Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[NH2:26].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C.C(OCC)(=O)C>[O:21]=[C:20]([NH:26][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)[C:24]([F:38])([F:37])[F:23])/[CH:19]=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]2
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)O)ccc21
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 50 °C
Yield: 89.9 %

Procedure:
1.5 g (4.95 mmol) of (2E)-3-{1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}acrylic acid and 1.2 g (4.95 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine were dissolved in 100 ml of DMF, 1.5 g (5.44 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride were added, and the reaction mixture was heated to 50° C. overnight. The reaction solution was diluted with ethyl acetate, washed with sal. NaHCO3 solution, 1N hydrochloric acid and sat, sodium chloride solution, dried over sodium sulphate, filtered and concentrated. Chromatographic purification gave 2.3 g (4.45 mmol) of tert-butyl {5-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2,3-dihydro-1H-inden-1-yl}carbamate (87%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:13]([O:14][CH2:15][CH3:16])=[O:17])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: A solution of 96.6 g of 4-chloro acetophenone in 300 ml of diethyl carbonate is added dropwise to a suspension of 34 g sodium hydride (55% in mineral oil, washed twice with diethyl ether) in 400 ml of diethyl carbonate at ice bath temperature, then at room temperature for 2 days. To the dark solution is then added crushed ice and 5N hydrochloric acid to adjust the pH to 6-7. After dilution with diethyl ether, the layers are separated, the organic phase washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After removal of the solvents, the oily ethyl 3-(4-chloro-phenyl)-3-oxo-propionate is obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:18]([OH:20])=[O:19])[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)=O)(C)(C)C.[ClH:21].CCOCC>O1CCOCC1>[ClH:21].[NH2:8][CH2:9][C:10]1([C:18]([OH:20])=[O:19])[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC1(C(=O)O)CC12CCCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid (200 mg, 0.706 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3 mL). The reaction was stirred for 18 hours at room temperature. Ether (20 mL) was added and the precipitate was isolated by vacuum filtration. The solid was dried in a vacuum oven at 48° C. to give 133 mg (86%) of 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid hydrochloride as a white solid: mp 240–242° C.; 1H NMR (300 MHz, D2O) δ 0.92 (d, J=5.2 Hz, 1H), 1.40 (d, J=5.2 Hz, 1H), 1.4–1.6 (m, 10H), 3.12 (d, J=14.0 Hz, 1H), 3.61 (d, J=14.0 Hz, 1H); MS (APCI) m/z 184 [M+H]+. Anal. Calcd. For C10H17NO2—HCl: C, 54.67; H, 8.26; N, 6.38; Cl, 16.14. Found: C, 54.91; H, 8.36; N, 6.25; Cl, 15.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]2=[N:39][N:40]([CH3:43])[C:41]([CH3:42])=[C:35]2[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][C:36]5=[N:39][N:40]([CH3:43])[C:41]([CH3:42])=[C:35]5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: Cc1c2c(nn1C)CCN(CCCCl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCc2nn(C)c(C)c2C1
Temperature: 80 °C
Yield: 207.9 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.50 g, 0.16 mmol, 1.0 eq) and K2CO3 (0.05 g, 0.32 mmol, 2.0 eq) in 20 mL of DMF was added 5-(3-chloropropyl)-2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (0.05 g, 0.19 mmol, 1.2 eq). The reaction mixture was heated at 80° C. for 8.0 h and concentrated in vacuo. The residue was poured into a mixture of water (100 mL) and CH2Cl2 (150 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a yellow solid (0.17 g, 21.23%), HPLC: 96.27%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 513.02 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.93-2.18 (m, J=4.0 Hz 2H), 2.41 (s, 3H), 2.88 (s, 3H), 2.90-2.95 (m, 6H), 2.97-3.01 (m, 2H), 3.89 (s, 3H), 4.19-4.25 (m, 2H), 7.35 (s, 1H), 7.49 (t, J=8.42 Hz, 1H), 7.57-7.61 (m, 2H), 8.17 (t, J=5.66 Hz, 1H), 8.61 (s, 1H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:14][C:15]([C:17]2([NH:32]C(=O)OC(C)(C)C)[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:11][NH:12][CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:32][C:17]1([C:15]([NH:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][NH:12][CH3:13])=[O:16])[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1
Reactant: CNCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Hydrogen chloride (4M in dioxane, 0.461 mL, 1.84 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-(methylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 68) (10 mg, 0.02 mmol) in a mixture of DCM (3 mL) and methanol (1 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 hours. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(methylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (7 mg, 86%) as a colourless gum.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CNS(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4-Methoxy-N-methylbenzenesulfonamide (1.02 g, 4.82 mmol) was dissolved in dichloromethane (50 ml). A solution of boron tribromide (1M in dichloromethane, 14.5 mL, 14.5 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 650 mg (68% yield) of the title compound. Purity 95%.
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[C:31]([O:43]CC2C=CC=CC=2)[CH:30]=1)[C:12]([O:14][C@H:15]([CH3:27])[C@H:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])[CH3:17])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.[Pd]>[OH:43][C:31]1[CH:30]=[C:29]([CH2:28][C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[C:12]([O:14][C@H:15]([CH3:27])[C@H:16]([O:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH3:17])=[O:13])[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
200 mg of 10% Pd—C pre-mixed with 10 mL of methanol was added to a solution of (1R,2R)-1-methyl-2-phenylcarbonyloxypropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.6 g, 3.9 mmol) in 40 mL of tetrahydrofuran under a nitrogen atmosphere. The resulting mixture was stirred under hydrogen at room temperature for 2 hrs. After filtration and washing with methanol, the filtrate was concentrated and chromatography (silica gel, 30% ethyl acetate in hexane) of the residue afforded 1.8 g (95%) of (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate. MS (ESI) m/z 474.31 (M+H)+ and 472.18 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.IC.[C:19](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:16])[N:4]([CH3:19])[CH:5]=[C:6]([C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])[CH:7]=1
Reactant: O=C(c1c[nH]c(=O)c(Br)c1)N1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(C(=O)N2CCOCC2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-(morpholine-4-carbonyl)pyridin-2(1H)-one (430 mg, 1.498 mmol), iodomethane (0.112 mL, 1.797 mmol), and potassium carbonate (207 mg, 1.498 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 30-70% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[CH:28]=[CH:29][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.[CH3:30]N1C(C2C=C(N3C(=O)CC(=O)NC4C5CCCCC=5C=CC3=4)C=CC=2)=NN=N1>>[CH3:30][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[CH:28]=[CH:29][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:5]1
Reactant: O=C1CC(=O)N(c2cccc(-c3nnn[nH]3)c2)c2ccc3c(c2N1)CCCC3
Reactant: Cn1nnnc1-c1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)c1
Agent: [Na]
Product: Cn1nnc(-c2cccc(N3C(=O)CC(=O)Nc4c3ccc3c4CCCC3)c2)n1

Procedure:
5-[3-(1H-Tetrazol-5-yl)phenyl]-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione sodium salt (40 mg, 0.10 mmol) obtained in Example 2 was used in a process similar to Example 6 to give 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione as slightly brown crystal (18 mg, yield 46%) and 5-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione as slightly brown crystal (3 mg, yield 8%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCO
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCCCCCCCCCO
Yield: 74.1 %

Procedure:
In 600 ml of methanol was dissolved while warming 48.0 g of N-(12-hydroxydodecyl)phthalimide, 50 ml of hydrazine monohydrate was added at room temperature with stirring and the mixture was stirred overnight. The crystal thus separated out was filtered off and the solvent was distilled off. The residue was extracted with hot chloroform and insolubles were filtered off. The filtrate was distilled, the residue was extracted with hot chloroform (100 ml×3) and then the solvent was distilled off. The residue was dissolved in methanol and recrystallization from methanol-ethyl acetate gave 21.6 g of the title compound as a crystal.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH2:17]([C:19]1[O:20][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1)[CH3:18]>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:24]([C:22]3[N:23]=[C:19]([CH2:17][CH3:18])[O:20][C:21]=3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CCc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[CH2:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:26])[CH2:22][CH2:21][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:25][CH2:24]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)cc3)CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To 1-bromo-4-chlorobenzene (397 mg, 2.07 mmol) in tetrahydrofuran (10 mL), at −78° C., was added n-butyllithium (0.91 mL of a 2.5 M solution in hexanes, 2.3 mmol) dropwise. After 0.5 h, a solution of the ketone (500 mg, 2.28 mmol) from Step B above in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h and then warmed to 0° C. After 1 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(4-chlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (370 mg, 53%) as a colorless oil: 1H NMR (DMSO-d6, 500 MHz) δ 7.50 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.24-7.21 (m, 1H), 6.90-6.89 (m, 2H), 6.81-6.79 (m, 1H), 4.87 (s, 1H), 3.74 (s, 3H), 3.47 (s, 2H), 2.61-2.59 (m, 2H), 2.43-2.38 (m, 2H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:27](OC)=[O:28]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:27]=[O:28])[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)COC2(C=O)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A solution of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (2.4 g, 10 mmol) in THF (15 mL) was added to a solution of LDA (11 mmol) in THF (25 mL) at −78° C. under an atmosphere of nitrogen. The mixture was allowed to warm to −40° C. during 45 min. Freshly distilled methyl formate (0.75 mL, 12 mmol) was added at this temperature, and stirring was continued for 1 h while warming to 0° C. Then the mixture was poured into ice/saturated ammonium chloride solution, and extracted with Et2O (3×100 mL). The organic extracts were washed with brine, dried and evaporated. Silica gel chromatography (heptane, EtOAc 4:1) of the residue gave the product (1.3 g, 50%). 1H NMR (CDCl3) δ 5.35 (2H, s); 7.10 (2H, t, J=9.0 Hz); 7.50 (1H, dd, J=5.2 and 9.0 Hz); 7.57 (1H, s); 7.60 (1H, d, J=8.0 Hz); 7.70 (1H, d, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH2:37][CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH2:35][OH:36])[CH2:37][CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (R)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2450, observed 539.2447.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CO>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: CO
Product: Cc1cc(O)c(C(=O)O)cc1Br
Temperature: -20 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
After dissolving 2-hydroxy-4-methylbenzoic acid (24.54 g, 161.29 mmol) in methanol (300 ml), the solution was cooled to −20° C. A solution of bromine (26.03 g) in methanol (50 ml) was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was heated to dissolution in methanol (100 ml) and water (40 ml) was added. The precipitated crystals were filtered off and washed with 50% methanol-water. The precipitated crystals in the filtrate were also filtered off and washed with 50% methanol-water. The crystals were combined and dried to yield the title compound (24.8 g) as white crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15](O)=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>ClCCl>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[C:4]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=5[N:19]=4)[CH:5]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)O)CC4)ccc3F)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)CC4)ccc3F)nc2c1
Temperature: 35 °C
Yield: 14.7 %

Procedure:
Method I—Step a To a vial with [1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid hydrochloride (obtained as described in general method 8, step b) (0.10 g, 0.26 mmol) and HATU (0.10 g, 0.27 mmol) in dichloromethane (2 mL), TEA (0.08 mL, 0.56 mmol) and tert-butyl-1-piperazinecarboxylate (0.32 mmol, 0.06 g) were added. The reaction mixture was heated at 35° C. overnight, washed with water (3×2 mL) and saturated Na2CO3 solution (3×2 mL). The crude was then purified by flash chromatography (eluent: EtOAc), and then a filtration on an NH2 cartridge was run (eluent EtOAc), to obtain 0.02 g of the title compound (15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(N(CC)CC)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of triethylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid. Yield: 95%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]3([C:23]([NH:25][C@H:26]([CH2:31][OH:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]3([C:23]([NH:25][C@H:26]([CH:31]=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSCC[C@@H](C=O)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Under ice-cooling, 356 mg (0.84 mmol) of Des Martin periodinane was added to a solution of 65 mg (0.14 mmol) of N-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol in 5 ml of methylene chloride, and the mixture was stirred for 1 hour. At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturated aqueous sodium bicarbonate solution were added to the reaction solution. Sodium thiosulfate was added thereto until the solution became transparent, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 55 mg (85%) of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[CH:54]=[N:55][N:56](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:57]=1)CCC>>[NH:24]1[CH:25]=[C:21]([C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:53]4[CH:57]=[N:56][NH:55][CH:54]=4)[CH:8]=3)[CH:13]=2)([OH:45])[CH:18]([CH3:20])[CH3:19])[N:22]=[CH:23]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(-c3cn[nH]c3)ccc2c1)c1c[nH]cn1
Yield: 233.1 %

Procedure:
In a similar manner to that described in Example 2-(i), the reaction was carried out by using 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (3.0 g) and 4-tributylstannyl-1-trityl-1H-pyrazole (5.48 g) to give the titled compound (3.54 g) as a pale brown powder.