Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[CH2:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH:2]([CH3:4])[CH3:3]>[Rh].O1CCCC1>[CH2:1]([CH:5]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[CH2:8]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1C=C(C(=O)O)C1
Agent: [Rh]
Solvent: C1CCOC1
Product: CC(C)CC1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 70.4 %

Procedure:
3-Isobutyl-1-cyclobutenecarboxylic acid (188 g) and tetrahydrofuran (2000 mL) were mixed. To the mixture was added 5 w/w % rhodium on activated carbon (5.64 g). The resulting mixture was stirred at RT for 7 hr under hydrogen atmosphere (1 atm). The 5 w/w % rhodium on activated carbon was filtered off and the filtrate was concentrated in vacuo to give the title compound (134.06 g) as a crude product.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])(=O)=O)=CC=1.[OH:22][C:23]1[CH:32]=[CH:31][C:26]2[CH:27]([CH3:30])[CH2:28][O:29][C:25]=2[CH:24]=1>>[CH3:20][CH:13]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][O:22][C:23]1[CH:32]=[CH:31][C:26]2[CH:27]([CH3:30])[CH2:28][O:29][C:25]=2[CH:24]=1
Reactant: CC1COc2cc(O)ccc21
Reactant: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1
Product: CC(C)=CCCC(C)CCOc1ccc2c(c1)OCC2C

Procedure:
3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-2,3-dihydrobenzofuran of boiling point 126°-128° C./0.001 mmHg; nD20 = 1.5223; and 3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-3-methyl-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-3-methyl-2,3-dihydrobenzofuran of boiling point (bulb-tube) 130° C./0.14 mmHg; nD20 = 1.5150.
Reaction SMILES: [C:1]1([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CI.[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[Na+]>CC(C)=O>[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[C:1]1([C:11]2[CH:12]=[NH+:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncc(-c3cccc4ccccc34)cc2c1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CI
Solvent: CC(C)=O
Product: c1ccc2[nH+]cc(-c3cccc4ccccc34)cc2c1
Reaction time: 10 h

Procedure:
Furthermore, the 3-(1-naphthyl)quinoline (2-2) (70 mg, 0.27 mmol) was dissolved in 10 ml of acetone, and further methyl iodide (130 μl, 2 mmol) was added thereto, which then was stirred for 10 hours. The solvent was removed therefrom and 20 mL of methanol was then added thereto. Subsequently, sodium perchlorate (0.12 g, 1.0 mmol) was added thereto and thereby salt exchange (ion exchange) was performed. Thus, perchlorate of 3-(1-naphthyl)quinolinium ion (quinolinium ion derivative 2) was obtained. The yield amount of the quinolinium ion derivative 2 perchlorate thus obtained was 93 mg and the yield from the 3-(1-naphthyl)quinoline (2-2) was 93%. The instrumental analysis data of this quinolinium ion derivative 2 perchlorate is indicated below.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
In a similar manner as described for example 33, 45.8 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[4-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[CH2:25][N:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:12]3[CH2:11]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[F:35][C:36]([F:48])([F:47])[C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl.FC(F)(F)C(O)=O>[F:48][C:36]([F:35])([F:47])[C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:16]2[CH2:15][CH2:14][N:13]3[CH2:25][C@H:10]([O:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:8][N:7]=4)[CH2:11][C@H:12]3[CH2:17]2)(=[O:45])=[O:44])=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Oc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCN2C[C@H](Oc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of the product from Example 226A (0.14 g, 0.361 mmol) in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in a mixture of dichloromethane (3 mL) and triethylamine (0.30 mL, 2.17 mmol), and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.097 g, 0.398 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, and then it was partitioned between water and dichloromethane. The organic extract was dried over Na2SO4. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-3% ethyl acetate in heptane to give the title compound as a colorless solid (0.132 g, 74%). 1H NMR (300 MHz, CDCl3) δ ppm 1.72-1.90 (m, 1H) 1.91-2.06 (m, 1H) 2.06-2.20 (m, 1H) 2.33 (dd, J=9.49, 4.75 Hz, 1H) 2.37-2.70 (m, 3H) 3.00 (d, J=7.80 Hz, 1H) 3.58-3.73 (m, 1H) 3.77 (d, J=8.82 Hz, 1H) 3.92 (d, J=10.17 Hz, 1H) 5.41 (q, J=6.22 Hz, 1H) 6.79 (d, J=8.82 Hz, 1H) 7.76 (dd, J=8.65, 2.54 Hz, 1H) 7.79-7.94 (m, 4H) 8.39 (d, J=2.37 Hz, 1H); MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: C([Li])CCC.CC1CCCN(C)C1(C)C.[F:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([F:24])[CH:18]=1.[CH:25](=[O:27])[CH3:26]>O1CCCC1>[F:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([F:24])[C:18]=1[CH:25]([OH:27])[CH3:26]
Reactant: CC=O
Reactant: Fc1cc(F)cc(I)c1
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1c(F)cc(I)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
To a solution of 2.5 M n-butyl lithium in hexanes (2 mL, 5.0 mmol) and tetrahydrofuran (20 mL) at −78° C. under an atmosphere of nitrogen was added dropwise tetramethylpiperidine (0.85 mL, 5.0 mmol). The resulting light yellow solution was stirred for approximately 15 minutes, then 1,3-difluoro-5-iodo-benzene (1 g, 4.17 mmol) was added dropwise. This solution was stirred at −78° C. for 1 hour, followed by the addition of acetaldehyde (0.70 mL, 12.5 mmol) via syringe. The reaction mixture was stirred at −78° C. for 10 minutes then allowed to warm to room temperature. TLC indicated the reaction to be complete. The reaction was quenched with saturated aqueous ammonium chloride solution (2 mL), diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 0 to 25% v/v ethyl acetate/hexanes to give 1-(2,6-difluoro-4-iodo-phenyl)-ethanol (561 mg, 47%).
Reaction SMILES: [Li].[CH3:2][C:3]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([CH3:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.O>O1CCCC1>[CH3:9][C:3]([NH:10][S:11]([CH2:14][CH:21]([OH:22])[C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)(=[O:12])=[O:13])([CH3:2])[CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)CC(C)(C)NS(C)(=O)=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)CC(O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
nButyl lithium (1.6M in hexanes) (31.3 mL, 50 mmol) was added dropwise to N-(1,1,3,3-tetramethyl-butyl)-methanesulfonamide (5.23 g, 25 mmol) in tetrahydrofuran (30 mL) at −78° C. under an atmosphere of nitrogen. The mixture was warmed to 0° C. for 30 minutes then cooled to −78° C. 3-Pyridine carboxaldehyde (2.4 mL, 25 mmol) in tetrahydrofuran (20 mL) was added dropwise to the mixture over 20 minutes and the mixture was warmed to room temperature and stirred for a further 1 hour. Water (100 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate (2×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a pale yellow solid. The solid was washed with dichloromethane (10 mL) in heptane (100 mL) to afford 2-hydroxy-2-pyridin-3-yl-ethanesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide as a pale yellow solid (5.67 g, 72%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{(1R,2R)-2-[5-Chloro-2-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 322. Product isolated as a pale yellow solid (90 mg, 36%). m.p.=193-196° C.; LCMS (m/e) 503 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.35-7.25 (m, 1H), 7.08 (d, 1H, J=7.8 Hz), 6.82 (s, 1H), 5.40 (d, 1H, J=7.5 Hz), 5.38-5.32 (m, 1H), 3.94-3.83 (m, 1H), 3.45 (d, 2H, J=2.0 Hz), 3.31-3.20 (m, 1H), 3.00-2.90 (m, 4H), 2.80 (s, 3H), 2.83-2.71 (m, 4H), 2.28-2.18 (m, 3H), 1.89-1.79 (m, 2H), 1.45-1.33 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[O:13])[NH:10]2)=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].[N:15]1C=CC=CC=1>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:12]=[C:11]3[NH:10][C:9](=[O:13])[CH2:8][C:7]3=[CH:6][C:5]=2[O:14][N:15]=1
Reactant: CC(=O)c1cc2c(cc1O)CC(=O)N2
Reactant: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)NC(=O)C3
Yield: 11.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (2.75 g, 10.97 mmol) and pyridine (8.9 mL, 109.7 mmol) in DMF (110 m). After concentration in vacuo, the residue was purified by silica gel flash chromatography (2% MeOH--CH2Cl,) to give the title compound (0.245 g, 12%) as a pastel yellow solid.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].C([O-])=[O:15].[Na+]>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH:2]([OH:15])[CH3:13]
Reactant: CC(Br)C(=O)c1ccc(F)cc1F
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(=O)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
2-Bromo-2',4'-difluoropropiophenone (141 g) was dissolved in methanol (1100 ml), to which was added sodium formate (176.2 g), and the mixture was stirred for 2 days at 50° C. Methanol was distilled off under reduced pressure. The residue was subjected to extraction by the addition of ethyl acetate (700 ml) and water (500 ml). The ethyl acetate layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was crystallized from hexane (200 ml) to afford 2',4'-difluoro-2-hydroxypropiophenone (50.5 g) as colorless prisms, m.p. 49°-51° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].[H-].[Na+].I[CH3:43].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:43])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reaction time: 0.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (0.100 g, 0.145 mmole) in N,N-dimethylformamide (4 ml) was added sodium hydride (55% suspension in oil, 0.0067 g, 0.153 mmole). After the gas evolution had stopped, iodomethane (0.010 ml, 0.023 g, 0.160 mmole) was added. After 0.5 hour, the reaction mixture was poured on to water (15 ml) and the product was extracted with ethyl acetate. The organic solution was washed with water, then brine and dried over sodium sulfate. After removal of the solvent the crude was purified by column chromatography over silica gel using ethyl acetate-cyclohexane to yield the title compound (Compound G17 of Table G) as amorphous material showing by LC-MS analysis under the conditions 6 (described hereafter) a retention time of 1.09 min and a M+H+ mass of 700.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[NH3:14]>CCO>[NH2:14][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N
Solvent: CCO
Product: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A 500 mL pressure flask was charged with 2,6-dichloro-3-nitrobenzonitrile (30.0 g, 138 mmol) and a 5.1 M solution of ammonia in EtOH (170 mL). The flask was sealed and heated in an oil bath at 80° C. with stirring for 1.5 h. The cooled solution was filtered, the crystals washed with water and dried to yield 2-amino-6-chloro-3-nitrobenzonitrile (18.4 g, 68%), mp 181-184° C.; MS (ES−) 196, 198 (M−H−).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:42]([O:44][CH3:45])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:19][CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[ClH:56]>CO>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:42]([O:44][CH3:45])=[O:43])[CH:39]([CH3:40])[CH3:41])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:19][CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9].[ClH:56]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(C)C)C(C)C

Procedure:
7 g of Z-Lys(Boc)-Glu(OBut)-Val-Val-OMe are dissolved in 150 ml of methanol. The solution is subjected to catalytic hydrogenation at pH 4.5 after adding Pd-on-BaSO4 and 2 N methanolic hydrochloric acid. When the reaction is complete, the catalyst is filtered off and the filtrate is concentrated. The residue crystallizes on being triturated with ether. Yield 5.45 g, melting point 194°-198°, [α]D23 =-33.1° (c=1, in methanol).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:27][C:28]([C:30]1[NH:31]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O>>[OH:27][CH2:28][CH2:30][NH:31][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NCCO)n(C)n1
Yield: 86 %

Procedure:
As described for example 6, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (73 mg, 0.21 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (68 mg, 86%) which was obtained as a white solid. MS: m/e=376.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:26][C:25]=3[CH3:37])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCN
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCNCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][CH2:14][CH2:15][CH3:16].[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCOCC(C#CCOC1CCCCO1)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOCC(CCCOC1CCCCO1)OC(C)=O

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-propoxy-2-pentyne (10.8 g., 0.04 mole) is dissolved in ethyl acetate (100 ml.). 5% Palladium on carbon is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 41 lbs./in2 and 25° C. When 0.08 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](O)=[O:8].N>>[CH3:1][C:2]1[C:3]2[C:7](=[O:8])[CH2:6][O:5][C:4]=2[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Agent: N
Product: Cc1cc(C)c2c(c1)OCC2=O
Temperature: 50 °C
Yield: 100 %

Procedure:
A mix of polyphosphoric acid and 2-(3,5-dimethylphenoxy) acetic acid was heated at 50° C. for 8 hours. The mix was poured in ice, treated with ammonia until a pH 7 was obtained. The mix was extracted with methylenechloride and the organic phase was treated with a solution of bicarbonate, made anhydrous (Na2SO4) and freed from the solvent under reduced pressure, to produce 4,6-dimethyl-3-benzofuranone (40% conversion, 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[OH-].[K+].CO.[K].Br[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CC(Br)c1ccccc1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Br)cc1C(=O)Nc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-bromo-2-hydroxy-N-3-pyridinylbenzamide (may be prepared as described in Description 35; 300 mg, 1.02 mmol) was added to a solution of potassium hydroxide (57.4 mg, 1.02 mmol) in methanol (2 ml, 49.4 mmol). The mixture was then stirred at room temperature for 15 min and the solvent was removed in vacuo. To the potassium salt was added DMF (10 ml) and (1-bromoethyl)benzene (189 mg, 1.023 mmol), The reaction mixture was then heated under reflux for 2 h. The mixture was cooled, diluted with water (20 ml) and the precipitate was collected, and finally crystallized from ethyl acetate to yield the title compound. 63 mg.
Reaction SMILES: O[C:2]1([CH3:14])[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([CH3:14])=[CH:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: COc1ccc2c(c1)OCCC2(C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OCC=C2C

Procedure:
The carbinol of step (a) (73.3 g) was stirred with phosphorus oxychloride (19.3 g; 11.6 ml) in dry pyridine (380 ml) for 20 hours under nitrogen. The reaction mixture was poured into water, extracted with ether and the ethereal extracts were washed with dilute acid, then sodium bicarbonate solution, then water and dried. Evaporation of the solvent left 58 g of residue (87.2%). MS evidence was correct for the required compound. NMR suggested that the product was in fact a mixture of isomeric alkenes.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[C:31]1([CH:37]([NH2:45])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([CH:37]([NH:45][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: NC(Cc1ccccc1)c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Example 3(b) was repeated, except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1,2-diphenylethylamine were employed as starting materials, in relative proportions similar to those used In that Example, to give the title compound in a quantitative yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[F:44])[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[F:83]C1C=C(B(O)O)C=CC=1F>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][C:43]([F:44])=[C:2]([F:83])[CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(F)c(F)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 25 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3,4-difluorophenylboronic acid (42 mg, 0.2625 mmol) to produce the title compound (26 mg, 25% yield).