Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[N:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1.C(Cl)Cl>[C:17]([C:15]1[C:14]2[N:19]=[N:20][N:21]([CH3:22])[C:13]=2[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:36](=[O:38])[CH3:37])=[C:6]([C:23]([F:25])([F:24])[F:26])[CH:7]=2)[N:16]=1)#[N:18]
Reactant: CC(=O)Cl
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCN)c(C(F)(F)F)c3)cc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(4-(2-Aminoethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo-[4,5-c]pyridine-4-carbonitrile (0.276 mmol, 0.1 g) and Hunig's base (0.828 mmol, 0.137 ml, 0.107 g) were stirred in THF (1 ml) at 0° C. acetyl chloride (0.552 mmol, 0.039 ml, 0.043 g) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The resulting residue was taken up in DCM and washed with water. The organic was concentrated at reduced pressure. The resulting residue was purified by silica chromatography, eluting with DCM—3% MeOH/DCM to afford N-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)acetamide. (0.024 g)
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[F:16][C:12]1[CH:11]=[C:10]([C:3]2([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC1CCCC1(C(=O)O)c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2cccc(F)c2)CCCC1

Procedure:
To a solution of methyl 1-(3-fluorophenyl)cyclopentanecarboxylic acid (5.0 g, 24.01 mmol) in anhydrous methanol was added 1 mL of concentrated sulfuric acid. The mixture was refluxed overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL, dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[OH:12][C:3]1[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)cnc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)cnc1O)c1ccncc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
A mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 0.69 g of isonicotinic acid, 1.40 g of WSC and 7 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.22 g of N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]N=O)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCCCCCCCC1.N(C1CCCCCCCCCCC1)=O.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)ON=O
Reactant: C1CCCCCCCCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=NC1CCCCCCCCCCC1
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Cyclododecane (1.66 g; 9.88 mmol), t-butylnitrite (2 mmol), N-hydroxyphthalimide (0.4 mmol), and acetic acid (2 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas for 1 hour. The resulting reaction mixture was analyzed to find that cyclododecanone oxime, nitrosocyclododecane dimer, nitrocyclododecane, and cyclododecanone were formed in yields of 10%, 38%, 6%, and 3%, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH:15]1(O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[O:9][C:4]=3[CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCCC1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Product: CC1(C)OC(=O)c2ccc(OC3CCCCC3)cc2O1

Procedure:
7-Cyclohexyloxy-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 7-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and cyclohexanol under conditions analogous to example 51-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.82 (d, J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 2.4 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 4.30 (m, 1H), 2.02-1.28 (m, 10H), 1.73 (s, 6H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1([C:9]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:10][C:11]([Cl:18])=[C:12]([Cl:17])[C:13](O)([CH3:15])[CH3:14])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:5][C:6]1([C:9]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:10][C:11]([Cl:18])=[C:12]([Cl:17])[C:13]([CH3:15])=[CH2:14])[CH2:7][CH2:8]1
Reactant: CC(C)(O)C(Cl)=C(Cl)CC(O)(Cn1cncn1)C1(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=C(C)C(Cl)=C(Cl)CC(O)(Cn1cncn1)C1(Cl)CC1
Yield: 29.7 %

Procedure:
0.71 g (6 mmol) of thionyl chloride are added at room temperature with stirring to a mixture of 1.77 g (5 mmol) of 6-(1-chlorocyclopropyl)-3,4-dichloro-2,6-dihydroxy-2-methyl-7-(1,2,4-triazol-1-yl)-hept-3-ene and 20 ml of methylene chloride, and the mixture is then heated at reflux for 5 hours. Aqueous sodium carbonate solution is subsequently added to the reaction mixture, which is then subjected several times to extraction with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The product which remains is chromatographed over silica gel using ethyl acetate. Concentration of the eluate gives 0.5 g (20% of theory) of 6(1-chlorocyclopropyl)-3,4dichloro-6-hydroxy-2-methyl-7-(1,2,4-triazol-1-yl)hepta-1,3-diene in the form of a colourless oil.
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[CH:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.[H][H]>CO.[Pd].[C]>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: O=C(C=C1CCC2(CC1)OCCO2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Product: O=C(CC1CCC2(CC1)OCCO2)OCc1ccccc1
Reaction time: 5 h
Yield: 81.4 %

Procedure:
Diphenyl sulfide (33 mg, 0.18 mmol) and 10% Pd-carbon (1.08 g) were added to a solution of benzyl 2-(1,4-dioxaspiro[4,5]decan-8-ylidene)acetate (5.0 g, 17.34 mmol) in methanol (50 ml) under a nitrogen gas stream, the atmosphere in the system was replaced five times with nitrogen gas, was then filled with hydrogen gas, followed by stirring under a hydrogen gas stream for 5 hr. The catalyst was removed by filtration through Celite pad and was washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (4.1 g, yield 82%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)C>[Cl:9][C:5]1[N:4]=[C:3]([CH:10]=[N:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:2]([NH2:1])=[N:7][C:6]=1[Cl:8]
Reactant: COc1ccc(N)cc1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: CCO
Product: COc1ccc(N=Cc2nc(Cl)c(Cl)nc2N)cc1

Procedure:
In a manner similar to that described in Example 9, 1.92 grams (0.01 mole) of 3-amino-5,6-dichloropyrazinaldehyde, 1.23 g (0.01 mole) of p-anisidine and 15 milliliters of ethanol were mixed together and heated at reflux temperature to obtain a 5,6-dichloro-3-[(4-methoxyphenyl)imino]methylpyrazinamine product which precipitated in the reaction mixture. The product was recovered by filtration, recrystallized from ethanol to obtain 2.14 grams of a purified product, m.p. 167°-168° C. (dec). Elemental analyses were as follows:
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[CH3:40][O:41][C:42]1[N:47]=[C:46]([CH3:48])[C:45](B(O)O)=[CH:44][CH:43]=1>>[CH2:36]([C:11]1[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:45]2[C:46]([CH3:48])=[N:47][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[N:10]=1)[CH3:37]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: COc1ccc(B(O)O)c(C)n1
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate but substituting 6-methoxy-2-methylpyridin-3-ylboronic acid provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.41–7.36, 6.64, 5.17–5.15, 4.78, 4.11, 4.02–3.97, 3.73–3.35, 2.70, 2.46, 2.28, 1.32–1.21, 1.13; IR (liq.) 2236 (w), 2018 (w), 1949 (w), 1709 (s), 1596, 1565, 1499, 1474 (s), 1420 (s), 1396, 1360, 1350, 1304 (s), 1126, 1097 cm−1 HRMS (ESI) calcd for C29H37N5O4+H1 520.2924. found 520.2924.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: NC1CCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Cyclobutylamine (0.192 g, 2.7 mmol) was added to a solution of Example 133 (0.600 g, 1.3 mmol) in DMF (1 mL). The reaction mixture was stirred at 120° C. for 4 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 3-4% methanol/chloroform) to obtain the title compound. Yield: 0.450 g, (66.6%); 1H NMR (CDCl3-d6): δ 1.80 (m, 6H, 3CH2), 1.94 (t, 3H, CH3), 2.2 (t, 1H, CH), 2.9 (s, 3H, CH3), 3.3 (s, 2H, CH2), 3.9 (s, 3H, CH3), 4.7 (s, 2H, CH2), 7.5 (s, 1H, Ar), 7.8 (s, 1H, Ar), 8.4 (s, 1H, Ar), 9.5 (s, 1H, Ar); MS: m/e (ES+) 423 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[Cl:32][C:33]1[CH:44]=[CH:43][C:36](/[CH:37]=[CH:38]/[S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36](/[CH:37]=[CH:38]/[S:39]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:5])(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Agent: Cl
Product: O=C(CNS(=O)(=O)/C=C/c1ccc(Cl)cc1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 16 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with (E)-4-chlorostyrylsulphonyl chloride to give 2-[(E)-4-chlorostyrylsulphonamido]-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}acetamide as a gum (0.1 g, 16%);
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:12]([OH:14])=O.[OH-].[K+]>O>[CH3:25][N:24]([CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:11]1[NH:10][C:8](=[O:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:14])[CH3:26]
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)CCOc1ccccc1C(N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCOc1ccccc1C1NC(=O)N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.4 ml of phenyl isocyanate are slowly added to a solution of 4 g of 2-amino-2-{[2(N,N-dimethylamino)ethyl]oxy-phenyl}-acetic acid and 1.65 g of potassium hydroxide in water (about 20 ml). The mixture is stirred for 12 hours at ambient temperature, filtered, acidified with aqueous HCl solution (10%) (about pH 2) and refluxed. After 6 hours it is slowly cooled and made alkaline with aqueous Na2CO3 solution (10%). The precipitate obtained is recrystallised from ethyl acetate. 3 g of the title compound are obtained in the form of a white solid (melting point: 120-124° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][C:2]1=[O:8].[Br:9]Br.ClCCl>C(O)(=O)C>[Br:9][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][NH:1][C:2]1=[O:8]
Reactant: BrBr
Reactant: O=C1CCNC(=O)C1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCNC(=O)C1Br
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a mixture of piperidine-2,4-dione (0.072 g, 0.637 mmol) in acetic acid (1.591 mL) was added bromine (0.033 mL, 0.637 mmol) dropwise. The reaction mixture was stirred at rt 70 min. Dichloromethane was added and the cloudy mixture was concentrated in vacuo. The residual solution was treated with ethyl ether. A white solid crashed out and the AcOH/ether was decanted. The white solid, presumed to be product was carried forward. The white solid started liquifying and turning red rapidly upon exposure to light and standing.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH2:37]([O:41][C:42]1[CH:74]=[CH:73][C:45]([C:46]([NH:48][C:49]2[N:50]=[CH:51][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([O:68]C)=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[N:53][CH:54]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:74]=[CH:73][C:45]([C:46]([NH:48][C:49]2[N:50]=[CH:51][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:71])[CH3:72])[C:66]([OH:68])=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[N:53][CH:54]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C(=O)Nc2cnc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cn2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCOc1ccc(C(=O)Nc2cnc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cn2)cc1
Yield: 77 %

Procedure:
The compound of example 509 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 508.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH2:5]Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=[CH:19][C:20]=1[OH:21]>CO>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(CCl)ccc1OC(C)C
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Solvent: CO
Product: Cc1cc(COc2ccc(CC(=O)O)cc2Cl)ccc1OC(C)C
Yield: 35.2 %

Procedure:
3-chloro-4-(3'-methyl-4'-isopropoxybenzyloxy) phenylacetic acid was prepared in 35.2% yield, m.p. 104°-105° C. (methanol) by reaction of 3-methyl-4-isopropoxybenzyl chloride with methyl 3-chloro-4-hydroxyphenylacetate.
Reaction SMILES: C(=[N:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:31][C:32]3[CH:33]=[C:34]([C:38]([OH:43])([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:35]=[CH:36][CH:37]=3)=[CH:20][CH:21]=2)[N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.NO.C([O-])(=O)C.[K+]>CO>[NH2:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:22]2[C:17](=[CH:18][C:19]([S:31][C:32]3[CH:33]=[C:34]([C:38]([OH:43])([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:35]=[CH:36][CH:37]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(N=C(c4ccccc4)c4ccccc4)nc3c2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(N)nc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10p (990 mg, 15.5 mmol), hydroxylamine hydrochloride (220 mg, 31.1 mmol), and potassium acetate (310 mg, 31.1 mmol) were dissolved in MeOH (1.5 mL) and stirred overnight at room temperature. The reaction was concentrated and purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10q.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=O)[CH3:7])[CH3:2].[CH:11]1([NH2:14])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH:6]([NH:14][CH:11]1[CH2:13][CH2:12]1)[CH3:7])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C(C)NC1CC1
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
To a solution of 2.3 g (0.016 mole) of 2-methyl-3-oxobutanoic acid ethyl ester in 50 mL of dichloroethane was added 1.00 g (0.016 mole) of cyclopropylamine. The mixture was stirred for 1.5 hours and then 5.1 g (0.023 mole) of sodium triacetoxyborohydride and 0.96 g (0.016 mole) of acetic acid were added. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate. The mixture was stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with twice with 30 mL of dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (30:70) gave 1.5 g of (rac)-3-cyclopropylamino-2-methyl-butanoic acid ethyl ester.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[CH:28][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23]>C1C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[CH:21]([O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(Oc2ccccc2)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 41.4 %

Procedure:
To a mixture of 4.66 g of p-phenoxyphenol, 1.19 g of sodium methoxide, 10 ml of benzene and 40 ml of methanol is added 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 10 ml of benzene. The mixture is refluxed for 22 hours and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as eluent giving a viscous oil which is again chromatographed over silica gel with dichloromethane as eluent. There is obtained 4.3 g of viscous oil which is crystallized from methylcyclohexane-methanol to give 3.6 g of white crystals, mp 78°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:20](OC)=[O:21])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][OH:21])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cnn(-c3ccc(F)cc3)c2cc1C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(cnn2-c2ccc(F)cc2)cc1CO
Reaction time: 12 h
Yield: 93 %

Procedure:
Methyl 1-(4-fluorophenyl)-6-isopropyl-1H-indazole-5-carboxylate (175 mg, 0.56 mmol) was dissolved in 5 mL THF and 1M LiBH4 in THF (3 mmol) was added. Heated at reflux. After 12 h, the reaction was quenched with MeOH, poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using 1:3 EtOAc/hexane. Obtained 148 mg (93% yield) of (1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)methanol. MS found: (M+H)+=285.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH3:18]>CN(C)C=O>[CH2:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOCc1ccc(CCl)cc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(Cn2cc(-c3cccnc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 and N,N-dimethylformamide (1 mL) was added sodium hydride (6.8 mg, 0.19 mmol, 66% in oil), which was stirred for 30 minutes at room temperature. 1-Butoxymethyl-4-chloromethyl-benzene (29 mg, 0.14 mmol) described in Manufacturing Example 33-1-4 was added to the reaction mixture at room temperature, and stirred for 1.5 hours at 40° C. The reaction mixture was cooled and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (33 mg, 78%).