Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@:6]([CH3:18])([C:14]([F:17])([F:16])[F:15])[O:5]1.[CH3:19]N(C=O)C>>[CH3:19][O:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@:6]([CH3:18])([C:14]([F:15])([F:17])[F:16])[O:5]1
Reactant: CN(C)C=O
Reactant: C[C@@]1(C(F)(F)F)OC(O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: COC1Cc2ccccc2[C@](C)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred mixture of sodium hydride (3.47 g, 0.145 mol) in DMF (50 mL) was added (1R)-hydroxy-1-methyl-1-trifluoromethylisochroman (28.0 g, 0.121 mol) solution in DMF (370 mL) at 0° C., then the mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched with water and diluted with saturated aqueous ammonium chloride. This was extracted with ethyl acetate-toluene (4:1). The organic fraction was washed with water and brine, and dried over magnesium sulfate. The solvent was removed in vacuo, the residue was purified by column chromatography on silica-gel eluted with hexane and ethyl acetate (40:1) to give the title compound as a colorless oil (29.1 g, 98%). The 1H-NMR spectra of this material was identical with that of racemate.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.ClC1C=CC2[S:26]C3C(=CC=CC=3)NC=2C=1>>[Cl:14][C:10]1[C:9]2[S:26][C:3]3[C:4](=[CH:5][CH:6]=[CH:1][CH:2]=3)[NH:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: Clc1cccc(Nc2ccccc2)c1
Product: Clc1cccc2c1Sc1ccccc1N2

Procedure:
The conversion rate of the 3-chlorodiphenylamine is 80%, and the yield of 2-chlorophenothiazine is 63% with respect to the 3-chlorodiphenylamine converted.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH2:21][CH:20]=[CH2:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: C=CCBr
Reactant: CC(C)(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
To a slurry of hexanes-washed NaH (0.534 g of a 60% suspension in mineral oil, 13.4 mmol) in DMF (10 mL) at 0° C. was added a solution of 4-[(2,2-dimethylpropyl)amino]-2-(trifluoromethyl)benzonitrile (1.71 g, 6.68 mmol) in DMF (4 mL), dropwise over 10 min. The resulting solution was stirred 15 min and neat allyl bromide (1.16 mL, 13.4 mmol) was added dropwise over 3 min. The resulting solution was stirred 1 h, poured into water and the whole was extracted with Et2O (×3). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.82 g of the title compound as a colorless syrup: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 1H), 6.83 (dd, J=8.9, 2.5 Hz, 1H), 5.73 (ddt, J=17.2, 10.6, 4.6 Hz, 1H), 5.23 (app. d, J=10.6 Hz, 1H), 5.05 (app. d, J=17.5 Hz, 1H), 4.09 (overlapping ddd, 2H), 3.26 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(O)(=O)C>C1C=CC=CC=1>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:14]=[C:15]([NH:16][C:2]([CH3:10])=[CH:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=CC(=O)OC(C)C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4.33 g (30 mmol) isopropyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
47 mg (0.09 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 33 mg (78% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: Cc1ccc2cccc(N3CCNCC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc2cccc(N3CCN(C4CCN(c5cccc6cccnc56)CC4)CC3)c2n1

Procedure:
Using the synthetic methods described in previous examples, 2-methyl-8-(piperazin-1-yl)quinoline (Oruz, et al., J. Med. Chem. 45:4128 (2002)) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a light brown semi-solid; MS (ES) m/z (relative intensity) 438 (M+H)+ (100).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C(C)(C)C)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 2,2-dimethylpropanoyl chloride as a colorless oil (88%). 1H NMR (CDCl3, 300 MHz) δ 7.72 (d, J=2.5 Hz, 1H), 7.43 (m, 4H), 7.15 (m, 4H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.84 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.75 (s, 6H), 1.61 (m, 2H), 1.36 (m, 2H), 1.07 (s, 9H), 0.94 (t, J=7.4 Hz, 3H). M+ (ESI): 524.2. HPLC, Rt: 5.85 min (Purity: 99.5
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12](N(OC)C)=[O:13])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:24]1COCC1>>[CH2:1]([C:3]1([CH:8]([CH3:24])[CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCC1(CCCCC(=O)N(C)OC)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(C(C)CCCC=O)OCCO1
Temperature: 25 °C

Procedure:
To a stirred mixture of 5-(2-ethyl-1,3-dioxolan-2-yl)-N-methoxy-N-methyl-pentanamide (1 eq.) [Prepared by coupling 7-oxononanoic acid with N, O-dimethylhydroxylamine and subsequent ketal protection] in anhydrous THF at −78° C. was added a 1 M LiAlH4 solution in THF (1.6 eq.) slowly over 5 min. After 45 min the reaction was quenched by addition of Et2O and then aq. Rochelle's salt solution (10% w/v). The mixture was warmed to RT with a vigourous stirring. The organic phase was separated, washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5% EtOAc/Petroleum ether to afford the desired aldehyde. 1H NMR (300 MHz, CD3CN) δ: 9.77 (1H, s), 4.00 (4H, s), 2.44 (2H, t, J=7.0 Hz), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m), 1.00-0.80 (3H, t, J=7.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10]Br)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][N:14]([CH3:15])[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of m-nitro-α-bromotoluene (3.2 g) in dimethylformamide (50 ml) was added dropwise to a solution of dimethylamine hydrochloride (1.45 g) and triethylamine (4.36 ml) in dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 1 h and then its temperature was raised to 50° C., at which it was stirred for 3 h. The reaction mixture was distilled under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 2.56 g of the titled compound (yield, 96%).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([I:11])=[CH:6][C:5]=1[O:12][CH3:13].[OH-].[Na+]>CO>[Cl:10][C:8]1[C:7]([I:11])=[CH:6][C:5]([O:12][CH3:13])=[C:4]([CH:9]=1)[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(I)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(I)c(Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A mixture of 5-chloro-4-iodo-2-methoxy benzoic acid methyl ester of Step B (3.00 g, 9.19 mmol) and sodium hydroxide (1.10 g, 27.6 mmol) in methanol (92 mL) was refluxed for 12 hours. The reaction was cooled to room temperature and the solvent evaporated. The residue was dissolved in 1 N sodium hydroxide (75 mL), the solution washed with diethyl ether and the organic washings discarded. The aqueous phase was acidified with 2 N HCl and extracted with diethyl ether. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title carboxylic acid (2.64 g) as orange crystals, m.p. 150-151° C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:26])[N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][N:13]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>C(O)(=O)C>[C:2]1([C:1]2[C:9]3[C:10](=[O:26])[N:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]=3[NH:29][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c(-c3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
850 mg (2.5 millimoles) of Compound 101 was suspended in 5 ml of glacial acetic acid, and 0.26 ml (5.5 millimoles) of hydrazine monohydrate was added to the suspension. The mixture was heated under reflux for 5 hours and the reaction mixture was cooled to room temperature. The precipitate was collected by filtration, and recrystallized from DMF-water to obtain 440 mg (yield 52.4%) of Compound 1.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[CH2:17]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH3:29])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:21]([CH2:17][CH:18]([CH3:20])[CH3:19])[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1OC
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-(chlorosulfonyl)-2-methoxybenzoate (1 g, 3.78 mmol) in pyridine (3 mL) at 25° C. was added N-isobutyl-2,4-dimethylaniline (0.670 g, 3.78 mmol) and the reaction mixture stirred at 25° C. for 2 hours, then stood for 12 hours. The pyridine was evaporated in vacuo to give a yellow oil which was purified by silica (Si) chromatography (0-50% ethyl acetate-cyclohexane). The appropriate fractions were combined and evaporated in vacuo to give the required product, 1.485 g, as a colourless oil. LCMS [LCMS2] Rt 1.37 min, m/z (ES+) 406 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:17](O)=[O:18].C(Cl)(=O)C(Cl)=O.[CH3:26][O:27][C:28](=[O:50])[C@@H:29]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH:30]([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:26][O:27][C:28](=[O:50])[C@@H:29]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([NH:49][C:17]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[C:2]=3[CH3:1])=[O:18])=[CH:47][CH:48]=2)=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: Cc1c(C(=O)O)oc2cccc(-c3ccccc3)c12
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccccc5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To 60 mg (0.24 mmol) 3-methyl-4-phenyl-benzofuran-2-carboxylic acid was added 1 mL of oxalyl chloride and the mixture was refluxed for 1 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 129 mg (0.36 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, 87 mg (0.714 mmol) of 4-(dimethylamino)pyridine and 2 mL of in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 41 mg (29% yield) of (S)-3-methyl-2-{4′-[(3-methyl-4-phenyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11].C(NC(C)C)(C)C>[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a mixture of 4-fluoroiodobenzene (710.0 mg, 3.82 mmol), bistriphenylphosphine palladium chloride (27.0 mg, 0.038 mmol), CuI (3.64 mg, 0.019 mmol) and propargyl alcohol (214.0 mg, 3.82 mmol), was added diisopropylamine (6.1 mL, 1.6 mL/mmol) under nitrogen atmosphere. The reaction mixture was stirred at r.t. for 6 h. After the completion of the reaction as confirmed by TLC, the crude product was extracted with ethylacetate (50 mL). The organic layer was washed with 10% HCl (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet.Ether) to afford 3-(4-fluoro-phenyl)-prop-2-yn-1-ol (366.0 mg, 64%) as a viscous oil.
Reaction SMILES: C(OC1C=CC=CC=1[C:15]1[N:20]=[C:19](OCC(N)=O)[C:18](C#N)=[C:17](S(C)=O)[CH:16]=1)C1C=CC=CC=1.C[N:32]([CH:34]=[O:35])C>>[NH:20]1[CH2:15][CH2:16][CH:17]([C:34]([NH2:32])=[O:35])[CH2:18][CH2:19]1
Reactant: CN(C)C=O
Reactant: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)nc(OCC(N)=O)c1C#N
Product: NC(=O)C1CCNCC1

Procedure:
A mixture of 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(methylsulfinyl)-2-pyridinyl]oxy}acetamide (500 mg, 1.19 mmol), which was obtained in the step (4) of Example 34-1, and isonipecotamide (228 mg, 1.78 mmol) in DMF (2 mL) was stirred at 130° C. for 5 hrs. After cooled to room temperature, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 1-{2-(2-amino-2-oxoethoxy)-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-4-piperidinecarboxamide as a solid (485 mg, yield; 84%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:10]2)=[O:6])[CH2:2][CH3:3].[ClH:24].O1CCOCC1>C(O)(=O)C>[ClH:24].[CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([NH2:16])[CH2:10]2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCNC(=O)c1ccc2c(c1)CC(N)C2

Procedure:
Using N-propyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (22 mg, 0.070 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6.0 ml), a similar procedure to Example 24 was carried out to obtain N-propyl-2-amino-5-indan carboxamide hydrochloride. Then using ethanol (1 ml), triethylamine (0.50 ml, 3.6 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (18 mg, 1.0 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain the title compound (12 mg, 0.033 mmol) having the following physical properties:
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[F:10])[C:3]([OH:21])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(F)c(OCCc2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(F)c(OCCc2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.75 g (2.43 mmol) of 3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-benzoic acid methyl ester was dissolved in 25 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 2 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:13](=[O:14])[N:12]([C:15](=[P:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@@H:11]1[CH2:41][C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([OH:49])=O)=[O:43])[CH3:9])=[O:6])[CH:2]=[CH2:3].[NH3:53]>>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:13](=[O:14])[N:12]([C:15](=[P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@@H:11]1[CH2:41][C:42]([C:44]1[CH:52]=[CH:51][CH:50]=[C:46]([C:47]([NH2:53])=[O:49])[CH:45]=1)=[O:43])[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CC(=O)c1cccc(C(=O)O)c1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CC(=O)c1cccc(C(N)=O)c1

Procedure:
Allyl ((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[3-(aminocarbonyl)phenyl]-2-oxoethyl}-4-oxo-1-azetidinyl)(triphenylphosphoranylidene)acetate (324 mg) was obtained from a half amount of 3-({(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranylidene)ethyl]-4-oxo-2-azetidinyl}acetyl)benzoic acid obtained in Step e) and a 28% aqueous ammonia solution in a similar manner to Reference Example 2-c).
Reaction SMILES: [C:1]1([CH:7]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:28]=[S:29])C.S>O1CCCC1>[S:29]=[CH:28][NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CCOC=S
Reactant: NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: S
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C(NC=S)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 15.9 g. (0.05 mol.) of α-phenylglycine, diphenylmethyl ester, and 9 g. of (0.1 mol.) of ethylthioformate in 50 ml. of tetrahydrofuran is stirred overnight at room temperature. Then a stream of hydrogen sulfide is passed into the solution for 10 minutes, the reaction mixture is permitted to stand overnight, then concentrated and petroleum ether is added to the residue. 16.9 g. of α-[(thioxomethyl)amino]benzeneacetic acid, diphenylmethyl ester, crystallizes. The crude product is recrystallized from methanol, m.p. 129°-130°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:33][C:34]([OH:36])=[O:35])C=1)(=O)C>>[F:15][C:2]([F:1])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:33][C:34]([OH:36])=[O:35])[CH:6]=1)=[O:4]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Product: O=C(O)Cn1cc(C(=O)C(F)(F)F)c2ccccc21

Procedure:
was prepared from 2,2,2-trifluoro-1-(1H-indol-3-yl)-ethanone in a similar manner as described in Scheme A13 (step B and C) for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. White solid. MS: 272.0 [M+H]+; tR (HPLC conditions c): 4.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c2cc1OC
Yield: 46.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from Example 118A (114 mg, 0.42 mmol) were reacted as described in Example 115C to give 1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (71 mg, 0.14 mmol, 48%). 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.70 (s, 2H), 7.84 (s, 1H), 7.53-7.39 (m, 3H), 7.35 (s, 2H), 7.28-7.17 (m, 3H), 7.02 (d, 1H), 3.99 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 489 (M+H)+.