Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[F:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1.[NH4+].[Cl-]>O1CCCC1>[F:18][C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][CH:20]=1)[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)=[O:5]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2cccc(F)c2)C1
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To an ice cooled solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (D26) (61.8 mg, 0.25 mmol) in dry tetrahydrofuran (2 ml), 3-Fluorophenylmagnesiumbromide (1M in tetrahyfrofuran) (0.506 ml, 0.506 mmol) was added dropwise the under stirring under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h then NH4Cl sat. sol. (10 ml) was added and the mixture was extracted with ethylacetate (3×20 ml). The organic layers were collected, dried with Na2SO4 and filtrated. The solvent was evaporated in vacuo to afford the title compound (D27) (69 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[CH3:16][N:17]1[C:22](=[O:23])[C:21]2[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][S:26][C:20]=2[N:19]([CH:32]([CH3:34])[CH3:33])[C:18]1=[O:35].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][CH:43]=1>O1CCCC1.CN1C(=O)N(C)CCC1>[OH:47][CH:46]([C:45]1[CH:44]=[CH:43][C:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)=[CH:49][CH:48]=1)[C:25]1[S:26][C:20]2[N:19]([CH:32]([CH3:34])[CH3:33])[C:18](=[O:35])[N:17]([CH3:16])[C:22](=[O:23])[C:21]=2[C:24]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2C(C)C
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(O)c2ccc(-c3ccccn3)cc2)sc2c1c(=O)n(C)c(=O)n2C(C)C
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
Lithium diisopropylamide, freshly made by adding n-buthyllithium (1.1 mL, 2.5M in hexanes) to a solution of diisopropylamine (0.46 mL) in dry tetrahydrofuran under nitrogen at 0° C. and stirring for 20 min, was added to a solution of 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester (0.7 g), 4-(2-pyridyl)benzaldehyde (0.52 g) and DMPU (057 mL) in dry tetrahydrofuran under nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 4 hours then quenched with glacial acetic acid (10 mL) and allowed to reach room temperature. Water was added and the mixture was extracted with ethyl acetate (twice). The organics were washed with brine, dried over MgSO4 and concentrated under vacuum to give a brown oil which was purified by silica chromatography eluting with isohexane/ethyl acetate (1/1) to give the sub-title compound as a pale yellow foam (0.47 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C(=O)([O-])O.[Na+]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1C1OCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 49.3 mmol), ethylene glycol (27.5 mL, 493 mmol), camphorsulfonic acid (115 mg, 0.493 mmol), and toluene (250 mL) was stirred for 5 hours under reflux. The mixture was cooled to room temperature and a saturated sodium hydrogencarbonate aqueous solution was added thereto. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (12.5 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[K+].[CH3:36]I.[NH4+].[Cl-]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:36])[CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Reactant: CI
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D146) (320 mg) in dimethyl sulfoxide (5 mL) was added KOH (152 mg) and MeI (0.64 mL). The reaction solution was stirred at room temperature overnight. Saturated aqueous NH4Cl (10 mL) solution was added, and the resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine and dried over sodium sulphate. The organic solution was concentrated to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoate (D147) (330 mg). MS (ES): C25H25ClFN3O4 requires 485; found 486.2 (M+H+).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (500 mg), thiomorpholine 1,1-dioxide (240 mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (280 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3:7-1:9, volume ratio) to give the title compound (210 mg, yield 35%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][NH:6][CH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.C(N(CC)CC)C>>[CH3:5][N:6]([CH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1)[C:1]([Cl:4])=[O:2]
Reactant: CNC1CCSCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)Cl)C1CCSCC1

Procedure:
Similarly to the method described in intermediate 1.2, 22.8 g (0.23 mol) of phosgene, 10 g (76 mmol) of methyl(tetrahydro-2H-thiopyran-4-yl)amine and 7.8 g (76 mmol) of triethylamine were reacted. Yield 13.4 g. MS (m/z): 193 [M]+, 158 [M−Cl]+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9].Cl.[NH2:39]O.CC([O-])=O.[Na+]>CO.O>[F:36][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[O:23][N:39]=[C:20]([CH3:21])[CH:19]=2)[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: NO
Reactant: CC(=O)CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(c2cc(C)no2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-[8-chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.13 mmol, 72 mg), hydroxylamine hydrochloride (1.3 mmol, 90 mg) in MeOH (2 mL) was added NaOAc (20 mg) at room temperature. The resulting suspension was stirred vigorously at 70° C. for 12 h. After completion, the mixture was diluted with water (20 mL), extracted with EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness. Flash chromatography (EtOAc-Hexane as eluent 1:1) afforded the title compound as viscous foam; Rf 0.35 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 564 (M+H2O).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([SH:12])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[Na].[C:14]1([CH2:20][C:21]([NH:23][C@@H:24]2[C:52](=[O:53])[N:26]3[C:27]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[C:28](OS(C)(=O)=O)[CH2:29][S:30][C@H:25]23)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C>O1CCCC1.O.CO>[C:14]1([CH2:20][C:21]([NH:23][C@@H:24]2[C:52](=[O:53])[N:26]3[C:27]([C:36]([O:38][CH:39]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:37])=[C:28]([S:12][C:9]4[S:10][CH:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[N:8]=4)[CH2:29][S:30][C@H:25]23)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Sc1nc(-c2ccncc2)cs1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc(-c4ccncc4)cs3)CS[C@H]12
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4-(4-Pyridyl)-1,3-thiazole-2-thiol (225 g, 1.16 mol) was suspended in tetrahydrofuran (1.5 L) and 28% sodium methylatemethanol solution (235 g, 1.22 mol) was added dropwise at 25° C. over 10 min. The mixture was stirred for 1 hr. The reaction mixture was ice-cooled and benzhydryl 7β-[(phenylacetyl)amino]-3-[(methylsulfonyl)oxy]-3-cephem-4-carboxylate (479 g, 0.83 mol) dissolved in tetrahydrofuran (3.5 L) was added dropwise over 30 min. The mixture was stirred at 0° C. for 1 hr and a mixture of acetic acid (50 mL), methanol (5 L) and water (7 L) was added dropwise over 30 min. The mixture was stirred at 0° C. for 2 hr, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol (1 L×2) and dried in vacuo to give the title compound (438 g, 0.63 mol). yield: 76%.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=3)=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31](N(CC)C(C)C)(C)C.IC>C(#N)C.ClCCl>[CH3:31][N:12]1[CH2:11][CH2:10][N:9]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:30])[F:28])=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCNC(c2ccccc2)C1
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 80 °C

Procedure:
This compound could be made in the following manner: 100 mg of (3-phenyl-piperazin-1-yl)-(2′-trifluoromethyl-biphenyl-4-yl)-methanone would be dissolved in 3 mL of acetonitrile, 2 equiv. of N,N-diisopropylethylamine would be added followed by 1.1 equiv. of iodomethane. The reaction would be heated to 80° C. overnight. After cooling to room temperature, the reaction would be diluted with dichloromethane and washed with 1M aqueous sodium hydroxide solution, dried over sodium sulfate and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)=O.[NH2:38][CH2:39][C@@H:40]([C:49]1[CH:50]=[CH:51][C:52]([OH:58])=[C:53]([NH:55][CH:56]=[O:57])[CH:54]=1)[O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO>[Si:42]([O:41][C@H:40]([C:49]1[CH:50]=[CH:51][C:52]([OH:58])=[C:53]([NH:55][CH:56]=[O:57])[CH:54]=1)[CH2:39][NH:38][CH2:1][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (150 mg, 0.30 mmol) and N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide (112 mg, 0.36 mmol) in a 1:1 mixture of dichloromethane and methanol (3.0 mL total) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (191 mg, 0.9 mmol) was added and the resulting mixture was stirred at room temperature overnight. Acetic acid was added to quench the reaction and the mixture was concentrated under reduced pressure to give biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)-ethyl]piperidin-4-yl ester, which was used without further purification. LCMS (10-70) Rt=4.55; [M+H+] found 794.6.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1>C(N)CCC>[CH2:2]([NH:3][C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:30])([F:31])[F:29])[N:3]=1)[CH2:7][CH2:6][CH3:5]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Solvent: CCCCN
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2NCCCC)cc(F)c1NS(C)(=O)=O
Yield: 24.6 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (30 mg, 0.057 mmol) was reacted with n-butylamine (500 μl) as in example 65 to give the title compound (3.6 mg, 12%) after purification by column chromatography (Hex EtOAc=1/1).
Reaction SMILES: C1(CCCN2CCN(C3C=C(F)C(OC)=CC=3F)CC2)CCCCC1.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:56])[CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[C:50]([F:52])[C:49]([O:53]C)=[CH:48][C:47]=3[F:55])[CH2:42][CH2:41]2)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:56])[CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[C:50]([F:52])[C:49]([OH:53])=[CH:48][C:47]=3[F:55])[CH2:42][CH2:41]2)=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cc(F)c(N2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)cc1F
Agent: COc1cc(F)c(N2CCN(CCCC3CCCCC3)CC2)cc1F
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCN(c3cc(F)c(O)cc3F)CC2)cc1
Yield: 45.7 %

Procedure:
Production Example 94 was repeated except that 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine was replaced with 1-(4-tert-butylphenyl)-4-[4-(2,5-difluoro-4-methoxyphenyl)piperazin-1-yl]butan-1-one (330 mg). The resulting crude product was purified on TLC (developer, ethyl acetate: hexane=2:1) to provide 1-(4-tert-butylphenyl)-4-[4-(2,5-difluoro-4-hydroxyphenyl)piperazin-1-yl]butan-1-one (146 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:20][N:21]([CH3:23])[CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC
Temperature: 90 °C
Yield: 79.8 %

Procedure:
A stirred mixture of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (10.02 mmol, 1 eq) and 1,1-dimethoxy-N,N-dimethylmethanamine (3.0 mL, 22 mmol, 2.2 eq) was heated at 90° C. for 2 hours. After evaporation of excess 1,1-dimethoxy-N,N-dimethylmethanamine, the crude product was purified by flash chromatography on silica gel (0 to 80% ethyl acetate in dichloromethane) to yield 2.493 g (80%) of ethyl 2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate. LCMS (ESI) m+H=312.2.
Reaction SMILES: C([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(COC)OC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:21]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 80 °C

Procedure:
Benzyl Boc-4-iodophenylalanine (1 eq.), arylboronic acid (1.5 eq.), sodium carbonate (2 eq.), palladium acetate (0.05 eq.) and tri ortho-tolylphosphine (0.1 eq.) was added to a degassed mixture of dimethoxyethane (6 ml/mmol amino acid) and water (1 ml/mmol amino acid). The reaction mixture was kept under argon and heated to 80° C. for 4-6 h. After cooling to room temperature, the mixture was filtered through a short pad of silica gel and sodium carbonate. The filter cake was further washed with ethyl acetate and combined with the other fraction before the solvents were removed under reduced pressure. The products were purified using flash chromatography using mixtures of ethyl acetate and n-hexane as eluent.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:11]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1>O1CCCC1>[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CCCCCCCC(=O)O
Reactant: NCCCn1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCC(=O)NCCCn1ccnc1

Procedure:
The requisite starting amine was prepared as follows: reaction of n-octanoic acid and 1,1'-carbonyldi(1-imidazole) in tetrahydrofuran solution with 3-(1H-imidazol-1-yl)propanamine gave N-3-(1H-imidazolyl) propyl-n-octanamide, which upon reduction with BH3 in tetrahydrofuran solution gave N-(3-(1H-imidazol-1-yl) propyl-N-(n-octyl))amine.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][NH:13][C:14]([NH:16][OH:17])=[NH:15].[ClH:18].[CH:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH2:26])=[NH:25])=O>O.Cl.CO>[ClH:18].[ClH:18].[OH:17][NH:16][C:14]([NH:13][N:12]=[CH:19][C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[NH:25])[NH2:26])[CH:22]=1)=[NH:15]
Reactant: N=C(N)c1cccc(C=O)c1
Reactant: N=C(NN)NO
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(NO)NN=Cc1cccc(C(=N)N)c1

Procedure:
A solution of 7.3 g (0.028 mol) of 1-amino-3-hydroxyguanidine toluenesulfonate in 14 ml of water and 14.5 ml of 2N hydrochloric acid is added to a solution of 6.9 g (0.028 mol) of crude 3-formylbenzamidine hydrochloride (prepared as described in Example 1b) in 28 ml of methanol, and the reaction mixture is heated at 70° for 1 hour. It is then cooled and concentrated by evaporation, and the crude product is recrystallised from water/ethanol; m.p. 248°-250°.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:62]=[N:61][NH:60][CH:59]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)cccc4c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)cccc4c3=O)cc2)CCC1
Yield: 83 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(1H-pyrazol-4-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 20 g C18 cartridge {gradient 10 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (73 mg, 83%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 3H), 8.14-8.08 (m, 3H), 7.95 (dd, J=7.9 and 1.8 Hz, 1H), 7.53-7.32 (m, 8H), 7.25 (d, J=8.3 Hz, 2H), 3.83 (bs, 1H), 2.57-2.43 (m, 4H), 2.19-2.06 (m, 1H), 1.82-1.69 (m, 1H). LCMS (Method E): RT=3.03 min, [M+H]+=434.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N:22]#[C:23]Cl>C(Cl)Cl>[C:23]([N:13]1[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][C:12]1([CH3:19])[CH3:18])#[N:22]
Reactant: N#CCl
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1C#N

Procedure:
104.5 g (0.4 mole) of 4-benzoyloxy-2,2,6,6-tetramethyl piperidine are dissolved in 400 ml of methylene chloride, 400 ml of 1N sodium hydroxide are introduced and 21 ml of cyanogen chloride are added dropwise over a period of 30 minutes with cooling at -5° to -5° C. The cooling is then removed and the mixture is stirred until it reaches room temperature. The organic phase is separated off, dried with sodium sulphate, filtered and the methylene chloride distilled off. Recrystallisation from acetonitrile gives 94 g (82% of the theoretical) of 1-cyano-4-benzoyloxy-2,2,6,6-tetramethyl piperidine melting at 150° to 152° C. The IR-spectrum no longer shows an NH-band, but instead a nitrile band at 2170 cm-1 and a carbonyl band at 1700 cm-1.