Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[C:8]([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([NH:6][C@H:7]([C:12]([OH:14])=[O:13])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:4]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C

Procedure:
23.5 ml (305 mmol) of chloroformic acid methyl ester (Fluka, Buchs, Switzerland) are added over a period of 20 minutes to a solution of 20 g (152 mmol) of (L)-tert-leucine (=2(S)-amino-3,3-dimethyl-butyric acid=L-α-tert-butylglycine; Fluka, Buchs, Switzerland) in a mixture of 252 ml (504 mmol) of 2N aqueous sodium hydroxide solution and 80 ml of dioxane and the reaction solution is heated at 60° C. for 14 hours. After the reaction solution has cooled to room temperature, it is washed twice with methylene chloride. The aqueous phase is acidified to pH 2 with 4N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic extracts are combined, dried over sodium sulfate and concentrated by evaporation, the product beginning to solidify. Digestion of the solidified solid with hexane yields the title compound in the form of a white powder. M.p. 106-108° C. 1H-NMR (CD3OD) δ=4.0 (m, 1H); 3.65 (s, 3H); 1.01 (s, 9H). Anal. (C8H15NO4.0.02 H2O) C: calc. 50.69, found 50.69; H: calc. 8.00, found 7.95; N: calc. 7.39, found 7.35.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33]C(OCC=C)=O)[C:28]=2[F:40])[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl.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>[NH2:33][C:29]1[C:28]([F:40])=[C:27]([C:9]2[N:10]=[C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (670 mg, 1.139 mmol) in dichloromethane (8 mL) were added tributylstannane (332 mg, 1.139 mmol), tetrakis (65.8 mg, 0.057 mmol) and water (66 μl, 3.66 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated and residue was purified using column chromatography (hexane/EtOAc, 0 to 100%) to obtain the title compound (482 mg). MS (ESI): 504.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[CH2:32][CH2:31]1)=[O:29]
Reactant: Nc1ccccc1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added aniline (0.015 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (24.5 mg, 53%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[NH:23][CH2:22]1.[H-].[Na+]>CN(C=O)C>[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[N:23]([C:2]2[C:11]3[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (235 mg, 0.86 mmol), 4-(3,3-dimethylindolin-6-yl)morpholine (200 mg, 0.86 mmol), sodium hydride (41 mg, 1.72 mmol) in DMF (2.0 mL) and heating at 130° C. for 4 h. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-8-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.64-8.79 (1H, m), 7.87-7.98 (2H, m), 7.60-7.65 (1H, m), 7.32-7.42 (3H, m), 7.08 (1H, d, J=7.8 Hz), 6.31 (1H, dd, J=8.0, 2.2 Hz), 5.59 (1H, d, J=2.3 Hz), 3.63-3.83 (6H, m), 2.86-3.05 (4H, m), 2.43 (3H, s), 1.52 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: C(O[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])C.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>C(Cl)Cl>[C:12]([N:8]1[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]1)(=[O:15])[CH:13]=[CH2:14]
Reactant: CCOC(CCCN)OCC
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)N1CCCC1OCC
Temperature: 15 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Aminobutyraldehyde diethyl acetal (AmBDA, 75 g, 1.09 mol, Aldrich Chemical) was combined with a two phase mixture of 955 mL of CH2Cl2 and 160 mL of 14N NaOH in a 3 neck flask equipped with a thermometer and an efficient mechanical stirrer. This was cooled to 15° C. with an ice bath. Acryloyl chloride (98.3 g, 1.09 mol, Aldrich) was added via an addition funnel at a rate slow enough to maintain the reaction temperature below 30° C. Reaction monitoring by capillary glpc revealed essentially complete AmBDA consumption when the acryloyl chloride addition was complete. Agitation was continued for 1 h. The layers were separated (water may be added to dissolve precipitated salt and improve phase separation) and the organic phase was washed with saturated brine. The brine was combined with the aqueous layer and back extracted with CH2Cl2. The combined organic layers were neutralized with saturated aqueous NaH2PO4, dried over anhydrous MgCl2 and concentrated on a rotary evaporator at 40° C. to give 99% pure ABDA (by glpc) in 87% yield. The product can be freed of any high molecular weight by-products by kugelrohr distillation (120°-125° C. at 0.2 torr), but this produces significant yield losses and partial isomerization to N-acryloyl-5-ethoxy pyrrolidine (AEP) and related products. The pot temperature should not exceed 60° C. during these operations. The yield loses are minimized by adding a basic reagent, such as Na2CO3, and a radical inhibitor, such as methylene blue, to the distillation vessel.
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([CH3:15])[N:6]=1.[CH2:16]([O:18]CC)C.O>CO>[CH3:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:18][CH3:16])=[N:6][C:7]=1[CH3:15]
Reactant: CCOCC
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 7 h
Yield: 82.6 %

Procedure:
To a solution of 28% sodium methoxide (1.11 mL) and methanol (5.5 mL) was added dropwise a solution of 2-chloro-5,6-dimethyl-3-nitropyridine (1-013-05) (837 mg) in methanol (6.6 mL) for 5 min at room temperature under nitrogen atmosphere, and the reaction mixture was heated with stirring, in oil-bath at 50° C. for 7 h. To the reaction mixture was added diethyl ether and the reaction mixture was poured into water, extracted with twice with diethyl ether, washed once with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5,6-dimethyl-2-methoxy-3-nitropyridine (1-013-06) (675 mg, 82.6%, m.p.: 71-73° C.) as an orange crystal.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][SH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:18][C:19]([F:33])([F:32])[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=2)[O:22][CH2:21]1.O>CN(C)C=O.C(O)(=O)C>[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][S:14][CH2:21][C:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)([OH:22])[C:19]([F:18])([F:32])[F:33])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOc1ccc(C2(C(F)(F)F)CO2)cc1
Reactant: SCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(O)(CSCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a suspension of sodium hydride (0.1 g) in N,N-dimethylformamide (10 cm3) at 0° C. was added 3-phenoxybenzyl thiol (0.28 g). After stirring for 30 minutes, 1,1,1-trifluoro-2-(4-ethoxyphenyl)-prop-2-ene oxide (0.3 g) was added. The reaction mixture was stirred for ten minutes before being added to water (25 cm3) and neutralised with acetic acid. The product was extracted into diethyl ether (200 cm3). The organic layer was dried over anhydrous sodium sulphate and the solvent removed by evaporation under reduced pressure. The resulting oil was purified by chromatography to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-2-hydroxyprop-3-yl 3-phenoxybenzyl sulphide as a colourless oil (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1O)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1O)C2
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
To a mixture of 7-(5-fluoro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.75 g) and aminoguanidine hydrochloride (0.333 g) were added ethanol (8 ml) and concentrated hydrochloric acid (0. 5 ml), and the mixture was stirred at 110° C. (bath temperature) for 2.5 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(5-fluoro-2-hydroxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 169) (1 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH:15]([CH2:17][O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:14][C:13]2=[O:29])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH:15]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH2:14][C:13]2=[O:29])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OS(C)(=O)=O)cc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(N2CC(COc3ccc(C(=O)O)cc3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
Methyl 4-[1-(4-methanesulfonyloxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (1.78 g) is dissolved in dioxane (20 ml) and thereto is added a solution of sodium hydroxide (0.34 g) in water (5 ml). The mixture is stirred at room temperature for 16 hours. After adding conc. hydrochloric acid (about 0.7 ml), the reaction mixture is concentrated under reduced pressure. Water is added to the resulting residue and the precipitate is collected by filtration, washed with water and recrystallized from about 15% aqueous methanol to give the desired product (1.43 g), m.p. 199°-201° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:23]2[C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:25][C:24]=2[CH3:26])=[O:28])[CH2:35][CH2:34]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f58) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[Mg+2].[Cl-].[Cl-].[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([O:46][P:47]([OH:50])([OH:49])=[O:48])[C@@H:32]3[OH:51])([OH:28])=[O:27])([OH:24])=[O:23])[C@@H:17]([OH:52])[C@H:16]2[OH:53])[CH:12]=[C:11]([C:54]([NH2:56])=[O:55])[CH:10]=1>>[CH:42]1[N:43]=[C:44]([NH2:45])[C:39]2[N:38]=[CH:37][N:36]([C@@H:34]3[O:35][C@H:31]([CH2:30][O:29][P:26]([O:25][P:22]([O:21][CH2:20][C@H:18]4[O:19][C@@H:15]([N:13]5[CH:12]=[C:11]([C:54]([NH2:56])=[O:55])[CH2:10][CH:9]=[CH:14]5)[C@H:16]([OH:53])[C@@H:17]4[OH:52])([OH:24])=[O:23])([OH:28])=[O:27])[C@@H:32]([OH:51])[C@H:33]3[O:46][P:47]([OH:50])([OH:49])=[O:48])[C:40]=2[N:41]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
Cell membrane fractions derived from insect cells transfected with recombinant baculoviruses expressing 11-hydroxylase and complementary electron transport proteins were analyzed for 11-hydroxylase activity in a reaction mixture containing 80 mM phosphate buffer, pH 7.4, 8 mM MgCl2, and 0.9 mM NADP+ in a final volume of 200 ul. In order to insure an adequate source of reducing equivalents, an NADPH regenerating system was provided by adding glucose-6-phosphate dehydrogenase (1.5 U/ml) and 8 mM glucose-6-phosphate. Steroid substrate (e.g., androstenedione) was provided at a final concentration of 0.3 mM. Reaction mixtures were incubated at 37° C. for 30 min. The reactions were terminated by the addition of 200 ul methanol and then placed on ice. Samples were pelleted by centrifugation to remove precipitated protein.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([C:27](O)=[O:28])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18]>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([C:22]12[CH2:25][CH2:26][C:19]([C:17]([O:16][CH3:15])=[O:18])([CH2:20][CH2:21]1)[CH2:24][CH2:23]2)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C12CCC(C(=O)OC)(CC1)CC2

Procedure:
The product from Example 92B and 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (Oakwood) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.23-1.36 (m, 2H), 1.58 (s, 9H), 1.58-1.66 (m, 2H), 1.70-1.83 (m, 12H), 2.61-2.66 (m, 2H), 3.58 (s, 3H), 8.49 (s, 1H). (ESI+) m/z 407 (M+H)+. Anal. calcd. for C22H34N2O3S: C, 64.99; H, 8.43; N, 6.89. Found: C, 64.65; H, 8.24; N, 6.72.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:15]([NH:21][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1)[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnc(SC)nc1O
Reactant: NCc1ccco1
Solvent: CCCCO
Product: CCOC(=O)c1cnc(NCc2ccco2)nc1O

Procedure:
2-Methylthio-5-ethoxycarbonyl-4-hydroxypyrimidine (535 mg, 2.5 mmol) was refluxed in butanol overnight with furfurylamine (335 μl, 3.8 mmol). The named product crystallized out and was filtered off (577 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
The title compound was prepared by an adaptation of the procedure described by Mundla, S. R. (Tetrahedron Lett. 2000, 41, 4277-4279). 2-Bromo-6-nitrotoluene (1.09 g, 5.05 mmol) was placed in a 50 mL round-bottom flask equipped with a magnetic stir bar. Conc. H2SO4 (10 mL) was added, and the solid was allowed to dissolve. The reaction was cooled in an ice bath, and fuming nitric acid (1.5 eq., 0.340 mL, 7.57 mmol) was added dropwise via syringe at a rate such that the temperature of the mixture remained below 10° C. After completion of the addition, the reaction was allowed to warm to RT and stir for 2 h. The reaction mixture was poured into crushed ice, and the precipitate was isolated by filtration. The solid was washed with water (30 mL) and allowed to air dry. The crude product was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 879 mg (67%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[CH3:25])=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:26]([O-])=O)=[N+]=[N-].[H][H]>[Pd].C(O)C.O1CCCC1>[NH2:26][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[NH2:1])[N:11]=[CH:10][C:9]([C:14]#[N:15])=[C:8]2[NH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH3:25]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Yield: 72.4 %

Procedure:
A mixture of 0.65 g (1.73 mmol) of 7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile and 0.12 g of 10% palladium on carbon in a 1:1 mixture of ethanol/tetrahydrofuran is shaken on Parr apparatus with hydrogen gas at 40 psi for 2 hours. The mixture is filtered through a pad of diatomaceous earth, washed with methanol and tetrahydrofuran, then dried to provide a dark solid. The crude product is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 88:12) to yield 0.4 g of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile as a dark solid, mp 245° C. (dec).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:6][N:5]=[C:4]2[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:3]=12.Cl.[NH2:24]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:21]([N:18]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:17][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:3]=2[CH:20]=[N:19]1)[CH3:22]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3cccc(OC)c3)cnc21
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c3noc(-c4cccc(OC)c4)c3cnc21

Procedure:
Five grams of 4-chloro-1-ethyl-5-(3-methoxybenzoyl)-1H-pyrazolo[3,4-b]pyridine was refluxed for 2 hours in 500 ml of acetic acid containing 15 g of hydroxylamine hydrochloride and 1 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed well with water, dried, evaporated and chromatographed over 230-400 mesh silica gel. The appropriate fractions were combined and evaporated to give 3.05 g of product, mp 170°-171°. After recrystallization from water it had mp 169°-171° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].O1CCCC1.C(OC(Cl)=O)C.[CH2:21]([N:23](CC)CC)C>>[C:21]([C:2]([CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4])#[N:23]
Reactant: CCN(CC)CC
Reactant: CCCCC(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCCCC(C)(C#N)CO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
A mixture of 1.25 g (8.1 mM) of (-)-2-methylhexanoic acid ([α]D26 -6.15 degrees (c 1.073, methanol)), 20 ml of dry tetrahydrofuran and 0.90 g (8.9 mM) of dry triethylamine was cooled on an ice bath, and 0.84 g (8.1 mM) of ethyl chloroformic acid was added dropwise thereto in 5 minutes, followed by 1 hour of stirring at 0° C. A white salt precipitated at this time was removed by filtration. To a mixture of 0.46 g (12.1 mM) of sodium borohydride and 8 ml of distilled water under stirring at 0° C., the above filtrate was added dropwise in 20 min., followed by stirring at room temperature for 3 hours. After the reaction, 2N-hydrochloric acid was added to give pH 1, and the organic layer was separated. The remaining aqueous layer was subjected to extraction with ether, and the ether extract was mixed with the organic layer. The mixture was washed with 1N-sodium bicarbonate aqueous solution and dried on sodium sulfate. After the removal of solvent by distillation, the product was subjected to distillation by a Kugelrohr distiller. At 95° C./4 mmHg, (+)-2-cyano-2-methyl-1-hexanol was obtained in an amount of 0.55 g (Yield:48.5%), [α]D26 +0.66 degree (c 1.823, ether).