Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: Cc1ccc(B(O)O)cc1C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1C
Yield: 67.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.048 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:18])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNS(=O)(=O)c1cncc(Br)c1
Yield: 13.3 %

Procedure:
A solution of 5-bromopyridine-3-sulfonyl chloride (3.5 g, 14 mmol) and glycine ethylester (2.1 g, 20 mmol), diisopropyl ethyl amine (2.6 g, 20 mmol) in THF (70 mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic solution was separated, dried and evaporated under reduced pressure. The residue was purified using flash silica gel column chromatography using ethyl acetate/hexanes to obtain ethyl 2-(5-bromopyridine-3-sulfonamido)acetate (600 mg, 14%); LCMS Method T: retention time 1.31 min; [M+1]=323, 325.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])C(OC)=O.[Cl-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120° C. (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105° C. 1H NMR (CDCl3) 8.3 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.12 (s, 2H), 3.60 (s, 3H). MS (FAB) m/z: 275.2 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][CH:20]=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:22]1[CH2:25][CH:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:19][CH2:20][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23]2)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:6][CH:7]=1
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
tert-Butyl [(2S)-2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate (1.57 g, 5.3 mmol) and 4-azetidin-3-ylmorpholine (0.83 g, 5.8 mmol) were dissolved in CH2Cl2 (60 mL) together with DIPEA (1.4 g, 10.6 mmol). The mixture was stirred for 20 min and then sodium triacetoxyborohydride (1.6 g, 7.4 mmol) was added. The mixture was stirred at room temperature for 6 h and then the solvent was removed by evaporation. The residue was partitioned between an aqueous solution of NaHCO3 and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the organic solution was dried over MgSO4 and then removed by evaporation. The product was chromatographed on a silica gel using a mixture of methanol and CH2Cl2 (5%-20% methanol) and there was obtained 440 mg (20%) tert-butyl [(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4ylazetidin-1-yl)butyl]methylcarbamate as an oil. 1H NMR (400 MHz, CDCl3): 1.3 (s, 9H), 1.4-1.6 (m, 2H), 2.1-2.3 (b, 5H), 2.5-3.8 (cm, 16H), 6.9 (t, 2H), 7.0-7.1 (b, 2H); LCMS: m/z 422 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C@H:14]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](O)=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[NH2:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([NH2:47])=[N:42][CH:41]=[CH:40]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C@H:14]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:23])[NH:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([NH2:47])=[N:42][CH:41]=[CH:40]2)=[O:16])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH3:2]
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of {[2-{2-(S)-Carboxy-pyrrolidin-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester (0.240 g), 6-aminomethyl-isoquinolin-1-ylamine (0.092 g), N-methyl morpholine (0.170 mL) and 0.160 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 8 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. Removal of the solvent in vacuo followed by purification of the remaining residue by silica chromatography (dichloromethane/methanol 80/20) gave 0.310 g (100%) of the title compound as a light yellow solid. (+)-APCI-MS: 634 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[N+:25]([O-])([O-:27])=[O:26].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[C:4]([N+:25]([O-:27])=[O:26])[CH:3]=1
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN(CCc1ccc(F)cc1[N+](=O)[O-])S(=O)(=O)c1csc2c1CCCC2=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
7-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-ethyl]-methyl-amide (the compound of Preparation Example 41) (222 mg) was dissolved in a concentrated sulfuric acid (1.5 mL), potassium nitrate (74 mg) was added in small amounts on an ice bath. After stirring for 45 minutes, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and dried with anhydrous magnesium sulfate. Spots for two products were identified by silica gel TLC (hexane/ethyl acetate=1:1). The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), fractions with a high RF value were collected, and the title compound (78 mg) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32](=[O:34])[NH:31][C:30]=2[CH:35]=1>>[CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:26]2[CH:27]=[CH:28][C:29]3[O:33][C:32](=[O:34])[NH:31][C:30]=3[CH:35]=2)[CH:8]=[N:7][CH:6]=1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3oc(=O)[nH]c3c2)c1)c1ccccc1
Yield: 40.5 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromo-2-benzoxazolinone (102 mg, 0.46 mmol) were reacted to give the title compound as light yellow solid (71 mg).
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
5.0 g of 3-pentafluorosulfanylaniline were suspended in 50 ml of a 35% aqueous H2SO4 solution. Then, at 0° C., a solution of 1.57 g of NaNO2 in 5 ml of water was added dropwise over the course of 10 minutes. The mixture was stirred at 0° C. for 40 minutes. Then a solution, cooled to 0° C., of 8.56 g of Cu(NO3)2 in 50 ml of water was added to this suspension. Immediately thereafter, 3.26 g of Cu2O was also added, whereupon marked evolution of gas was observable. 3 extractions each with 100 ml of CH2Cl2 were carried out, the org. phase was washed with 100 ml of a saturated aqueous NaCl solution and dried over MgSO4, and the solvent was removed in vacuo. Chromatography with DIP on a short silica gel column afforded 3.5 g of the phenol as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1.C(N(CC)CC)C>O1CCCC1>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:30])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]6([C:28]#[N:29])[CH2:27][CH2:26]6)[CH:20]=5)[CH:12]=4)=[N:6][N:5]3[CH:31]=2)=[O:38])=[CH:35][N:34]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccc(Cl)nc6)cn5n4)c3)c2)CC1
Yield: 75.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (120 mg, 0.292 mmol), 6-chloronicotinoyl chloride (61 mg, 0.350 mmol), triethylamine (62 μL, 0.438 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 385, the title compound (121 mg, 75%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11]([OH:13])=O)=[O:5])[CH3:2].Cl.Cl.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[CH2:29][CH2:30][NH2:31]>>[CH3:14][N:9]1[C:10]([C:11](=[O:13])[NH:31][CH2:30][CH2:29][C:19]2[N:18]([CH3:17])[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]=2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Agent: Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C

Procedure:
The product was obtained starting from 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.01 mmol, prepared as described in US 2011/0071128) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine hydrochloride (288 mg, 1.21 mmol, example 7, step 4) according to the method described in example 37, step 1 as light yellow solid (252 mg, 661 μmol, 65.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.C1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31](C2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:8][C:6]1[CH:5]=[C:4]([Si:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([C:7]2[CH:2]=[CH:3][CH:4]=[C:36]([C:35]3[C:34]4[O:33][C:32]5[CH:12]=[CH:11][CH:10]=[CH:15][C:31]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)[CH:6]=2)[CH:7]=1
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3oc3ccccc34)c2)OC1(C)C
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: O
Product: Brc1cc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of (3,5-Dibromophenyl)triphenylsilane (4.27 g, 8.64 mmol), 2-(3-(dibenzo[b,d]furan-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 4.32 mmol), Pd(PPh3)4 (0.100 g, 0.086 mmol) and K2CO3 (1.792 g, 12.96 mmol) in toluene (100 mL) and water (10 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (4/1 to 3/1, v/v) as eluent to yield (5-Bromo-3′-(dibenzo[b,d]furan-4-yl)[1,1′-biphenyl]-3-yl)triphenylsilane (1.3 g, 45%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH3:7][N:6]1[C:2]([NH2:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:4]([O:8][CH2:27][CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)=[N:5]1
Reactant: CCOc1ccccc1Br
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N)cc1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (50 mg) in dimethylformamide (2 ml) at room temperature was added sodium hydride (60% dispersion in oil, 10 mg) and bromophenetole (49.5 mg). The mixture was stirred for 2 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ether to yield the title compound as a white solid (20 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[C:10](O)[CH:11]=[CH:12][C:13]=3O)[C:7](=[O:8])[C:5]=2[CH:6]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[N:22]1([CH2:21][CH2:20][NH:19][C:13]2[C:14]3[C:15](=[O:16])[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:7](=[O:8])[C:9]=3[C:10]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:11][CH:12]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCCN1CCCCC1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCCCC3)ccc(NCCN3CCCCC3)c21
Reaction time: 8 h

Procedure:
A mixture of 4.07 g. or quinizarin, 21.74 g. of N-(2-aminoethyl)piperidine and 26 ml. of water is stirred under reflux for 2 hours and then allowed to stand overnight. The gummy solid is collected and washed with water by centrifugation, giving 1.99 g. of blue-black solid. This solid is dissolved in 15 ml. of chloroform and chromatographed by an abbreviated wet-column procedure on 100 g. of alumina, eluting with chloroform. A total of 180 ml. of eluate is collected in eight separate cuts from the time the eluate turns blue until a black band nears the bottom of the column. Cuts 1-6 are combined and evaporated giving 1.42 g. of blue-black crystals which are recrystallized from ethanol giving 1.35 g. of the desired product as blue-black needles, mp. 140°-141° C. Product dried in vacuo at 78° C. melted at 156°-157° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)[CH3:21]
Reactant: CCc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
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: [Na+]
Solvent: CC#N
Product: CCc1ccccc1-c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Yield: 14.6 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-ethylphenylboronic acid (60 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 297 (11 mg). ESI-MS: 349.1(M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1/[O:14][C:15]([CH3:26])([CH3:25])[C:16]([C:18]2[CH:19]=[N:20][C:21](F)=[CH:22][CH:23]=2)=[CH:17]/1.[CH3:27][NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32].O>CN(C=O)C>[OH:33][CH:30]([CH2:31][OH:32])[CH2:29][N:28]([CH3:27])[C:21]1[N:20]=[CH:19][C:18]([C:16]2[C:15]([CH3:26])([CH3:25])[O:14]/[C:13](=[C:5]3/[C:6](=[O:12])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)/[CH:17]=2)=[CH:23][CH:22]=1
Reactant: CNCC(O)CO
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(F)nc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(O)CO)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cn1
Temperature: 100 °C

Procedure:
A mixture of (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and 3-methylamino-1,2-propanediol (50 mg, 0.48 mmol) in 5 mL of DMF was heated in 100° C. bath under nitrogen for 16 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-[4-{6-[(2,3-dihydroxypropyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-5,6-difluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 51 mg, 82%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:22].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (25 g), methylboronic acid (8.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1, 2.9 g) and potassium fluoride (16 g) was added tetrahydrofuran (140 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g). The obtained 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g) was dissolved in chloroform (100 mL), 4N hydrogen chloride/ethyl acetate (50 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (200 mL), and the precipitate was collected by filtration to give the title compound (10 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[CH:17][N:16]=1>>[NH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:25][C:20]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH2:3]1
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: c1cc(NC2CCCNC2)c2ccncc2c1

Procedure:
Reaction of tert-butyl 3-oxopiperidine-1-carboxylate and isoquinolin-5-amine using the method of Example 3 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: ClC1C=CC([CH:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17]C(OC)=CC=3OCC)=NC2CC)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44]N(C)[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH:59]2CCCC2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44][CH:8]([N:12]4[CH2:11][CH2:13][CH2:18][CH2:17]4)[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH3:59])=[CH:29][CH:28]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-1H-imidazole (Example 20) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 539.2792, calculated for C30H40N4O3Cl [(M+H)+]539.2784.