphine (15.34 g) in Et2O (150 mL) is added 4-nitrobenzylbromide (12.96 g). The solution is allowed to stir overnight and the resulting solid is filtered and dried to yield 10.95 g of (4-nitrobenzyl)(triphenyl)phosphonium bromide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:15])([CH3:14])[NH:12][C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH3:15])([CH3:14])[N:12]([CH3:37])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)N(C)C2(C)C)cc1
Reaction time: 4 h
Yield: 30.8 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (150 mg, 0.35 mmol) in DMF (10 mL) were added NaH (15 mg, 0.7 mmol) and CH3I (100 mg, 0.7 mmol) at 0° C. under an inert atmosphere. The mixture was then stirred for 4 h, diluted with cold water and filtered. The resulting residue was dried to afford 4-(4-methoxyphenyl)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (50 mg, 37%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.04 (d, J=7.2 Hz, 1H), 8.02-7.98 (m, 2H), 7.81-7.78 (m, 1H), 7.62-7.58 (m, 2H), 7.31-7.28 (m, 2H), 7.19-7.16 (m, 2H), 6.99-6.84 (m, 4H), 5.36 (s, 2H), 3.89 (s, 3H), 2.96 (s, 3H), 1.24 (s, 6H). MS: M+H: m/z=465.2; M+Na: m/z=487.2. HPLC: 92%, (Condition-I).
Reaction SMILES: [C:1]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]([C:31]([O:33]C)=[O:32])=[C:29]([Cl:35])[N:28]=[C:27]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=1)(=[O:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]([Cl:35])[N:28]=[C:27]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=1)(=[O:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
To a stirred suspension of 1-((2'-((benzoylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (25 mg, 0.044 mmol) in methanol (1.0 ml) was added 2N sodium hydroxide solution (0.50 ml). The pale yellow solution was stirred at room temperature for 3 hours then the methanol was removed in vacuo. Saturated sodium dihydrogen phosphate solution was added followed by ethyl acetate and the organic phase separated. The aqueous phase was re-extracted twice with ethyl acetate, then the combined organic phase washed with brine, dried, (magnesium sulfate) and the solvent removed in vacuo. Flash chromatography (silica gel, 0.25% acetic acid-2.5% methanolmethylene chloride) afforded 1-((2'-((benzoylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (11.5 mg, 47%) as a white solid; 1H NMR (300 MHz, CD3OD) δ8.27 (d, J=8.5 Hz, 1H), 7.71-7.50 (m, 3H), 7.50-7.36 (m, 4H), 7.35-7.23 (m, 3H), 6.98 (d, J=8.0 Hz, 2H), 5.70 (s, 2H), 2.67 (apparent t, 2H), 1.64 (apparent quin, 2H), 1.35 (apparent sext, 2H), 0.90 (t, J=7.3 Hz, 3H); FAB-MS: 574 (M+Na), 552 (M+H).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1.Br[C:20]1[CH:21]=[C:22]([C:32]2[N:37]=[C:36]([C:38]3[CH:39]=[C:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:41]=[C:42](Br)[CH:43]=3)[N:35]=[C:34]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:33]=2)[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=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.O1CCCC1>[C:13]1([C:9]2[N:8]=[C:7]([C:20]3[CH:21]=[C:22]([C:32]4[N:37]=[C:36]([C:38]5[CH:39]=[C:40]([C:45]6[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=6)[CH:41]=[C:42]([C:7]6[CH:12]=[CH:11][CH:10]=[C:2]([C:1]7[CH:4]=[CH:14][CH:13]=[CH:9][CH:3]=7)[N:8]=6)[CH:43]=5)[N:35]=[C:34]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:33]=4)[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=3)[CH:12]=[CH:11][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]C(C)(C)C
Reactant: Brc1cc(-c2ccccc2)cc(-c2nc(-c3ccccc3)nc(-c3cc(Br)cc(-c4ccccc4)c3)n2)c1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cc(-c3cccc(-c4ccccc4)n3)cc(-c3nc(-c4ccccc4)nc(-c4cc(-c5ccccc5)cc(-c5cccc(-c6ccccc6)n5)c4)n3)c2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
In a stream of argon, tetrahydrofuran (3 mL) was cooled to −78° C. To the cooled tetrahydrofuran, a tetrahydrofuran solution (1.18 mL) of tert-butyllithium (1.58 mol/L) was added. Then a tetrahydrofuran solution (2 mL) of 2-bromo-6-phenylpyridine (211 mg) was dropwise added to the tert-butyllithium solution. The mixture was stirred for 15 minutes while the mixture was maintained at −78° C. To the reaction mixture, zinc chloride tetramethylethylenediamine complex (530 mg) was added to allow the temperature to rise naturally to room temperature. Then, to the reaction mixture, a tetrahydrofuran suspension (2 mL) having suspended therein 2,4-bis(5-bromobiphenyl-3-yl)-6-phenyl-1,3,5-triazine (185.8 mg) and tetrakis(triphenylphosphine)palladium (13.9 mg) was dropwise added. The resultant mixture was stirred at 50° C. for 19 hours. The reaction mixture was left to stand at room temperature, and then low-boiling ingredients were distilled away under a reduced pressure. Methanol was added, and the solid precipitate was recovered by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (2:1) mixed liquid as a developing solvent, to give 120 mg of the target 2,4-bis[5-(6-phenylpyridin-2-yl)biphenyl-3-yl]-6-phenyl-1,3,5-triazine as a white powder (yield: 52%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>C1COCC1>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CNCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-Fluorobenzylamine (13.86 g, 110 mmol) was dissolved in 25 ml THF and the solution was cooled to 0° C. Bromo-acetic acid ethyl ester (8.35 g, 50 mmol) dissolved in 25 ml THF was added dropwise at 0° C. After stirring for 2 hours at room temperature the solid was filtered off and the fitrate was evaporated. The title compound was purified by chromatography (SiO2, c-hexane/ethyl acetate, 2/1) and was isolated as yellow oil (10.35 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](S(C)(=O)=O)=[N:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)=[N:7][CH:8]=1.[OH:22][C:23]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:22][C:23]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][CH:24]=2)=[N:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: COc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Reactant: Oc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
A mixture of 0.4 g (1.24 mmol) of 5-methoxy-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.27 g (1.60 mmol) of 3-hydroxy-5-trifluoromethyl-thiophene and 0.34 g (2.47 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.3 g of 5-methoxy-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)(Cl)Cl>[Br:1][CH2:20][CH:19]1[CH2:18][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][O:17]1
Reactant: C=CCC(CO)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCC1CC(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
N-Bromosuccinimide (1.78 g) is added to a stirred solution of 1.6 g of 2-phenyl-4-penten-1-ol in 15 ml of chloroform at room temperature. The resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is then poured into 10 ml of water. The chloroform layer is separated and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant to give 1.67 g of 2-(bromomethyl)-4-phenyltetrahydrofuran as colorless oil.
Reaction SMILES: Cl.ClCC1N=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][C:16]=2[F:24])C2C(=CC=CC=2)N=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([CH2:36]Cl)[N:27]=1.C(OC1C=CC([NH2:47])=C(F)C=1)C>C(O)(C)C.Cl>[NH2:47][CH2:36][C:28]1[N:27]=[C:26]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][C:16]=2[F:24])[CH3:12])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1
Reactant: CCOc1ccc(Nc2nc(CCl)nc3ccccc23)c(F)c1
Reactant: ClCc1nc(Cl)c2ccccc2n1
Reactant: CCOc1ccc(N)c(F)c1
Agent: Cl
Solvent: CC(C)O
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-amine hydrochloride: To 4-chloro-2-chloromethyl-quinazoline (500 mg, 2.3 mmol) dissolved in isopropanol (7.6 mL) was added 4-ethoxy-2-fluoro-phenylamine (540 mg, 2.8 mmol) and HCl (12 M, 1 drop). The reaction was stirred overnight at room temperature. The resulting precipitate was filtered to give 613 mg of the title compound. 1H NMR (DMSO-d6) δ 8.76 (d, 1H), 8.1 (t, 1H), 7.98 (d 1H), 7.85 (t, 1H), 7.47 (t 1H), 7.04 (d, 1H), 6.90 (d, 1H), 4.75 (s, 2H), 4.1 (q, 2H), 1.36 (t, 3H); LC-MS (ESI+; 351 ([M+H]+)).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[CH3:22].Cl.[CH:24]1([CH2:27][O:28][NH2:29])[CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[CH:24]1([CH2:27][O:28][NH:29][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[CH3:22])=[C:2]([F:1])[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH:5]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Reactant: NOCC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2nc[nH]c2c1F
Reaction time: 0.5 h

Procedure:
A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid, O-cyclopropylmethylhydroxylamine hydrochloride (1.25 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 equiv.), and diisopropylethylamine (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is taken up into diethyl ether. The ether phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product may be recrystallized with an appropriate solvent like methanol or chloroform if further purification is necessary.
Reaction SMILES: [CH3:1][C@@H:2]1[S:8][C@@H:7]([C:9]([OH:11])=O)[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19].[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.O>ClCCl.CN(C)C=O>[CH2:31]([O:30][P:26]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:9]([C@H:7]2[CH2:6][C:5]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:4]=3[C:3](=[O:19])[C@H:2]([CH3:1])[S:8]2)=[O:11])=[CH:35][CH:34]=1)([O:27][CH2:28][CH3:29])=[O:33])[CH3:32]
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc4c(cc3C(=O)[C@H](C)S2)OCO4)cc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidee hydrochloride (0.39 g) in dichloromethane (7 ml) was added to a solution of (2R,4S)-(−)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.47 g) and diethyl 4-aminobenzylphosphonate (0.41 g) in N,N-dimethylformamide (DMF) (7 ml) at 0° C., followed by the addition of 1-hydroxybenzo-triazole (HOBt) (0.28 g). This mixture was stirred at 0° C. for 1 hour and at room temperature (25° C.) for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (using MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration, followed by recrystallization from ethyl acetate-hexane and then recrystalized from methanolhexane to yield (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzo-thiepin-2-carboxamide (0.37 g, 44%). Colorless Prisms. Melting point 181-182° C. Optical rotation [α]D (23° C.) −187.4° (c=0.50, CHCl3).
Reaction SMILES: C(C(O)=O)(F)(F)F.C([O:12][C:13](=[O:41])[CH2:14][N:15]([S:23]([C:26]1[CH:35]=[C:34]2[C:29]([C:30]([Cl:40])=[CH:31][N:32]=[C:33]2[NH:36][C:37]([NH2:39])=[NH:38])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)(C)(C)C>C(Cl)Cl>[ClH:40].[ClH:40].[Cl:40][C:30]1[C:29]2[C:34](=[CH:35][C:26]([S:23]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH2:14][C:13]([OH:41])=[O:12])(=[O:24])=[O:25])=[CH:27][CH:28]=2)[C:33]([NH:36][C:37]([NH2:39])=[NH:38])=[N:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccncc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccncc3)cc12
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 58.2 %

Procedure:
CF3CO2H (1.0 mL) was added to a stirred solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-pyridylmethyl)glycine t-butyl ester (88 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and the mixture was stirred at 23° C. for 3.5 h. The solvents were evaporated in vacuo, azeotroping with CH2Cl2. The oily residue was dissolved in CH2Cl2 -MeOH (1.0 mL, 9:1) and a solution of EtOAc saturated with HCl (3.0 mL) was added which gave a precipitate. The white solid was collected by filtration and dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-pyridylmethyl)glycine dihydrochloride (18 mg, 0.033 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O[C:16]1[CH:17]=[C:18]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.N1(C2C=CC(COC3C=C(C4(OC)CCOCC4)C=CC=3)=CC=2)C=CN=C1>>[CH3:29][O:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:12][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:17]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: COC1(c2cccc(O)c2)CCOCC1
Reactant: Cc1nccn1-c1ccc(CO)cc1
Agent: COC1(c2cccc(OCc3ccc(-n4ccnc4)cc3)c2)CCOCC1
Product: COC1(c2cccc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1

Procedure:
The title compound was prepared from 4-(2-methylimidazol-1-yl)benzyl alcohol and 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran according to the procedure described for 4-[3-[4-(1-imidazolyl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran. (Example 1)