Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3]CCCCC.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2.CI>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([N:29]([CH3:3])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)N(C)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 0.23 g (5.7 mmol) of a 60 percent NaH/oil dispersion and 10 ml of hexane was stirred under N2 for 10 minutes. The hexane was decanted off, replaced with 20 ml of DMF and a solution of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide in 20 ml of DMF was added dropwise over a period of 30 minutes. The mixture was stirred at ambient temperature for 1.5 hours when a solution of 1.45 g (10 mmol) of methyl iodide in 10 ml of DMF was slowly added. The mixture was stirred at ambient temperature for 2 days and then quenched by cautious addition of a few drops of acetic acid and then water. The mixture was poured into water, extracted with three portions of ether and the combined organic layers dried over MgSO4 and evaporated to dryness. The residue was taken up in hot methylcyclohexane, treated with charcoal and filtered and then allowed to cool to give 1.03 g (50 percent) of the above-named product as colorless crystals, m.p. 137°-139° C. (Compound 41)
Reaction SMILES: Br[C:2]1[C:3]2[O:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[OH-:11].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:10]1[C:3]2[C:2]([OH:11])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9]1
Reactant: [OH-]
Reactant: Brc1cncc2ccoc12
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Oc1cncc2ccoc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A mixture of 7-bromofuro[3,2-c]pyridine (9.15 g, 46.2 mmol), potassium hydroxide (7.78 g, 139 mmol), Pd2(dba)3 (0.02 eq) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.08 eq) in H2O (22.5 mL) and 1,4-dioxane (22.5 mL) was vigorously stirred at 100° C. overnight. LC-MS showed completion of the reaction. The reaction mixture was washed with DCM (3×30 mL). The aqueous layer was neutralized and concentrated by freeze dryer. The resulting solid was washed with massive amount of acetone to give the title compound as a white solid (6.2 g, 81% yield). 1H NMR (DMSO-d6, 400 MHz): δ=7.05 (d, J=2.0 Hz, 1H), 8.04 (s, 1H), 8.06 (d, J=2.2 Hz, 1H), 8.44 (s, 1H). MS (ES+): m/z=136.15 [MH+].
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([OH:19])[C:13]([NH2:18])([CH2:16][OH:17])[CH2:14][OH:15]>CN(C=O)C.O>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([OH:19])[C:13]([NH2:18])([CH2:16][OH:17])[CH2:14][OH:15]
Reactant: COC(=O)c1ccccc1O
Agent: NC(CO)(CO)CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])c1ccccc1O

Procedure:
Methyl salicylate (2.3g, 15.1 mmole) was reacted with Tris (14.8 g, 120.8 mmole) in DMF (182 ml) and water (121 ml) at pH 9.0 and 60° C. for 48 h. The formation of the title product (Rt 3.95) from methyl salicylate (Rt 7.66) was monitored by HPLC (System A) until the reaction stopped at 75% of completion. The mixture was then evaporated to dryness under reduced pressure and the sample dissolved in water. The pH was adjusted to 4.5 and the title product purified by preparative HPLC followed by ion exchange chromatography (Amberlite IR63 resin) to give the chromatographically pure salicylate-Tris (3.66, 65% of theoretical).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C1N=C(N)C2N=CN([C@@H]3[O:34][C@H](CO)[C@@H](O)[C@@H]3O)C=2N=1.O.OO>C(O)(=O)C.[C].[Pd]>[C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-:34])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Pd]
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Twenty grams of adenosine with a product code of A9251-25G, commercialized by Sigma-Aldrich Japan K.K., Tokyo, Japan, was dispersed in one liter of acetic acid and admixed with 100 mL of 30% hydrogen peroxide solution, followed by stirring the resulting mixture at ambient temperature for five days. An excessive amount of the remaining hydrogen peroxide was decomposed by the addition of five grams of 5% palladium carbon, commercialized by Kawaken Fine Chemicals Co., Ltd., Tokyo, Japan, followed by filtering the mixture to remove the palladium carbon, drying the resulting solution in vacuo, adding ethanol to the dried product to disperse the formed crystals, and filtering the resulting mixture to obtain crude crystals of adenosine N1-oxide. Eight grams of adenosine N1-oxide with a purity of 99.5% was obtained by dissolving the crude crystals in ethanol by heating, filtering the resulting solution, ice-chilling the filtrate to effect recrystallization, and repeating these steps twice.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([S:64](Cl)(=[O:66])=[O:65])[CH:59]=1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:64]([C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)(=[O:66])=[O:65])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and 3-pyridinesulfonyl chloride (94 mL, 0.430 mmol), the title compound was obtained as a tan solid (34 mg, 24% yield). MS (ESI): 485.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[I:12][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc[nH]c1=O
Solvent: ClCCl
Product: COC(=O)c1cc(I)c[nH]c1=O
Yield: 46.7 %

Procedure:
A solution containing 19.48 g of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate and 36.15 g of N-iodosuccinimide in 500 ml of anhydrous methylene chloride is heated at reflux under a nitrogen atomosphere in the dark for 48 hours. The reaction mixture is concentrated to 150 ml under reduced pressure and the solid which forms is collected by filtration and washed with small portions of cold methylene chloride and benzene to give 16.59 g (47%) of methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate as a pale yellowish solid. This material is sufficiently pure for the next reaction; its properties upon recrystallization from ethyl acetate are as follows: m.p. 190°-192° C.; NMR (DMSO-d6, 300 MHz) delta 3.71 (s, 3H), 7.93 (d, 1H, J=2.26 Hz), 8.10 (d, 1H, J=2.26 Hz), IR (KBr) 2500-3050 (broad), 1725, 1630, 1585, 1475, 1425, 1320, 1260, 1235, 1180, 1150, 1105, 1065, 965, 875 and 800 cm-1M/S (279, M+), 247, 127 and 93.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CCOc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOc1ccccc1-c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Yield: 11.4 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-ethoxyphenylboronic acid (66 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 295 (9 mg). ESI-MS 365.1 (M)+
Reaction SMILES: [CH2:1]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(O)(=[O:29])C>O>[CH2:1]([C:16]1[C:17](=[O:26])[C:18]2[C:23]([C:24](=[O:29])[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCc1ccc2ccccc2c1O
Solvent: O
Product: CCCCCCCCCCCCCCCC1=CC(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
2-Pentadecyl-1-naphthol (48 , 135 mmol) was dissolved in acetic acid with slight warming. Chromic oxide (55.5 g, 555 mmol) was dissolved in 50 ml water and then 50 ml acetic acid was added. This chromic oxide solution was then added dropwise with stirring to the solution of the pentadecylnaphthol maintaining the temperature between 45°-50° C. The mixture was then stirred for several hours while slowly cooling to room temperature. The pentadecylnaphthoquinone, which had crystallized from solution was filtered off, washed with acetic acid, water, and air dried. Yield: 24 g (48 percent). (Method of L. F. Fieser et al, J. Am. Chem. Soc., 74, 3910 (1952)).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1.[I-].[Na+]>O1CCCC1.O>[F:45][C:41]1[CH:40]=[C:39]([C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([CH2:10][O:1][C@H:2]4[CH2:6][CH2:5][O:4][CH2:3]4)[CH:12]=3)[N:16]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: O[C@H]1CCOC1
Reactant: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CCl)cc23)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CO[C@H]4CCOC4)cc23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of 40 mg of (S)-3-hydroxytetrahydrofuran in tetrahydrofuran was added 15 mg of 60% sodium hydride (oily) in an atmosphere of nitrogen gas, and the mixture was stirred at room temperature for 15 minute. To the reaction mixture were added 150 mg of 5-(chloromethyl)-3-(3-fluorophenyl)-1-trityl-1H-indazole produced in Production Example I-32 and 45 mg of sodium iodide, followed by stirring at room temperature for five days. After adding water to the reaction mixture, it was extracted with 20 ml of ethyl acetate. The organic layer was sequentially washed with half-saturated aqueous sodium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=0:1 to 1:9), to give 84 mg of the title compound as a white amorphous powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:43][CH2:44][CH2:45][CH3:46])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:35]=[N:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47]>C(Cl)Cl.O1CCOCC1>[ClH:47].[ClH:47].[CH2:43]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=2)[CH:22]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Reaction time: 0.67 h

Procedure:
To a solution of 4-(6-butyl-5-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-pyridazin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.107 mmol, 68 mg) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction mixture was stirred for 40 min. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to give 3-butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (59.5 mg).
Reaction SMILES: [CH:1]1[C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=[C:3]([I:10])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[I:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:1][CH:2]=1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of p-iodobenzoic acid (5 mmole) in a dry tetrahydrofuran (20 ml) at -70° is added a suspension of lithium aluminum hydride (10 mmole) in tetrahydrofuran (10 ml). The mixture is allowed to warm to 0° and stirred at 0° for 2 hours. The reaction mixture is then poured into a dilute hydrochloric acid -- ice mixture and extracted with ether. The ether extract is washed with dilute bicarbonate solution, washed, dried over sodium sulfate and concentrated to dryness. Chromatography of the residue on a silica gel gives p-iodobenzyl alcohol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.N1C=CC=CC=1>ClCCl>[CH2:19]([N:16]1[CH2:15][CH2:14][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
Methanesulfonyl chloride (0.91 mL, 11.7 mmol) was added to a cooled (0° C.) solution of 1-(2-aminophenyl)-4-benzylpiperazine (2.61 g, 9.8 mmol) and pyridine (0.95 mL, 11.7 mmol) in dichloromethane (30 mL) and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and triethylamine (1.4 mL) was added. The mixture was azeotroped with xylene, diluted with ethyl acetate and washed with aqueous potassium carbonate (saturated, 3×). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99:1) to give the title compound as yellow oil (2.83 g, 84%). δH (250 MHz, CDCl3) 7.88-7.80 (1H, br s), 7.51 (1H, dd, J 1.6, 8.0 Hz), 7.34-7.27 (5H, m), 7.25 (1H, dd, J 1.6, 7.5 Hz), 7.16 (1H, dt, J 1.6, 7.5 Hz), 7.07 (1H, dt, J 1.7, 7.6 Hz), 3.59 (2H, s), 3.04 (3H, s), 2.90-2.85 (4H, m), and 2.66-2.60 (4H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[Cl:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Amino-4-(2-chloro-4-nitrophenoxy)pyridine (574 mg) was dissolved in tetrahydrofuran (10 ml) under a nitrogen atmosphere, and then triethylamine (0.602 ml) and phenyl chloroformate (0.542 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 10 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to provide a crude product of 4-(2-chloro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (1.272 g). The crude product (637.3 mg) was dissolved in tetrahydrofuran (6.5 ml), and then pyrrolidine (1.06 ml) was added at room temperature, followed by stirring for 1 hr and evaporating the solvents under a reduced pressure. The resultant residue was dissolved in ethanol (20 ml)-water (5 ml), and then electrolytic iron powder (500 mg) and ammonium chloride (1 g) were added thereto, followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and filtered through celite to remove an insoluble portion, which was washed with ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate) to provide the titled compound (227 mg) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1.[CH3:31][NH2:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[CH:24][C:25]([C:27]([NH:32][CH3:31])=[O:28])=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccc(F)cc3F)nc1-2
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccc(F)cc3F)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (30 mg, 0.07 mmol) was reacted with 2M methylamine (0.06 mL) in THF to provide 174. LC/MS (ESI+): m/z 422 (M+H). 1H NMR (400 MHz, DMSO) δ 8.52 (t, J=9.7, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.80-7.67 (m, 2H), 7.67-7.55 (m, 1H), 7.47-7.38 (m, 2H), 7.33 (t, J=8.4, 1H), 4.50 (d, J=7.7, 3H), 2.74 (t, J=17.2, 3H)
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][S:13][CH:14]([S:17][CH3:18])[S:15][CH3:16].[OH:19][C@H:20]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C:22](=[CH:23][CH2:24][C@@H:25]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:35])[CH2:31][CH2:32][CH:33]=[O:34])[CH2:21]1>O1CCCC1>[OH:19][C@H:20]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C:22](=[CH:23][CH2:24][C@@H:25]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:35])[CH2:31][CH2:32][CH:33]([OH:34])[C:14]([S:17][CH3:18])([S:15][CH3:16])[S:13][CH3:12])[CH2:21]1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CSC(SC)SC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSC(SC)(SC)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
Under an argon atmosphere at -78° C., 10.4 ml (17.7 mmoles) of a hexane solution of n-butyllithium was added to a solution of 2.4 ml (18.0 mmoles) of tris(methylthio)methane in 40 ml of tetrahydrofuran (THF for short), and the mixture was stirred for 40 minutes at the same temperature. To the mixture was added dropwise 15 ml of a THF solution of 798 mg (1.8 mmoles) of 3β-hydroxychol-5-en-24-al [compound of formula(VI)], and the mixture was stirred at -78° C. for 40 minutes. The mixture was extracted with ether in a customary manner, and the resulting residue was dissolved in a mixture of 10 ml of THF and 5 ml of methanol. Four drops of 2N hydrochloric acid was added, and the mixture was stirred at room temperature for 100 minutes. The mixture was extracted with ether in a customary manner, and the resulting crude product was purified by silica gel column chromatography [31 g; eluted with hexane/ethyl acetate (10:1)] to give 651 mg of the captioned compound having a melting point of141° to 143° C. (recrystallized from methanol).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH2:35])[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)[C:18](O)=[O:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][C:41](=[O:50])[NH:42][CH:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41](=[O:50])[NH:42][CH:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH:23]=[C:15]([O:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[NH2:35])=[CH:34][CH:33]=3)[CH:16]=2)[CH2:47][CH2:48]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)C(N)c1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3ccc(C(N)C(=O)OC(C)(C)C)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 80 %

Procedure:
Following the procedure of Example 5(c) 3-(4-(tert-butoxycarbonyl aminomethyl)benzyloxy)-5-(4-cyano phenoxy)benzoic acid 1.1 g (2.31 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.494 g, 2.31 mmol) were used to afford 1.24 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H, d), 5.15 (2H, s), 6.74 (1H, d), 6.88 (1H, s), 7.12 (2H, d), 7.18 (1H, s), 7.26 (2H, d), 7.4 (4H, d), 7.86 (2H, d), 8.26 (1H, d).