Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([CH3:36])=[C:5]([F:35])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18]C(=O)C(C)(C)C)=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:27]=1[NH:28]C(=O)C(C)(C)C>O1CCOCC1>[NH2:28][C:27]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:35])=[C:4]([CH3:36])[C:3]=1[F:2]
Reactant: Cc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 0 °C
Yield: 34.8 %

Procedure:
50 mL of 1,4-dioxane and 25 mL of concentrated hydrochloric acid were added to 800 mg (1.64 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-5-pivaloylamino-4H-1-benzopyran-4-one and the mixture was stirred under heating at reflux for 2 hours. The reaction solution was poured into ice water, and the solution was made basic and extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1) and recrystallized from ethyl acetate/n-hexane to give 183 mg of Compound 80 (yield: 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1([C:15]([OH:31])([CH2:24][N:25]2[C:29]([SH:30])=[N:28][CH:27]=[N:26]2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:11][C:12]1([C:15]([OH:31])([CH2:24][N:25]2[C:29]([S:30][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:28][CH:27]=[N:26]2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
At room temperature, a solution of 0.63 ml (5 mmol) of 4-chloro-benzoyl chloride in 5 ml of absolute tetrahydrofuran is added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 0.69 g (5 mmol) of anhydrous potassium carbonate and 20 ml of absolute tetrahydrofuran. The reaction mixture is stirred at room temperature for a further 20 hours and then filtered off with suction and concentrated under reduced pressure. In this manner, 2.4 g (99% of theory) of 2-(1-chloro-cyclopropyl)-1(2-chlorophenyl)-3-[5-(4-chloro-benzoyl-mercapto)-1,2,4-triazol-1-yl]-propan-2-ol are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30]>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: NCc1ccccn1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and 2-picolylamine in DME. ES-MS m/e (%): 292 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10](=[O:20])[C:11]([CH3:19])=[CH:12]C2C=CC=CC=2)[CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1>CCCCCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]2[C:8]=1[CH:19]=[C:11]([CH3:12])[C:10](=[O:20])[NH:9]2
Reactant: COc1ccc(C)c(NC(=O)C(C)=Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Temperature: 125 °C
Yield: 85.2 %

Procedure:
N-(5-Methoxy-2-methylphenyl)α-methylcinnamamide (21.3 g, 75.8 mmol) and aluminum chloride (50.4 g, 378 mmol) were combined with chlorobenzene (158 ml), and heated in a bath at 125° C. for 45 minutes while stirring. After cooling, the mixture was poured into ice-water, to which hexane was added. Precipitated crystals were collected by filtration, and dissolved in chloroform-methanol (4:1). After drying and condensing, the resultant residue was washed with chloroform to obtain 12.22 g of the title compound as pale brown crystals (85.3%).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][C:6]=1[N:13]=[C:14]1[S:18][CH2:17][C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:4].[CH3:28][C:29]#[N:30]>>[CH2:3]([C:5]1[CH:10]=[C:9]([CH:11]=[CH:28][C:29]#[N:30])[CH:8]=[CH:7][C:6]=1[N:13]=[C:14]1[S:18][CH2:17][C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:4]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Product: CCc1cc(C=CC#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reaction time: 4 h

Procedure:
To a solution of KOH (0.024 g, 0.36 mmol) in CH3CN (20 ml) at the reflux temp. was added 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (Method D11a; 0.127 g, 0.36 mmol). The reaction mixture was heated at the reflux temp. for 4 h, cooled to room temp., and concentrated under reduced pressure The residue was diluted with water (15 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with a saturated NaCl solution and dried (Na2SO4). The resulting material was purified by preparative TLC (30% EtOAc/hex) to give 2-(2-ethyl-4-(2-cyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as 1:3 cis/trans mixture of isomers (0.050 g): TLC (30% EtOAc/hex) Rf0.56.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([O:31][C:32]([NH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:39][NH:40][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:41][CH:42]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 89.3 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.32 g, 0.76 mmol) with a solution of 4-(tert-butoxycarbonylamino)-benzylamine (0.338 g, 1.524 mmol) in anhydrous toluene/dioxane (4:1, 10 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:1 gradient over 30 min; 3:1 over 3 min; 3:1 to 1:1 gradient over 30 min and 1:1 over 3 min; 35 mL/min) to obtain the desired intermediate as a yellow oil (0.338 g, 89%). MS (ES+) m/z: 498.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCN2CCCCC2)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CCCC2CCN(CCCc3ccccc3)CC2)cc1

Procedure:
3-Phenylpropylpiperidine (1 eq) was reacted with 3-phenylbromopropane (1 eq) in the presence of K2CO3 in refluxing acetonitrile over night. The product obtained was worked up and purified on a column of silica. The 500 MHz 1H NMR is in accordance with the expected structure.
Reaction SMILES: C(O)(=O)C.C(=O)([O-])O.[K+].[C:10]([NH:14][C:15]([C@@H:17]1[CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][NH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CS([O:31][C@@H:32]1[C@@H:38]([NH:39][C:40](=[O:52])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47]C(=O)C)[C:42]=2[CH3:51])[CH2:37]OC(C)(C)O[CH2:33]1)(=O)=O>>[C:10]([NH:14][C:15]([C@@H:17]1[CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][N:18]1[CH2:33][C@H:32]([C@@H:38]1[CH2:37][O:52][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([OH:47])[C:42]=2[CH3:51])=[N:39]1)[OH:31])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(O)cccc1C1=N[C@H]([C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)CO1
Temperature: 45 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
Production of compound [13] (Step 9) Acetic acid (14.0 ml, 245 mmol) was added to the mixture obtained in Example 8 at not more than 10° C. to make the mixture acidic, and potassium hydrogencarbonate (25.0 g, 250 mmol) and (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [12], 13.7 g, 57.6 mmol) were successively added. The mixture was stirred at 45° C. for 6 hours to give a pale yellow suspension. The suspension was concentrated to ⅕ and water (340 ml) was added. The suspension was stirred for one hour at room temperature. The resulting crystals were collected by filtration and washed successively with water (200 ml) and butyl acetate (340 ml). The crystals were dried under reduced pressure at 60° C. to give colorless crystals of (3S, 4aS, 8aS)-2-{(2R)-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [13], 17.3 g, yield 46%, from compound [9]), melting point 240° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:30](OC)=[O:31])=[C:12]2[C:16]=1[N:15]=[C:14]1[N:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[CH3:29])[CH2:18][CH2:19][CH2:20][N:13]21.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(#N)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].CS(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:30]=[O:31])=[C:12]2[C:16]=1[N:15]=[C:14]1[N:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[CH3:29])[CH2:18][CH2:19][CH2:20][N:13]21
Reactant: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(OC)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C=O)c23)c(C)c1
Yield: 88.9 %

Procedure:
To a suspension of lithium aluminum hydride (106 mg, 2.79 mmol) in tetrahydrofuran (3.5 mL) was added a solution of methyl 9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (301 mg, 0.700 mmol) in tetrahydrofuran (3.5 mL) at 0° C., and the resultant mixture was stirred at 0° C. for 10 min. After sodium sulfate decahydrate (1 g) was added at 0° C., the resultant mixture was filtered and concentrated in vacuo. To a solution of the residue in acetonitrile (7 mL) and dimethylsulfoxide (1.4 mL) was added Dess-Martin reagent (356 mg, 0.839 mmol) at room temperature. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate and aqueous sodium thiosulfate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (249 mg, 0.622 mmol, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([O:31][CH2:32][CH:33]([F:35])[F:34])[C:26]([C:28](O)=[O:29])=[CH:27][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1>CN(C=O)C.[Cl-].[Na+].O>[Br:60][C:61]1[CH:67]=[CH:66][C:64]([NH:65][C:28]([C:26]2[C:25]([O:31][CH2:32][CH:33]([F:34])[F:35])=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:29])=[CH:63][CH:62]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.12 g; 2.19 mmol), HBTU (831 mg; 2.19 mmol) and TEA (433 mg; 4.38 mmol) in DMF (10 mL) was stirred for 30 min at rt and thereafter added to a solution of 4-bromoaniline (377 mg; 2.19 mmol) in DMF (10 mL). The resulting mixture was stirred over night at rt, poured into brine and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give the sub-title compound. Yield: 1.35 g (93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].O1CCCC1.Cl>CO.[Pd]>[ClH:1].[NH2:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CN)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 167.6 %

Procedure:
A mixture of N-(2-chloro-4-cyanophenyl)methanesulfonamide (0.5 g, 2.2 mmol) and 10% Pd—C (100 mg) in methanol (7.5 ml)-tetrahydrofuran (7.5 ml)-12M aqueous solution of hydrogen chloride (3.0 ml) was stirred under H2 balloon pressure for 2 hours at ambient temperature. Then, filtration to remove 10% Pd—C, evaporation gave the crude residue, which was applied to recrystallization from methanol and diisopropylether to furnish 500 mg (85% yield) of title compound as a white solid.
Reaction SMILES: [Cl:1]C1C=CC(OCC2C=CC=CC=2)=CC=1.C1(C=NC2C=CC=CC=2)C=CC=CC=1.[CH2:30]([N:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:47]1[CH:48]=[CH:49][C:44]([N:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:45][CH:46]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(OCc2ccccc2)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Product: Clc1ccc(N(Cc2ccccc2)c2ccccc2)cc1

Procedure:
Chloro-4-(phenylmethoxy)benzene (2.18 g, 0.010 mol) and N-(phenylmethylene)benzenamine (1.81 g, 0.010 mol) were reacted in Na/DMF (1 g: 50 mL) at 50° C. for 7 hrs. The reaction was followed by HPLC to about 90% conversion. This technique indicated among other things the presence of the title compound, benzyldiphenylamine, and some unknown material in a ratio 65:18:17. Similar aqueous workup as for the preparation of benzyldiphenylamine and chromatography on silica gave 0.50 g of the title compound mp 94°-5° C. from methanol (lit8 mp 97°-7.5° C. 70% yield). This material is contaminated with a small amount of diphenylbenzylamine. 1H NMR (200 MHz, CDCl3) δ(assignment): 5.03 (s, 2H, Ph2NCH2Ph), 6.96-7.38 (m, 14H, aromatic). MS [m/e (70 eV, % of base peak)]C19H16ClN 293 (M+·, 52.8), 295 (M+· +2, 28.8), 202 (M+ --C7H7+, 22), 167((C6H4NPh)+·, 48.3), 91 (C7H7+, 100). FTIR (CDCl3): 3066, 3033, 1589, 1494, 1454 cm-1.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[OH:14]O>C(O)(=O)C.O>[S:10]([C:2]1[S:1][C:5]2=[N+:6]([O-:14])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)(=[O:12])(=[O:11])[NH2:13]
Reactant: NS(=O)(=O)c1cc2cccnc2s1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of thieno[2,3-b]pyridine-2 Sulfonamide (0.43 g, 2 mmol) and 30% hydrogen peroxide (1.0 ml) in acetic acid (5.0 ml) was stirred at 55° C. for 24 hours. The reaction mixture was diluted with water, chilled and the resulting solid was collected and dried; 0.35 g (76% yield); m.p. 278°-279° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)[CH3:4].C[N:16](C=O)C>>[CH2:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([NH2:16])[CH:6]=1)[CH3:4]
Reactant: CCc1c[nH]c2ncc(F)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(N)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of NaH (2.7 g, 68 mmol, 60% in mineral oil) in DMF (20 mL) at 0° C. is treated with 3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (745 mg, 4.5 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (2.5 g, 22.5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30% -50% EtOAc in heptane to afford 3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (685 mg, 84%). MS: 180 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.16 (s, 1H), 7.56 (m, 1H), 7.14 (s, 1H), 4.93 (s, NH2, 2H), 2.697 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccccc1Cn1nc(C(C)C)c(O)c(C(=O)NCC(=O)O)c1=O
Yield: 49.7 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 2-methoxyphenylboronic acid (26.9 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-[(5-hydroxy-6-(1-methylethyl)-2-{[2′-(methyloxy)-2-biphenylyl]methyl}-3-oxo-2,3-dihydro-4-pyridazinyl)carbonyl]glycine (40 mg, 0.088 mmol, 49.6% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.80 (s, 1H), 12.99 (br. s., 1H), 10.09 (t, J=4.93 Hz, 1 H), 7.26-7.39 (m, 3H), 7.04-7.19 (m, 4H), 6.98 (td, J=7.45, 0.76 Hz, 1H), 5.00-5.16 (m, rotomers, 2H), 4.06 (d, J=5.81 Hz, 2H), 3.74 (s, 3H), 3.08 (m, 1H), 1.03-1.13 (m, rotomers, 6H). MS (ES+) m/e 452 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[C:7]([NH2:18])(=[O:17])[C:8]1[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:10](N)=[O:11].[K].O>CN(C=O)C>[Cl:1][CH2:2][CH:3]=[CH:4][CH2:5][N:18]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11]
Reactant: ClC/C=C/CCl
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC=CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Trans-1,4-dichloro-2-butene (1.14 ml, 10.8 mmol) was dissolved in DMF (27 ml) and purged with argon. Potassium pthalamide (1.00 g, 5.40 mmol) was added to the solution and the reaction was allowed to stir at room temperature overnight. The reaction was then poured into water (75 ml), which precipitated a white solid. This solid was collected by filtration and purified using silica gel chromatography (3:1 Hex: EtOAc) to afford a 76% yield (961 mg) of a white solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH2:10]CC)=[O:7])=[CH:4][N:3]=[CH:2]1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:15][C:14]=1[CH2:19][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=[CH:2]1
Reactant: CCCCOC(=O)c1cnc[nH]1
Reactant: ClCc1ccccc1
Product: CCOC(=O)c1cncn1Cc1ccc2ccccc2c1
Yield: 162.3 %

Procedure:
2.4 g (17.1 mmol) of butyl imidazole-5-carboxylate were reacted with 4.1 g (32.1 mmol) of benzyl chloride analogously to procedure 8a. 7.3 g (78%) of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([C:20]#[N:21])=[C:16]([C:18]#[N:19])[N:17]=1.[OH-:22].[Na+].Cl>O>[C:20]([C:15]1[NH:14][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])=[N:17][C:16]=1[C:18]([NH2:19])=[O:22])#[N:21]
Reactant: N#Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(N)=O
Temperature: 40 °C
Yield: 17.5 %

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyanoimidazole (3.31 g, 0.01 mol) and sodium hydroxide (1.0 g, 0,025 mol) in water (10 ml) was stirred and heated at 40° C. overnight. Concentrated hydrochloric acid was added to the mixture and the precipitated solid was filtered off and purified by medium pressure liquid chromatography (mplc) on silica eluted with a mixture of ethyl acetate and dichloromethane (1:1). Recrystallization of the white solid from a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (1:1) gave 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole-4-carboxamide (0.61 g), m.p. 254°-255° C., as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[CH:26]=[C:27]([F:32])[C:28](F)=[N:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:32])[C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:29][CH:30]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Fc1cc(Br)cnc1F
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)cc4F)cc3n2C)c1
Yield: 65.5 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (4.06 g, 13.0 mmol), 5-Bromo-2,3-difluoropyridine produced in Example (9a) (2.77 g, 14.3 mmol), copper iodide (0.25 g, 1.30 mmol), 1,10-phenanthroline (0.23 g, 1.30 mmol), cesium carbonate (12.71 g, 39.0 mmol) and DMF (65 mL) to obtain the title compound (4.14 g, 66%) as a white solid.