Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OCC)(=O)C.C(OCC)(=O)C.C(OC(=O)[NH:20][C@@H:21]([CH2:36][O:37]CC1C=CC=CC=1)[CH2:22][O:23][CH2:24][C:25](=O)[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)(C)(C)C>[H][H]>[F:34][C:28]1[CH:27]=[C:26]([C@H:25]2[NH:20][C@@H:21]([CH2:36][OH:37])[CH2:22][O:23][CH2:24]2)[CH:31]=[C:30]([F:32])[C:29]=1[F:33]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (30 mL) was added to an ethyl acetate solution (30 mL) of {(S)-1-benzyloxymethyl-2-[2-oxo-2-(3,4,5-trifluorophenyl)ethoxy]ethyl}carbamic acid tert-butyl ester (3.55 g) at room temperature. The resulting reaction solution was stirred at room temperature for 1 hr and then concentrated under reduced pressure. To a methanol solution (50 mL) of the obtained residue, 10% palladium-carbon (containing 50% water, 167 mg) was added. The resulting reaction solution was stirred in hydrogen atmosphere at room temperature for 18 hr, and the palladium carbon in the reaction solution was removed by filtration. The filtrate was concentrated under reduced pressure, and a saturated sodium hydrogencarbonate aqueous solution and ethyl acetate were added thereto. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 1.52 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[CH:20][C:15]([C:16](=[N:18]O)[NH2:17])=[CH:14][CH:13]=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][N:18]=[C:16]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:21][CH:20]=2)[N:17]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1ccc(C(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A solution of 3-chloro-thiophene-2-carbonyl chloride (455 mg, 2.51 mmol) and 4-trifluoromethyl-benzamidoxime (513 mg, 2.51 mmol) in 1,4-dioxane (50 mL) was refluxed for 1 h, then BF3OEt2 (0.1 mL) was added dropwise. The solution was refluxed for 5 h and cooled to room temperature. To the stirred solution was added water (100 mL) to produce precipitates. The solid was collected by filtration, washed with dioxane:water (1:1), and dried to yield 687 mg (82%) of the title compound. 1H NMR (CDCl3): 8.29 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.63 (d, J=5.1 Hz, 1H), 7.15 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>>[O:30]=[S:27]1(=[O:31])[CH2:28][CH2:29][N:24]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:25][CH2:26]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 58 %

Procedure:
As described for example 147, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol) was converted, using thiomorpholine-S,S-dioxide instead of cyclopropylmethylamine, to the title compound (75 mg, 58%) which was obtained as an off white solid. MS: m/e=429.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH2:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>CCCCO.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>[CH2:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:16][CH:15]=1)(=[O:12])=[O:13])[CH3:10]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(Br)cn1
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: CCCCO
Product: CCS(=O)(=O)c1ccc(-c2ccc(N)nc2)cc1
Temperature: 100 °C
Yield: 46.5 %

Procedure:
In particular, a slurry of 2-amino-5-bromopridine (1.24 g, 4.67 mmol), 4-(ethylsulfonyl)phenylboronic acid (1.10 g, 5.14 mmol), and Pd(PPh3)4 (0.16 g, 0.13 mmol) in n-BuOH (20 mL) was treated with 2.0 M aq. Na2CO3 (4.5 mL). The reaction was sparged with dry N2 under sonication for 10 min to degas, and then refluxed for 16 h at 100° C. At completion, the reaction was cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc (50 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography over silica gel (30-100% EtOAc:hexane eluent) to provide 5-(4-(ethylsulfonyl)phenyl)pyridin-2-amine as a white solid (0.57 g, 47% yield). 1H NMR (300 MHz, MeOH) δ ppm 8.27-8.31 (m, 1H), 7.91-7.98 (m, 2H), 7.79-7.89 (m, 3 H), 6.71 (dd, J=8.7, 0.7 Hz, 1H), 3.30-3.35 (m, 2H), 3.24 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.4 Hz, 3H); MS (EI) m/z: 263 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([C:20]1[C:21]([CH3:30])=[C:22]([C:27]([OH:29])=[O:28])[NH:23][C:24]=1[CH:25]=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([C:20]1[C:21]([CH3:30])=[C:22]([C:27]([OH:29])=[O:28])[NH:23][C:24]=1[CH:25]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][C:6]1=[O:11])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C(=O)O)[nH]c(C=O)c1C(=O)c1ccccc1
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(=O)c1ccccc1

Procedure:
5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid using method D to give 4-benzoyl-5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:15]=1[C:16]([O:18]CC)=O)C.C(O)(=O)C>O1CCCC1>[F:25][C:23]1[CH:24]=[C:14]2[C:15]([C:16]([OH:18])=[C:7]([C:6]#[N:8])[CH:12]=[N:13]2)=[CH:21][CH:22]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(F)cc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(F)ccc2c1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
To a solution of 2.5 M n-butyl lithium in tetrahydrofuran (53.6 mL, 134 mmol) in 54 mL of tetrahydrofuran at −78° C. is added dropwise a solution of acetonitrile (7.1 mL, 136 mmol) in 100 mL of tetrahydrofuran. After stirring at −78° C. for 10 min, a solution of ethyl 2-{[(1E)-(dimethylamino)methylidene]amino}-4-fluorobenzoate (14.5 g, 60.9 mmol) in 100 mL of tetrahydrofuran is added over a period of 1.5 h. After stirring at −78° C. for 2 h, the reaction temperature is slowly allowed to warm to −10° C. The mixture is then cooled to −78° C. and acetic acid (18.3 g, 305 mmol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The precipitate is collected by filtration washing with tetrahydrofuran, water, diethyl ether, ethyl acetate and then additional diethyl ether to give 7.95 g of 7-fluoro-4-hydroxyquinoline-3-carbonitrile as an off-white solid, mp>250° C.
Reaction SMILES: [CH2:1]([P:4]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][C:7]#[N:8])[CH2:2][CH3:3].[OH:12]O>C(O)(=O)C>[C:7]([CH2:6][CH2:5][P:4](=[O:12])([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:10][CH3:11])#[N:8]
Reactant: OO
Reactant: CCCP(CCC)CCC#N
Solvent: CC(=O)O
Product: CCCP(=O)(CCC)CCC#N
Temperature: 75 °C
Yield: 100.2 %

Procedure:
To dipropyl cyanoethyl phosphine (6.88 grams, 0.04 mole) in 25 ml glacial acetic acid was added 5.67 grams (0.05 mole) of 30% hydrogen peroxide at 60° C. The reaction mixture was heated for 30 minutes at 75° C. to give 7.5 grams of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[ClH:20].[CH3:21]O>>[ClH:20].[CH3:21][O:10][C:9](=[O:11])[CH:8]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)C(NCc1ccccc1)c1ccc(F)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(NCc1ccccc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
4Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid (12.2 kg, 47.1 moles) was slurried in methanol (37 L), then hydrogen chloride gas was passed over the mixture. The resulting slurry was stirred at 35-45° C. for 3 hours, then concentrated to 30-35 L by distillation. Methyl-t-butyl ether (20 L) was added and the batch was seeded with 4-Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride. Upon development of the seed-bed, methyl-t-butyl ether (20 L) was added. The slurry was aged for 1 hour, then filtered. The filter cake was washed with methyl-t-butyl ether:methanol (95:5, 8.0 L), then dried under vacuum at 30° C. to give 12.2 kg (84% yield) of 4-fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C1COCC1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1
Reactant: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CO)CC1
Temperature: -78 °C

Procedure:
trans-[4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (26.50 g, 67.66 mmol) was charged in a 400 mL steel bomb and was dissolved in 2M NH3 in isopropanol (300 mL) and anhydrous THF (10 mL). The reaction mixture was cooled to −78° C. Ammonia gas was bubbled vigorously into the solution for 8 min; then the bomb was tightly sealed and heated to 120° C. for 20 h. The crude reaction mixture was concentrated in vacuo, then the reaction residue was taken up with MeOH/CHCl3, loaded onto silica gel. The mixture was purified by a silica gel glass column chromatography [eluted with 1:1 CH2Cl2/EtOAc to 10%˜7 N NH3 in MeOH/CHCl3] to afford the desired product as a beige cream white solid; MS (ES+): m/z 373.01 (100) [MH+], 373.98 (50) [MH+2]; tR (polar-5 min/openlynx) 1.57 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:11]=[C:10]([NH2:12])[O:9][N:8]=1)([CH3:6])[CH3:5].C(C1C=C(N[C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)ON=1)(C)C>>[CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][N:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCC(C)(C)c1cc(N)on1
Product: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1

Procedure:
Prepared from 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine (100 mg, 0.59 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate as an oil that was not purified further.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)NCCC(=O)O)C2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine (1.64 g) in ethyl acetate (16 ml) was added 4N HCl in ethyl acetate (9.37 ml) at 0° C., and the reaction mixture was stirred for 2 hours at room temperature. The precipitates were filtered, washed with ether and resolved in water, neutralized with saturated aqueous NaHCO3, desalted by using the resin of HP-20 eluting with isopropanol-H2O (1:1), then freeze-dried to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine as a white powder (690 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=1[F:25])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[F:25])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of di-tert-butyl(2-fluoro-5-nitrophenyl)imidodicarbonate (256 mg, 0.718 mmol) in methanol (10 mL) was added 10% palladium-carbon (50 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. 10% Palladium-carbon powder was filtered off by celite filtration, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:24](=[O:26])[CH3:25])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (1.2 g) and acetic anhydride (0.36 ml) in dichloromethane (12 ml) was stirred at ambient temperature for 2 hours, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give a brown powder of N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}acetamide (0.77 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23]I)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23][S:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCI)C(=O)OC)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCSc2ccc(Cl)cc2)C(=O)OC)cc1
Yield: 80.6 %

Procedure:
A solution of 0.958 g (2.0 mmol) of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-iodopentanoate, 0.35 g (2.4 mmol) of 4-chlorobenzenethiol, and 0.323 g of diisopropylethylamine in 50 ml of isopropyl alcohol was stirred at room temperature for 18 hours. Evaporation of solvent gave 0.8 g of methyl 2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}-(methyl)amino]-5-[(4-chlorophenyl)sulfanyl]-pentanoate as colorless crystals, mp 88-89° C., Electrospray Mass Spec 496.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:29]([C@H:38]([CH2:51][O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:39]C(=O)C1C=CC([N+]([O-])=O)=CC=1)[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][O:11][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(N(CC)CC)C.F.F.F.C(N(CC)CC)C>CO>[CH2:1]([O:8][C@H:9]([C@@H:29]([C@H:38]([CH2:51][O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[OH:39])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OC(=O)c1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: F
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
Compound 6 (110 g, 138.54 mmole) was dissolved in methanol (500 mL) and sodium methoxide (11 g, 204.0 mmole, 1.5 eq.) was added and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ether and water. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried in vacuo for 3 hrs and dissolved in dry THF under nitrogen. Triethylamine (TEA) (100 mL, 0.752 mole, 5 eq.) was added followed by triethylamine trihydrofluoride (TREAT.HF) (220 mL, 1.38 mole, 10 eq.) and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue partitioned between ether and water. The ether layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (40% ethyl acetate in hexane) to give 51 g of compound 7 in 90% yield (reported literature yield 81%).
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[F:11].C([Li])CCC.C([O:19][B:20](OCC)[O:21]CC)C>CCCCCC.O1CCCC1>[F:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[B:20]([OH:21])[OH:19]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CCOB(OCC)OCC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)c(F)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a 500 mL three-necked round-bottomed flask equipped with septum and N2 inlet were added 10.0 g (52.9 mmol) 4-bromo-3-fluorotoluene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 25.4 mL (63.5 mmol) of a 2.5 M solution of butyl lithium in hexane was added slowly so the temperature did not exceed −60° C. The clear solution was stirred at −70° C. for 1 hour, then treated with 10.8 mL (63.5 mmol) triethylborate. The reaction was stirred for 2 hours at −70° C., then warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, adjusted to pH 1-2 with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 6.1 g (75%), as a mixture of monoaryl and diaryl boronic acids.
Reaction SMILES: O[C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.CCN(S(F)(F)[F:32])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:32][C@@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@@H](F)C1
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.8 g, 2.29 mmole), in DCM (50 mL) at −78° C. was added DAST dropwise (0.59 mL, 4.80 mmole). After 2 h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (0.68 g, 85%) as a colorless oil: LC-MS (ES) m/e 353 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(/C=C/c2ccccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1CN1CCC(CCc2ccccn2)CC1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
332 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[(E)-2-(2-pyridyl)-1-ethenyl]piperidine obtained in Example 29 and 79 mg of 10% palladium-carbon powder (water-containing product) were suspended in 5 ml of ethanol. After replacing the atmosphere of a container with hydrogen, the mixture was stirred at normal temperature under normal pressure for 30 minutes. The reaction solution was filtered, and the filtrate was evaproated, to give 234 mg of the title compound as a colorless oil.
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][Br:19])=[CH:13][C:12]=1[C:21]#[N:22])=[O:9])C1C=CC=CC=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][C:8](=[O:9])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][Br:19])=[CH:13][C:12]=1[C:21]#[N:22])([CH3:26])([CH3:25])[CH3:24]
Reactant: N#Cc1cc(C(=O)CBr)ccc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)Nc1ccc(C(=O)CBr)cc1C#N

Procedure:
The starting compound, 4'-(3-tert. butyl-ureido)-2-bromo-3'-cyano-acetophenone was prepared by reacting 4'-phenoxycarbonylamino-2-bromo-3'-cyanoacetophenone with tert. butylamine at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH3:32])[CH:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: CNC1CCN(C)CC1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-piperidin-4-yl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Methyl-(1-methyl-piperidin-4-yl)-amine following General Procedure C.