Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:43]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:43])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 6, 1.0 mmol, 547 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then methyl iodide (1.5 mmol, 94 μL) was added. The resulting mixture was stirred at room temperature for 2 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give (±)-trans-4-(4-benzyloxy-phenyl)-3-butyl-6-(4-methoxymethyl-pyrrolidin-3-ylmethoxy)-pyridazine dihydrochloride.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-:26].[Na+].Cl>C(O)C>[CH2:14]([C:3]1[C:4](=[O:13])[C:5]2[C:10]([C:11](=[O:12])[C:2]=1[OH:26])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
A mixture of 10 parts of 3-chloro-2-n-dodecyl-1,4-naphthoquinone. 5 parts of 50% aqueous sodium hydroxide and 320 parts of 95% aqueous ethanol were heated at reflux for 15 minutes. The color of the mixture turned from yellow to dark red. The mixture was cooled to 25° and acidified with 10% aqueous hydrochloric acid. The color of the mixture was golden yellow after acidification. The product was filtered off and washed twice with water (25 parts) and twice with cold methanol (25 parts) to yield 8 parts of 2-n-dodecyl-3-hydroxy-1,4-naphthoquinone, mp. 85° - 87° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH: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.[NH2:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(O)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(O)C(F)(F)F)cn1
Yield: 46 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-amino-1,1,1-trifluoropropan-2-ol instead of methylamine, to the title compound (124 mg, 46%) which was obtained as a white solid. MS: m/e=420.1 [M−H]−.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C:37]=1[NH:48][C:49](=[O:52])[CH2:50][CH3:51].[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[Cl:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C@@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C@@H:37]1[NH:48][C:49](=[O:52])[CH2:50][CH3:51]
Reactant: CCC(=O)NC1=C(Cc2cccc(Cl)c2)c2cc(OC)ccc2CC1
Reactant: [H][H]
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2ccc(OC)cc2[C@H]1Cc1cccc(Cl)c1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (29.2 mg, 0.118 mmol of Rh), Josiphos SL-J216-2 (79.1 mg, 0.123 mmol), and N-(1-(3-chlorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (43.30 g, 122 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (435 ml) was added, then the mixture was agitated under argon at 45° C. for 20 min. The reactor was pressurized to 60 psig with hydrogen and agitated at 60° C. for 16 hrs. HPLC analysis showed complete conversion and 95.2% ee. The mixture was concentrated, and the resulting solid was slurried in heptane and dried in vacuo at 40° C. to yield 42.8 g (yield: 95%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn(C)c2cc(F)ccc2c1=O

Procedure:
A mixture of ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate (4.7 g), anhydrous potassium carbonate (3.0 g), dimethyl sulphate (2.52 g) and butanone (200 ml) can be boiled under reflux for 14 hours. The solvent can be evaporated and the residue can be triturated with dichloromethane (150 ml). The mixture can be filtered and the filtrate evaporated to a small volume. Diethyl ether can be added, causing a solid to precipitate. The solid can be collected, washed with ether, dried and recrystallised from industrial methylated spirit to give the compound ethyl 7- fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, m.p. 164° C.-166° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1NN(CC2CCCCC2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C(c2ccc(Cl)c(Cl)c2)C(c2ccncc2)N1CC1CCCCC1
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.4 g 1-Cyclohexylmethyl-4-(3,4-dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one and 20 mL THF, stirred at 0° C. under nitrogen. 1.32 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min. 0.11 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hour, quenched with 50 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 0.4 g as light solid. MS (ES+): 418 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
7-Hydroxyacetylimidazo[5,1-b]thiazole (1.42 g) was dissolved in 10 ml of DMF. Imidazole (847 mg) and 1.77 g of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere. The mixture was stirred at room temperature for 24 hr. Brine was added to the reaction solution, followed by extraction twice with ethyl acetate. The organic layers were combined together, washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.19 g of 7-t-butyldimethylsilyloxyacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18].C[O-].[Na+].S(OC)(O[CH3:26])(=O)=O>CN(C)C=O>[CH3:26][N:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCC2(CCC(=O)c3ccccc32)C1=O
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
To 24.3 grams (0.1 M) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione in 100 milliliters of dry dimethylformamide was added with stirring 5.4 grams (0.1 M) of sodium methoxide. This was followed by 17.0 milliliters of dimethyl sulfate. The reaction mixture became clear and was slightly exothermic. After stirring for 15 minutes, 50 milliliters of solvent was removed at reduced pressure on a steam bath. The resulting solution was cooled and added to 1 liter of ice water. The resulting precipitate was collected and washed with 5 per cent sodium hydroxide solution and finally with water. Recrystallization from butanone-petroleum ether (70°-90°) and then from aqueous ethanol gave 18.4 grams (17.5%) of 1'-methyl-2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 136°-137.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)CN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CC(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isobutyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (21%). mp 289° C.; LCMS: m/z=539.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 1H, J=1.0 Hz), 7.60 (s, 1H), 7.47 (s, 2H), 7.43 (d, 1H, J=7.3 Hz), 7.29 (m, 3H), 7.18 (d, 1H, J=8.6 Hz), 3.35 (m, 1H), 2.86 (s, 3H), 2.28 (m, 3H), 1.98 (m, 3H), 1.31 (m, 7H), 0.95 (d, 6H, J=5.8 Hz).
Reaction SMILES: C([O:8][C:9](=[O:49])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:30][C:31](=[O:40])[O:32]CC1C=CC=CC=1)[NH:14][C:15](=[O:29])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:49])=[O:8])[CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:41])[CH2:30][C:31](=[O:32])[OH:40])=[O:29])[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: O=C(CN1CCN(c2ccncc2)CC1)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)C[C@H](NC(=O)CN1CCN(c2ccncc2)CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of O-benzyl-N-[O-benzyl-N-[2-[4-(4-pyridyl)-piperazin-1-yl]acetyl]-L-aspartyl]-L-phenylalanine (0.92 g) in methanol (125 ml) under argon was added 10% Pd on C (0.45 g). The mixture was covered with a blanket of hydrogen and stirred at room temperature until deprotection was complete. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. The resultant white solid was dissolved in water and lyophilised overnight to yield the title compound (274 mg) as a white solid: m.p. 153° C. (dec.); NMR (d6DMSO+CD3CO2D) δ 2.65 (6H, m), 3.02 (4H, m), 3.63 (4H, m), 4.44 (1H, m), 4.67 (1H, m), 7.13 (2H, d), 7.23 (5H, m), 8.22 (2H, d); m/Z 484 (M+H)+ ; calculated for C24H29N5O6. m/Z 484 (H+H)+ ; amino acid analysis: found; Asp, 1.00; Phe 0.99; requires; Asp, 1.00; Phe, 1.00.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2[nH]ncc2c1
Product: O=C(c1ccccc1)n1ncc2ccccc21

Procedure:
To prepare 1-substituted 1H-indazoles of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl ##STR46## wherein R2', R5, X", p" and q' are as above, a 1-unsubstituted 1H-indazole 8 wherein R is as above, with the proviso that R is not hydrogen, and X, m, n and p are as before, is treated, respectively, with a formyl, alkanoyl or cycloalkylalkanoyl chloride, bromide or iodide, a compound of the formula ##STR47## R2'OCOHal or R5COHal wherein R2', R5, X", p" and q' are as above and Hal is iodo, bromo or chloro, or the corresponding acid anhydrides thereof, at an elevated temperature of about the reflux temperature of the reaction medium. For example, treatment of a 1H-indazole 8 wherein R is methyl with acetic anhydride at the reflux temperature of the reaction mixture affords a 1-acetyl-1H-indazole 14 wherein R2 is methyl, and treatment of a 1H-indazole 8 wherein R is methyl with benzoyl chloride at a reaction temperature of about 100° C. yields a 1-benzoyl-1H-indazole 14 wherein R2 is phenyl.
Reaction SMILES: [NH2:1][C:2](=[S:26])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[N:9]=[CH:8][C:7]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:15])=[C:6]2[OH:25].[C:27]1(C)C=CC(S(O)(=O)=O)=C[CH:28]=1.C(OC(OCC)CBr)C>C(O)(=O)C.C(OCC)(=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:25])=[CH:4][C:3]([C:2]2[S:26][CH:27]=[CH:28][N:1]=2)=[CH:12][C:11]=3[F:13])=[O:15])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: CCOC(CBr)OCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(-c3nccs3)cc2c1O
Temperature: 100 °C
Yield: 544.9 %

Procedure:
To a suspension of the title compound of Example 52 (0.14 g) and p-toluenesulfonic acid (0.0084 g) in 2 mL acetic acid is added bromoacetaldehyde diethyl acetal (0.08 mL). The reaction is heated at 100° C. for approximately 45 minutes. The reaction is cooled to room temperature and diluted with 30 mL ethyl acetate. The solid is filtered and dried to give the desired product (0.11 g).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH:7]([NH:11][CH:12]1[CH2:14][CH2:13]1)[CH:8]([CH3:10])[CH3:9])C.II.[H][H]>C1COCC1.CO>[CH:12]1([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][OH:5])[CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: CCOC(=O)C(NC1CC1)C(C)C
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(CO)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (167 mg) was added to dry THF (10 mL) under argon and cooled to 0° C. To this mixture was added 2-cyclopropylamino-3-methyl-butyric acid ethyl ester (341 mg, obtained in example 25, step A]) followed by a solution of iodine (467 mg) in THF (5 mL) that was added over a period of 30 minutes. A strong hydrogen evolution was observed. The mixture was stirred at 0° C. for 30 minutes and then heated to reflux for 12 hours. The mixture was cooled and methanol was carefully added until a clear solution was obtained. After 30 minutes, the mixture was evaporated. The residue was treated with 20% aqueous KOH solution for 4 hours. The mixture was extracted with DCM three times and the combined organic layers were dried over Na2SO4 and evaporated to give crude 2-cyclopropylamino-3-methyl-butan-1-ol as a light yellow liquid (195 mg) that was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](O)(=[O:16])[CH3:15]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>[C:14]([O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)Oc1c(C(C)C)cccc1C(C)C

Procedure:
A suspension of 2,6-diisopropylphenol (5.32 g) in 35 ml of trifluoroacetic anhydride is treated with 1.75 ml of glacial acetic acid under a nitrogen atmosphere. Upon completion of the addition of acetic acid, the solids are in mixture. Solvent evaporation gives an oil which is taken up in 150 ml of ethyl acetate and washed twice with saturated aqueous sodium bicarbonate and once with saline. Drying of the organic layer with sodium sulfate followed by filtration and solvent evaporation gives 6.55 g of an oil which is chromatographed on 330 g of silica gel eluting with chloroform/hexane (9/1). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, TMS) 7.2, 2.91, 2.36, 1.20.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 4 (34.29 g, 94.60 mmol) in tetrahydrofuran (234 mL) and methanol (234 mL) was added 1 N aq sodium hydroxide (473 mL). The solution was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 3 N aqueous hydrochloric acid was added dropwise to pH 2. The resulting slurry was filtered, and the solid was washed with water (300 mL, then 100 mL). The solid was dried by azeotropic removal of water first with toluene, then heptane (7×100 mL), followed by heating to 70° C. under reduced pressure to afford (+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid (Intermediate 5). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.66-7.58 (m, 3H), 7.40 (t, J=7.6 Hz, 1H), 5.56 (dd, J=6.0, 8.6 Hz, 1H), 2.49 (s, 3H), 2.24-2.10 (m, 1H), 2.08-1.95 (m, 1H), 1.66-1.52 (m, 1H), 1.52-1.39 (m, 1H), 1.03 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[F:34][C:2]([F:1])([F:33])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20][CH2:21]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (89 mg, 0.18 mmol, EXAMPLE 1, Step 5) in tetrahydrofuran (1 mL), methanol (1 mL) and 2 N aq. sodium hydroxide (1 mL) was stirred at 70° C. for 17 h. The mixture was neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate was filtered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Cc1ccc(S)c(C)c1
Product: Cc1ccc(Sc2ccc(F)cc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH2:26][CH2:27][CH3:28].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH3:28])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.031 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 1-iodopropane (0.33 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-propyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C16H20ClN3, 289.13. found, m/z 290.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.35 (m, 4H), 4.03 (t, J=7.2 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.95-2.93 (m, 2H), 1.76-1.69 (m, 2H), 0.84 (t, J=7.4 Hz, 3H).