Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[N:21]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccccc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCOCC2)c2ccccc21
Temperature: 65 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
Combine 3-bromo-1-triisopropylsilanyl-1H-indole (0.33 g, 0.94 mmol), morpholine (0.10 mL, 1.15 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.012 g, 0.03 mmol), and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.012 g, 0.01 mmol) in a pressure tube. Add 1N solution of lithium bis(trimethylsilyl)amide in THF (2.00 mL, 2.00 mmol), flush tube with nitrogen gas, and close the tube. Stir at 65° C. for 18 h, cool to room temperature, dilute with water, and extract with EtOAc. Wash EtOAc layer with water, brine, dry (Na2SO4), and concentrate under vacuum. Purify the residue by flash chromatography using 0 to 50% of EtOAc in hexanes to give the title compound (0.20 g 60%): MS (ES) 359.1 (M+1)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:2]3[S:3][C:4]([CH3:7])=[N:5][N:6]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: Cc1nnc(Br)s1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nnc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)s1
Temperature: 120 °C
Yield: 35.8 %

Procedure:
A mixture of 2.41 parts of 2-bromo-5-methyl-1,3,4-thiadiazole, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 1.6 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred and heated overnight at 120° C. The reaction mixture was cooled and poured onto water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts (35.8%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 190.6° C. (compound 15).
Reaction SMILES: [C@@H:1]1([N:10]2C3N=C(N)[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH:21]1C=NC(C(N)=O)=N1.[OH-].[K+]>>[CH:11]1[N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[N:21]=[C:13]([C:14]([NH2:16])=[O:15])[N:12]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: NC(=O)c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
Bioconversion media were prepared as in Example 1, except the initial amounts of guanosine and 1,2,4-triazole-3-carboxamide were 40 millimoles. The initial pH of each flask was adjusted to pH 7.2 with potassium hydroxide. The bioconversions were initiated as in Example 1. The cells were added promptly as the temperature reached 70° C. to avoid gelling of the bioconversion mixture. Forty millimole additions of both guanosine and 1,2,4-triazole-3-carboxamide were made at 6 and 12 hours into the bioconversion. Thus after the second addition, a total of 120 millimoles of the two reactants had been added. Potassium hydroxide was added at 6 hours to adjust the pH from 6.7 to 7.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[C:19]([S:21]([CH3:23])=O)[N:18]=[C:17]([NH2:24])[N:16]=2)=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.S[CH2:26][CH:27](C)[C:28]([OH:30])=[O:29]>>[NH2:24][C:17]1[N:18]=[C:19]([S:21][CH2:23][CH:27]([CH3:26])[C:28]([OH:30])=[O:29])[CH:20]=[C:15]([C:3]2[C:2]([Cl:1])=[CH:14][C:6]3[CH2:7][O:8][CH2:9][C:10]4[C:5]=3[C:4]=2[CH:13]=[CH:12][CH:11]=4)[N:16]=1
Reactant: CC(CS)C(=O)O
Reactant: CS(=O)c1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Product: CC(CSc1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1)C(=O)O
Yield: 99.9 %

Procedure:
Partially purified 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (99.9 mg) obtained in Step 5 of Example 314 was reacted with 3-mercapto-2-methylpropionic acid (133.0 mg) instead of mercaptoacetic acid using the same operation as the production method described in Step 6 of Example 314, and thus, 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-2-methyl-propionic acid (115.4 mg) was obtained. Then, the obtained 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-2-methyl-propionic acid (58 mg) was reacted with ammonium chloride (37.9 mg) using the same operation as the production method described in Step 6 of Example 314, and thus, 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-2-methyl-propionamide (compound 321) (41.4 mg) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](N)=[O:6].[OH-:22].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:22])=[O:6]
Reactant: [OH-]
Reactant: NC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzamide (1 g) and 1N sodium hydroxide (20 ml) was refluxed for 1 hour. After cooling, the 3-amino-4-phenoxy-5-sulphamyl-benzoic acid was precipitated from the reaction mixture by addition of 4N hydrochloric acid until pH 2.5. After several recrystallizations from aqueous ethanol and drying, the compound was obtained with a melting point of 252°-253°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.I[CH3:27].[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:25]([CH3:27])[CH:24]=[N:23][N:5]2[C:6](=[N:17][CH2:18][C:19]([F:21])([F:20])[F:22])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2NCC(F)(F)F)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cnn2c(=NCC(F)(F)F)c(-c3c(F)cc(F)cc3F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 5-chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (300 mg, 0.78 mmol) in 4 mL of dimethylsulfoxide at room temperature is added iodomethane (146 μL, 2.34 mmol) followed by sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol). The mixture is then stirred at room temperature for 18 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes. Concentration provides N-[5-chloro-3-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-ylidene]-2,2,2-trifluoroethanamine as a white solid (76 mg). MS: m/z 396.0 (M+H).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH2:8]([NH:10][C:11]([NH2:13])=[NH:12])[CH3:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>CC(C)=O>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([NH:13][C:11]([NH:10][CH2:8][CH3:9])=[NH:12])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CCNC(=N)N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCNC(=N)NC(=O)Cc1cccc(OC)c1
Reaction time: 1 h

Procedure:
8.80 g of a 50% aqueous sodium hydroxide solution, ethylguanidine sulfate (14.98 g), and 100 ml of acetone are stirred for 21/2 hrs at RT. The resulting mixture is treated with anhydrous sodium sulfate (6.0 g) and stirring continued for 1 hr. A solution of 3-methoxyphenylacetyl chloride (9.23 g) in 50 ml acetone is added to the mixture dropwise and the reaction mixture stirred overnight at RT. The mixture is filtered and the filtrate diluted with saturated aqueous sodium bicarbonate. The acetone is evaporated in vacuo. The aqueous residue is diluted with 100 ml of H2O and extracted with two 100 ml portions of methylene chloride. The combined extracts are dried with sodium sulfate, filtered and concentrated in vacuo. The resulting solution is acidified with ethereal hydrochloric acid and the solvent evaporated in vacuo. The residue is stirred with 200 ml of diethyl ether and the solid collected, washed with diethyl ether and recrystallized from acetone, affording the product, M.P. 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].[H][H]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15]
Reactant: CCN(CC)CCc1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc(N)cc1Cl
Reaction time: 2.5 h

Procedure:
A suspension of 2.00 g (7.790 mmol) [2-(2-chloro-4-nitro-phenyl)-ethyl]-diethyl-amine and 0.80 g Raney nickel in THF was hydrogenated for 2.5 h at RT and 25 psi hydrogen pressure. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]([SH:12])=[N:6][C:7]([SH:11])=[N:8][C:9]=1[NH2:10].[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.O>CO>[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH2:17][S:11][C:7]2[N:8]=[C:9]([NH2:10])[C:4]([NH2:3])=[C:5]([S:12][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])[N:6]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1c(Cl)cccc1CBr
Reactant: Nc1nc(S)nc(S)c1N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(SCc2cccc(Cl)c2F)nc(SCc2cccc(Cl)c2F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of potassium hydroxide powder (2.5 g) in methanol (80 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (3.6 g) followed by 3-chloro-2-fluorobenzyl bromide (6.3 g). The reaction mixture was stirred for one hour at room temperature then poured into water (180 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropyl alcohol and diethyl ether, to give the subtitled compound as a pale brown solid (5.4 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]([F:28])=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:27]=[CH:26][CH:25]=[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]=1[F:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1F
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a stirred mixture of tert-butyl 4-(3-(tert-butylcarbamoyl)-2-fluorobenzyl)piperazine-1-carboxylate (2.54 mmol, 1 g) in dichloromethane at room temperature was added trifluoro-acetic acid (53.9 mmol, 4 mL, 6.14 g). After 3 hours stirring the reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol and loaded on to strong cation exchange column (10 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (636 mg). MS (ESI) m/z 294.4 [M+H]+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-chlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Yield: 64 %

Procedure:
A mixed solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl bromopyruvate (0.36 mL) and N,N-dimethylacetamide (14 ml) was stirred at 100° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (403 mg, yield 64%) as pale-brown crystals. MS:462 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Product: O=[N+]([O-])c1cccc(Oc2ccccc2)c1

Procedure:
This compound is prepared according to a method analogous to that described in Example 1.1 using 1-fluoro-3-nitro benzene (15.4 g, 0.106 mol) and phenol (10 g, 0.106 mol) as starting compounds. After treatment, an orange-coloured oil is obtained.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]([CH3:37])[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33])=[O:26]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([F:33])=[C:27]([CH:28]=3)[C:25]([N:24]([CH3:37])[CH3:23])=[O:26])[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CN(C)C(=O)c1cc(B(O)O)ccc1F
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(F)c(C(=O)N(C)C)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 3-(dimethylcarbamoyl)-4-fluorophenylboronic acid (from Combi-Blocks). LCMS calculated for C25H26FN4O3 (M+H)+: m/z=449.2. Found 449.1.
Reaction SMILES: [CH:1]1([OH:14])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[OH:13].[CH3:15][CH2:16][CH2:17][CH2:18][CH:19]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl-].[Na+].O>[CH2:16]([CH:15]1[O:13][CH:2]2[CH:1]([CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]2)[O:14]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC=O
Reactant: OC1CCC=CCCC=CCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCC1OC2CCC=CCCC=CCCC2O1
Yield: 90 %

Procedure:
5 g of 5,9-cyclododecadien-1,2-diol, 2.4 g of valeric aldehyde, a spatula of p-toluenesulfonic acid and 200 ml of 80/100 petroleum ether were charged into a 250 ml two-neck flask equipped with a water separator and the mixture was taken to reflux for 1 h. The reaction mixture was then poured on ice, neutralized with brine, dried and concentrated. Distillation in a bulb-to-bulb apparatus produced 6.06 g of 14-butyl-13,15-dioxabicyclo[10.3.0]pentadeca-4,8-diene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH:12]=[O:13])[CH3:11])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[CH2:12][OH:13])[CH3:2]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=C(C)C=CC=C(C)CO
Temperature: 10 °C
Reaction time: 2 h

Procedure:
36 G. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester are dissolved in 600 ml. of absolute ethanol. The solution is treated portionwise with 1.8 g. of sodium borohydride. The mixture is stirred for 2 hours at 10° C. then poured onto ice water and 3 N aqueous hydrochloric acid and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate solution and once more with water, dried over sodium sulfate and evaporated. There is obtained 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([CH:32](O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[SiH](CC)(CC)CC.CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([CH2:32][CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(CC)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-(1-hydroxyethyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.08 g) in CH3CN (3 mL) at 0° C. was added Et3SiH (0.075 mL) followed by BE3.Et2O (0.0197 mL). The mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with CH3OH/H2O and the mixture was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1/2) to give 39 mg of N-(2,6-dichlorobenzoyl)-3-ethyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 500 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: [Zr+4]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of 4-(4-nitro-phenyl)-tetrahydro-pyran-4-carbonitrile (as prepared in the previous step) in THF is treated with ZrCl4 and NaBH4 (Synthesis, (12), 995-6 (1988)) at RT. The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([NH2:29])[N:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]=2[CH:34]=1.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH2:30]([N:26]1[C:25]2[CH:34]=[C:21]([C:42]#[C:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:22]=[CH:23][C:24]=2[N:28]=[C:27]1[NH2:29])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Cn1c(N)nc2ccc(Br)cc21
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: CC(C)Cn1c(N)nc2ccc(C#Cc3ccccc3)cc21
Yield: 60.8 %

Procedure:
Heat a mixture of Pd(OAc)2 (1.25 g, 5.59 mmol), CuI (0.42 g, 2.23 mmol), P(t-Bu)3 (2.76 mL, 11.2 mmol), K2CO3 (30.3 g, 223.8 mmol) and 6-bromo-1-isobutyl-1H-benzimidazol-2-ylamine (30 g, 111.9 mmol) in DMSO (200 mL) at 70° C. Add phenylacetylene (14.6 mL, 133.4 mmol) and heat the mixture for 6 hours at 70° C. Cool and dilute with H20. Filter the residue through a pad of celite. Recrystallize the crude mixture in toluene to give the desired compound as a white solid (19.68 g, 60%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: Oc1ccccc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccccc3F)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenol to give [1-(2-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [N:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[C:2]=[O:3].C1CCN2C(=NCCC2)CC1.Cl[CH2:25][CH2:26][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:31])[CH2:28][CH:29]=[CH2:30]>C1COCC1.CCOC(C)=O>[CH2:28]([C:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:31][C:2](=[O:3])[N:1]([CH:4]2[CH2:6][CH:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:25][CH2:26]1)[CH:29]=[CH2:30]
Reactant: O=C=NC1CC1c1ccccc1
Reactant: C=CCC(O)(CCCl)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)CCN(C2CC2c2ccccc2)C(=O)O1
Yield: 7.2 %

Procedure:
To a solution of (2-isocyanatocyclopropyl)benzene (800 mg, 5.03 mmol) in THF (15 mL) was added DBU (1.61 g, 10.48 mmol) and 1-chloro-3-phenylhex-5-en-3-ol (880 mg, 4.19 mmol), and the mixture was refluxed overnight. The solution was diluted with EtOAc, and washed with 1 N HCl (2×15 mL). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to afford 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (100 mg, 6%). 1H NMR (CDCl3): 1.05-1.21 (m, 3H), 1.36-1.42 (m, 1H), 2.13-2.34 (m, 1H), 2.39-2.61 (m, 2H), 2.92-3.15 (m, 1H), 3.76-4.01 (m, 1H), 4.95-5.10 (m, 2H), 5.42-5.73 (m, 1H), 6.95-6.99 (m, 1H), 7.10-7.24 (m, 10H).