Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][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](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][N:37]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:32])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH2:36][CH2:35]1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: NC1(C(=O)O)CCNCC1
Product: NC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-piperidine-4-carboxylic acid following General Procedure B.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1SC.[NH2:20][NH2:21].C(O)(C)C>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:20][NH2:21]
Reactant: NN
Reactant: CSC1=NCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCO
Product: NNC1=NCCN1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Amino-2-methylthio-2-imidazoline p-toluenesulfonate (2.123 g) in ethanol (4 ml) was treated with hydrazine (0.67 ml) and stirred at 25° C. for 2 hours. Isopropyl alcohol (6 ml) was added and after stirring for 10 min the crystalline precipitate was filtered out and washed with isopropyl alcohol to give 1.55 g of 1-amino-2-hydrazino-2-imidazoline p-toluenesulfonate, melting point 168°-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4](Br)[N:3]=1.[NH3:11]>>[Br:1][C:2]1[N:3]=[C:4]([NH2:11])[CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1
Reactant: CSc1cc(Br)nc(Br)c1
Reactant: N
Product: CSc1cc(N)nc(Br)c1
Temperature: 140 °C

Procedure:
A mixture of 0.500 g 2,6-dibromo-4-methylsulfanyl-pyridine and 10 ml 25% aqueous ammonia was heated in an autoclave to 140° C. for 24 h. The solvent was evaporated and the residue was purified by chromatohraphy on silica gel with heptane:ethyl aceate=1:1 to yield 0.300 g of the title compound as white crystals. MS (ISP) M+H+=219.1; 221.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.N[C:23]1C=CC(C2CCC(=O)CC2)=C2[C:31]=1C(=O)N(C)C2.N1CCCC1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:21][CH2:31][CH2:23][CH2:20]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Solvent: C1CCNC1
Product: CN1Cc2c(C3CCC(N4CCCC4)CC3)ccc(N)c2C1=O

Procedure:
The title product was prepared according to the procedure for Compound 233A using 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one and pyrrolidine. Product used crude in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C>CN(C=O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][CH:22]=[O:23]
Reactant: O=CO
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 1 mmol of phenylalanine methyl ester hydrochloride and 2 mmol of triethylamine in 1 mL of DMF at 0 ° C. was added 2 mL of formic acid and 0.7 mL of acetic anhydride. After stirring for 16 h at rt, extractive isolation provided N-formylphenylalanine methyl ester.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:7]1[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:27]2[CH:26]=[CH:25][S:24][C:23]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(O)(CCCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCC1(CCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.61 mL) was added dropwise to 6-([2,2′-bithiophen]-3-yl)undecan-6-ol (IIu) (0.33 g, 0.98 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over magnesium sulfate, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Iu) (0.0937 g, 30.0%). 1H-NMR (CDCl3): δ=7.13 (d, J=4.8 Hz, 2H), 6.92 (d, J=4.9 Hz, 2H), 1.83-1.78 (m, 4H), 1.21-1.04 (m, 8H), 1.00-0.87 (m, 4H), 0.77 (t, J=6.3 Hz, 6H). 13C-NMR (CDCl3): δ=158.76, 137.09, 125.09, 122.29, 53.87, 38.34, 32.87, 24.82, 23.05, 14.69
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:22])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[O:11])=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@@H:32]([CH3:43])[CH2:31]2)[CH:24]=1.O[Li].O.CC(O)=O>CO.O>[CH3:42][C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:25]2[CH:24]=[C:23]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH2:8][N:9]([CH3:22])[C:10]([C:12]4[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=4)[C:18]([OH:20])=[O:19])=[O:11])[CH:4]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:31][C@@H:32]1[CH3:43])=[O:37])([CH3:40])[CH3:41]
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Agent: [Li]O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(C)C(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-4-[(2′-fluoro-5′-{[methyl({3-[(methyloxy)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (0.215 g, 0.365 mmol) in MeOH/H2O (1.0/0.5 mL) was added LiOH.H2O (0.077 g, 1.83 mmol). The mixture was heated with a microwave at 80° C. for 30 min. Then it was acidified with HOAc. This mixture was extracted with DCM which was dried over Na2SO4, filtered, concentrated and purified using a Gilson HPLC to afford the title compound 0.0639 g (30%). LC-MS m/z 576 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19]C)C.B(Br)(Br)Br.CO>ClCCl>[CH3:1][O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19]
Reactant: CCOC(=O)CCCCN(CCc1cc(F)ccc1OC)Cc1ccc(C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCN(CCc1cc(F)ccc1O)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.6 g (5.84 mmol) of methyl 4-({(5-ethoxy-5-oxopentyl)[2-(5-fluoro-2-methoxy-phenyl)ethyl]amino}methyl)benzoate are dissolved in 50 ml of dichloromethane, the mixture is cooled to 0° C., and 19.3 ml (19.3 mmol) of a 1N solution of boron tribromide in dichloromethane are added dropwise. The solution is stirred at 0° C. for one hour. 50 ml of methanol are slowly added dropwise at 0° C., and the reaction mixture is heated at reflux overnight. The mixture is cooled and the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with sodium carbonate, the aqueous phase is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue is chromatographed over silica gel (cyclohexane:ethyl acetate (5:1) to ethyl acetate: methanol (9:1)).
Reaction SMILES: [CH3:1][C:2]([CH3:55])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:52])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:51])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:54])[CH3:53])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:45]1([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:51])([CH2:21][CH2:22]3)[C@@:19]3([CH3:52])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:53])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:55])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2CCCCC2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2CCCCC2)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(cyclohexylamino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (400 mg, 0.525 mmol) in DCM (10 mL) stirred at room temp was added TFA (5 mL, 64.9 mmol). The reaction mixture was stirred at 30° C. for 2 h. The mixture was evaporated to dryness, then diluted by 200 mL DCM. The organic phase was washed with saturated NaHCO3 solution, water and saturated brine, dried and concentrated under reduced pressure to afford crude product. This material was further purified by preparative-HPLC to afford the title compound (120 mg, 32%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=6.92 (d, J=15.8 Hz, 1H), 5.62 (d, J=15.8 Hz, 1H), 5.37 (d, J=8.3 Hz, 1H), 4.50 (dd, J=5.3, 11.0 Hz, 1H), 3.94-3.73 (m, 1H), 3.27-3.14 (m, 2H), 2.80-2.51 (m, 3H), 2.37-2.03 (m, 3H), 2.03-0.69 (m, 54H); LC/MS: m/z calculated 705.5. Found 706.3 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]#[N:19].[C:20](Cl)(=[O:22])[CH3:21]>>[C:18]([C:3]1[C:4]([CH3:17])=[N:5][N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[C:2]=1[NH:1][C:20](=[O:22])[CH3:21])#[N:19]
Reactant: CC(=O)Cl
Reactant: Cc1nn(-c2ccc(S(C)(=O)=O)cc2)c(N)c1C#N
Product: CC(=O)Nc1c(C#N)c(C)nn1-c1ccc(S(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a 50 mL round-bottomed equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 5-amino-1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazole-4-carbonitrile (85 mg, 0.31 mmol), and acetyl chloride (5 mL). The reaction mixture was stirred under N2 for 24 hrs at 60° C. The acetyl chloride was removed under reduced pressure and solid residue washed with CH2Cl2 and EtOAc and collected by filtration. The crude product was then purified by flash chromatography (EtOAc:Hex=1:1) and recrystallized from methanol. 55 mg of product was obtained (56% yield). 1H NMR (DMSO-d6, 400 MHz) δ 2.07 (s, 3H), 2.36 (s, 3H), 3.29 (s, 3H), 7.81 (d, 2H), 8.09 (d, 2H), 10.7 (s, 1H). LCMS: calculated C14H14N4O3S 318.08, observed 319.1 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].C1C=CC=CC=1.[C:22]([OH:26])([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Yield: 49 %

Procedure:
The crude 3,4-dinitrobenzoyl chloride, 500 ml. of benzene, 25 ml. of pyridine and 22 g. (0.3 mole) of t-butyl alcohol were reacted as in Example 2 (A), second paragraph, to provide 33 g. (49 percent yield) of t-butyl 3,4-dinitrobenzoate.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH3:3].[BH4-].[Na+].[CH2:8]([N:15]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH2:24])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[C:27]1(C)[CH:32]=CC=C[CH:28]=1>CCOC(C)=O>[CH2:8]([N:15]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([N:24]([CH2:28][CH2:27][CH3:32])[CH2:1][CH2:2][CH3:3])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1
Reactant: Nc1cc(C(F)(F)F)n(Cc2ccccc2)n1
Reactant: CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCN(CCC)c1cc(C(F)(F)F)n(Cc2ccccc2)n1
Temperature: 0 °C
Yield: 64 %

Procedure:
To a 0° C. solution of propionic acid (12.4 mL, 166.0 mmol) in PhMe (15.0 mL) was added NaBH4 (1.96 g, 51.8 mmol) portionwise to control the bubbling. The mixture was stirred at 0° C. until the evolution of H2 ceased. Next, 1-benzyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (625 mg, 2.59 mmol) in PhMe (10.0 mL) was then added dropwise via syringe. The resulting reaction mixture was heated at 110° C. overnight. Additional propionic acid (5.0 mL, 66.9 mmol) and NaBH4 (1.00 g, 25.9 mmol) were added, and the reaction mixture was stirred overnight at 110° C. The reaction mixture was then poured into EtOAc and 0.5N aq. NaOH solution (1:1). The layers were separated, and the organic layer was washed with 0.5N aq. NaOH solution. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with sat. aq. NaCl solution and dried over Na2SO4. Filtration and concentration in vacuo provided a crude residue which was purified by flash column chromatography (gradient from 0% to 20% EtOAc/hexanes) to give the title compound (597 mg, 64%) as a 4:1 mixture of regioisomers by 1H NMR. 1H NMR (CDCl3, major regioisomer) δ 7.41-7.25 (m, 3H), 7.19 (d, J=7.0 Hz, 2H), 6.22 (s, 1H), 5.34 (s, 2H), 2.82-2.72 (m, 4H), 1.48-1.33 (m, 4H), 0.78 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 326.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([O:15]C)=[O:14])=[C:6]2[S:17][CH3:18].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([OH:15])=[O:14])=[C:6]2[S:17][CH3:18]
Reactant: COC(=O)c1c(SC)c2cc(OC)ccc2n1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)c(SC)c(C(=O)O)n2C
Temperature: 0 °C
Yield: 86.2 %

Procedure:
A suspension of methyl 5-methoxy-1-methyl-3-(methylthio)-1H-indole-2-carboxylate (3.2 g, 12 mmol) in 65 mL of methanol is treated with a solution of potassium hydroxide (2.5 g, 45 mmol) in 25 mL of water. The mixture is stirred at reflux for 2 hours, then cooled and added to 400 g of ice and water. After washing with dichloromethane, the aqueous layer is stirred with celite filter-aid and filtered. The filtrate is acidified with 4.0N HCl and the precipitated solid is filtered and washed with 10% methanol-water to yield 2.6 g (87%) of product. A sample recrystallized from hexane-ethyl acetate has mp 165° C.-dec.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[F:41][C:42]([F:54])([F:53])[O:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1C(Cl)=O>CCOC(C)=O.C(Cl)Cl>[CH3:28][N:27]([CH3:29])[C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([NH:16][CH2:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([CH2:8][NH:7][C:6](=[O:30])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[O:43][C:42]([F:41])([F:54])[F:53])[CH2:14][CH2:13]2)[N:26]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)c3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester obtained in step G of example 1 (800 mg, 1.93 mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 60 min and concentrated to give a white solid. To a suspension of the solid in CH2Cl2 (10 mL) was added diisopropylethylamine (706 μL, 4.05 mmol). The mixture was cooled at 4° C. and a solution of 2-(trifluoromethoxy)benzoyl chloride (455 mg, 2.03 mmol) in CH2Cl2 (4 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 90 min. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give trans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide (772 mg, 80%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:32][CH2:31][C:30](=O)[CH2:29][CH:28]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH2:34][OH:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38]NC.[C:41]([BH3-])#[N:42].[Na+]>C(Cl)Cl.CO.CC(O)=O>[C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:32][CH2:31][CH:30]([N:42]([CH3:41])[CH3:38])[CH2:29][CH:28]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH2:34][OH:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3ncnc4[nH]c(C5=CCC(=O)CC5)cc34)c2CO)cc1
Reactant: [BH3-]C#N
Reactant: CNC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4CO)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Intermediate 49 (100 mg, 0.202 mmol) in DCM/MeOH/AcOH (4 ml, 100:93:7) was added dimethylamine (91 mg, 2.02 mmol). The mixture was stirred for 15 min at r.t. before adding sodium cyanoborohydride (12.7 mg, 0.202 mmol). The mixture was stirred at r.t. overnight and then quenched with 2N HCl (3 ml). After additional stirring for 30 min water and 2N NaOH were added. The mixture was extracted with EtOAc, and the organic layer was dried, filtered, and evaporated to dryness. The resulting residue was purified using flash chromatography (silica gel, EtOAc/MeOH/NH4OH gradient) to yield Example 56.
Reaction SMILES: [C:1](OC)(=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[OH:3].C(O)C(O)CCO>CO>[OH:3][CH:2]1[CH2:8][O:7][C:5](=[O:6])[CH2:4]1.[OH:3][CH:2]([CH2:1][OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(O)C(=O)OC
Agent: OCCC(O)CO
Solvent: CO
Product: COC(=O)CC(O)CO
Product: O=C1CC(O)CO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
[Ru(CH3CN)3(triphos)](CF3SO3)2 (11.5 mg), dimethyl DL-malate (0.65 g), and 1.0 ml of methanol were added into a 20-ml Schlenk tube under an argon atmosphere, and the mixture was stirred for 5 minutes at room temperature. This liquid was transferred to a 100-ml autoclave having a stirrer placed inside, under an argon atmosphere. The autoclave was purged with hydrogen, and then hydrogen was further included in the autoclave up to 4.0 MPa. The contents of the autoclave were heated and stirred at 100° C. for 14 hours. After cooling, the reaction liquid was analyzed by gas chromatography, and it was found that 1,2,4-butanetriol was produced at a yield of 30.6%, β-hydroxy-γ-butyrolactone at a yield of 42.3%, and methyl 3,4-dihydroxybutanoate at a yield of 21.4%.
Reaction SMILES: [CH2:1]([C:12]([CH3:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:15][NH:16]Cl.[OH-].[Na+]>C(O)C.O>[CH3:14][C:12](=[N:16][OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: ONCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCC(C)=NO
Yield: 93 %

Procedure:
A solution of 40 g of methyl undecyl ketone and 18 g of hydroxylamino hydrochloride in 200 ml of ethanol, 60 ml of water and 10 g of NaOH is refluxed for 5 hours and thereafter cooled. The ethanol is distilled off in vacuo and the reaction mixture is then diluted with water, extracted with ether and the ethereal extract is dried over Na2SO4. The ether is distilled off and the solid residue is then distilled in vacuo, affording 40 g of 2-tridecanone oxime. Melting point (after recrystallisation from ether); 51°-53° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1>C(OCC)C>[CH3:1][N:2]([CH3:3])[C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1
Reactant: CNC
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1sc(N(C)C)nc1C(F)(F)F
Yield: 64.8 %

Procedure:
To a vessel containing 591 g of ethyl ether cooled in a dry ice-acetone bath was added 12.5 g of dimethylamine with stirring. Then, to a reaction vessel cooled in a dry-ice acetone bath there was placed 11.5 g of the previously-prepared dimethylamine-in-ether solution followed by addition of 5.79 g (23 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate in 20 ml of ethyl ether. A white precipitate formed immediately. The reaction mixture was stirred for 10 minutes and filtered. The ether filtrate was washed with 5% sodium hydroxide, dried over anhydrous calcium sulfate and concentrated under reduced pressure. The residual solid was treated with petroleum ether and filtered to provide 4.0 g of white solid product (m.p. 78°-79° C.) identified in Table I. ##STR18##
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[OH:25])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[C:33]([OH:36])=[N:34][O:35][C:31]=2[CH:30]=1.O.[OH-].[Na+].Cl>CO>[CH:20]1([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:32]5[C:33]([OH:36])=[N:34][O:35][C:31]=5[CH:30]=4)=[C:6]([CH2:5][CH2:4][C:3]([OH:39])=[O:2])[CH:11]=3)=[O:26])=[C:14]([OH:25])[CH:15]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
In 182 mL of methanol, 26.0 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid methyl ester was suspended. After dropping 78 mL of water of 10.5 g of sodium hydroxide at room temperature, the result was stirred for 30 minutes at the same temperature. The reaction mixture was added to water. After adjusting to pH 1.5 with a 6 mol/L hydrochloric acid, solids were filtered. The obtained solids were dissolved in a mixture solution of chloroform and methanol. After washing with water, solvent was distilled off under reduced pressure to obtain 22.5 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid in the form of a light yellowish solid.