Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:38]C(=O)OCC2C=CC=CC=2)[C@H:18]([OH:37])[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH:12]=[C:13]([F:15])[CH:14]=1.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[NH2:38][C@@H:17]([CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([F:8])[CH:10]=1)[C@H:18]([OH:37])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=1[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]
Reactant: C=CCCCc1ccc(C(F)(F)F)cc1CNC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: C=CCCCc1ccc(C(F)(F)F)cc1CNC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 113 %

Procedure:
Step AM (2): To a solution of benzyl (2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(2-(pent-4-enyl)-5-(trifluoromethyl)benzylamino)butan-2-ylcarbamate trifluoroacetate salt (88 mg, 0.128 mmol) in DME (9.0 mL) and water (6.0 mL) was added barium hydroxide monohydrate (852 mg, 4.5 mmol). The reaction mixture was stirred at 110° C. in a high pressure vial for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(2-(pent-4-enyl)-5-(trifluoromethyl)-benzylamino)butan-2-ol double trifluoro-acetate salt (64 mg, 74%) as a colorless oil. LC-MS (M+H)+=443.36.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17].C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 78 %

Procedure:
Piperidine (0.50 mL, 5.1 mmol) was added to a suspension of 4-hydroxy-3-methoxybenzaldehyde (0.77 g, 5.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.0 g, 4.5 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(4-Hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.1 g, 78%) was obtained as a yellow crystalline solid; mp 207.5-208.5° C., lit. [25] 230-233° C.; δH (500 MHz, DMSO-d6) 3.83 (s, 3H, OCH3), 6.71 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.13 (dd, J5′,6′=8.5, J2′,6′=1.5 Hz, 1H, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.34 (d, J2′,6′=1.5 Hz, 1H, H2′), 7.52 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=2.0 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=2.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 9.57 (s, 1H, OH), 11.27 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [N+:1]([O-])(O)=[O:2].[N+:5]([C:8]1([N+:24]([O-:26])=[O:25])[CH2:15][NH:14][CH2:13][C:12]([N+:19]([O-:21])=[O:20])([N+:16]([O-:18])=[O:17])[CH2:11][N:10]([N:22]=[O:23])[CH2:9]1)([O-:7])=[O:6]>>[N+:24]([C:8]1([N+:5]([O-:7])=[O:6])[CH2:15][N:14]([N:1]=[O:2])[CH2:13][C:12]([N+:19]([O-:21])=[O:20])([N+:16]([O-:18])=[O:17])[CH2:11][N:10]([N:22]=[O:23])[CH2:9]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CNCC([N+](=O)[O-])([N+](=O)[O-])C1
Product: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CN(N=O)CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
To 7.0 ml 60 percent nitric acid at 40°-45° C. was added 0.2 g 3,3,7,7-tetranitro-1-nitrosoperhydro-1,5-diazocine (I). The mixture was heated at 40°-45° C. for five minutes and was then poured into ice. The solid was filtered off, washed with water and dried in a vacuum desiccator to give 0.109 g solid 3,3,7,7-Tetranitro-1,5-dinitrosoperhydro-1,5-diazocine. The solid was recrystallized from nitromethane to remove a small amount of starting material; mp: 190° C., onset of decomposition; 228°-229° C. melts; 1H NMR (acetone-d6): δ 4.81 (s), 5.26 (s), 5.73 (s), 6.16 (s).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(Br)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Yield: 62.7 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-bromo-1,3-thiazole-4-carboxylic acid (0.957 g, 4.60 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1 g, 3.84 mmol). Yield 62.7%. 1H-NMR (400 MHz; CDCl3): δ 1.32 (d, 3H), 4.36 (dd, 1H), 4.46 (dd, 1H), 4.58-4.63 (m, 1H), 6.63 (d, 1H), 7.51 (d, 1H), 7.65 (d, 1H), 7.70 (d, 1H), 7.76 (dd, 1H), 7.93 (d, 1H), 7.40 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]([C:7]1[C:2]([C:31]2[CH2:32][CH2:33][O:28][CH2:29][CH:30]=2)=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C3=CCOCC3)c(C#N)cn1)CCC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 60 mg, 0.155 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (65.0 mg, 0.309 mmol), PdCl2(PPh3)2 (10.9 mg, 0.015 mmol), Na2CO3 (2 M in water, 0.232 ml, 0.464 mmol) and DME (2 ml) were charged into a sealed vial under argon. The mixture was stirred at 100° C. for 1 h, cooled to room temperature, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product fractions were concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 1.19 min; ESI-MS 436.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].[CH3:21][C:22]([CH3:24])=O>>[CH2:17]([O:10][C:4]1[CH:5]=[C:6]([O:7][CH2:24][CH:22]=[CH2:21])[CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])[CH:18]=[CH2:19]
Reactant: CC(C)=O
Reactant: C=CCBr
Reactant: CCc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(CC)c(OCC=C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Ethylresorcinol (10 g, 73 mmol) was dissolved in acetone (250 mL), and potassium carbonate (30 g, 220 mmol) and allyl bromide (15 mL, 170 mmol) were added thereto and heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/9) to obtain 2,4-bis(allyloxy)-1-ethylbenzene (15 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Br[CH2:20][C:21]([NH2:23])=[O:22]>ClCCl.CO.C(O)(=O)C>[CH:2]([N:23]([CH:5]([CH3:6])[CH3:4])[C:21](=[O:22])[CH2:20][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([F:1])=[CH:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=2[F:11])=[CH:13][CH:14]=1)([CH3:7])[CH3:3]
Reactant: NC(=O)CBr
Reactant: O=C(O)c1cc(F)c(-c2ccc(O)cc2)c(F)c1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N(C(=O)COc1ccc(-c2c(F)cc(C(=O)O)cc2F)cc1)C(C)C
Yield: 97.4 %

Procedure:
An alkylation was carried out with 370 mg of the product of Stage D with 428 mg of bromoacetamide (Preparation 9) under the conditions as described in Example 13, Stage D to obtain 282 mg of the expected product with a Rf=0.35 dichloromethane/methanol/ acetic acid 95/4/1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]CCC(OCC)=O)=[C:17]([CH:31]=O)[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O-][CH2:34][CH3:35].[Na+].O.[C:38](=[O:45])([O:42][CH2:43][CH3:44])OCC>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][CH2:23][CH:35]([C:38]([O:42][CH2:43][CH3:44])=[O:45])[CH:34]=[CH:31][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc(OCCCCC(=O)OCC)c(C=O)c2)cc1
Reactant: CC[O-]
Reactant: CCOC(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=CC(C(=O)OCC)CCO3)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-[[4′-(2-butoxyethoxy)-3-formyl [1,1′-biphenyl]-4-yl]oxy]pentanoate (6.00 g) in diethyl carbonate (60 ml) was added a solution of 20% sodium ethoxide in ethanol (5.55 g). The mixture was stirred at 50° C. for 2 hours under a nitrogen atmosphere. The solution was allowed to cool. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain yellowish oil of ethyl 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-2H-1-benzoxocin-4-carboxylate (527 mg).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1nnc(Cl)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C#N)s2)CC1
Yield: 91.1 %

Procedure:
A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.5 g, 3.44 mmol) (prepared by a procedure similar to that described in U.S. Pat. No. 5,736,545), and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.69 g, 3.44 mmol) and diisopropylethylamine (0.72 ml, 4.13 mmol) in acetonitrile (10 ml) was stirred at 130° C. for 30 min., under microwave irradiation. After this period, the solvent was evaporated in vacuo. The crude product was dissolved in dichloromethane and extracted with a saturated solution of ammonium chloride. The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 3-5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield D5 (0.97 g, 63%) as a white solid. C13H19N5O2S requires 309. Found 308 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(N)=O.Cl>[OH-].[Na+]>[CH3:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: N=CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: CC(=O)O
Product: Cc1cccc2c(=O)[nH]cnc12
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
2-Amino-3-methylbenzoic acid (100 g, 0.66 mol), formamidine acetate (206 g, 1.98 mol) and formamide (26 mL, 0.6600 mol) were mixed in a 2 L R.B fitted with Mechanical stirrer. The reaction mixture was heated at 160° C. for 16 h. The reaction completion was monitored by LCMS. After completion, the reaction mixture was cooled to was RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reaction mixture neutralised with 1.5N HCl solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield (90 g, 86% yield) of the titled compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.21 (bs, 1H), 8.10 (s, 1H), 7.95-7.93 (dd, J=8.8, 7.9 Hz, 1H), 7.65-7.63 (d, J=7.9 Hz, 1H), 7.39-7.35 (t, J=15.2 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]#[N:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br>CN1C(=O)CCC1.CCOCC>[Br:7][C:8]1[CH:9]=[C:10]([C:16]2([C:17]#[N:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CC#N)cc1Br
Reactant: BrCCOCCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1Br
Temperature: 0 °C
Yield: 62.5 %

Procedure:
A mixture of sodium tert-butoxide (6.7 g, 70 mmol) in 100 mL NMP stirred at 0° C. was treated dropwise with a mixture of 2-(3-bromo-4-methoxyphenyl)acetonitrile (6.3 g, 28 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.5 g, 28 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and was stirred for 3 hours, M+Na=318/320. The mixture was quenched with 100 mL H2O carefully and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.18 g of crude product as a yellow solid. MS m/e=318/320 (M+Na)+.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[N:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH:11]=1
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Yield: 77.7 %

Procedure:
A solution of 2.5 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole in 7.5 gm of N,N-dimethylformamide diethylacetal was stirred at room temperature for 2 days. Addition of diethyl precipitated a solid which was filtered off and dried, yielding 2.4 gm of the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].P(Cl)(Cl)(Cl)=O.[CH3:20][NH2:21]>CN(C)C=O.O>[CH3:20][NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CN
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a solution of 5.7 g (0.030 mole) of 4-hydroxy-3-nitroquinoline in 50 ml of N,N-dimethylformamide was added 9.3 g (0.060 mole) of phosphorous oxychloride. The solution was heated on a steam bath for 5 minutes, then poured with stirring into 200 ml of 40% aqueous methylamine. The mixture was heated on a steam bath for fifteen minutes, then diluted with 200 ml of water. The solid was separated by filtration, then dissolved in dilute hydrochloric acid. The solution was filtered and the filtrate was basified with ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide yellow solid 4-methylamino-3-nitroquinoline, m.p. 167°-171° C.
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Cl)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:12]=2[CH:29]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 1 h

Procedure:
A stirred solution of N,N-dimethylhydroxylamine (3.67 g., 0.06 mole) in dry dimethylformamide (50 ml. is cooled in an ice bath, under nitrogen, and treated with a 57% mineral oil suspension of sodium hydride (0.84 g., 0.02 mole). The mixture of kept at ambient temperature for 1 hour (a precipitate formed) and then cooled in an ice bath and treated with 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (6.86 g., 0.02 mole). The mixture is kept at ambient temperature for 2 hours and concentrated in vacuo. Last traces of dimethylformamide are removed from the residue by the successive addition and distillation of xylene, toluene, and benzene. The resulting material is chromatographed on silica gel (250 g.) with methanol. The product thus obtained is crystallized from methanol-ethyl acetate following activated charcoal treatment) to give 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide, hydrate in three crops: 3.377 g. of melting point 160.5°-162.5° C.; 1.145 g. of melting point 160°-162° C.; and 0.785 g. of melting point 160°- 162° C. The analytical sample had a melting point of 157.5°-158.5° C. with decomposition.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[CH3:19][O:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][O:20][C:21]([NH:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:3]([OH:2])=[O:4])[CH2:6][CH2:7]1)=[O:22]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCC(C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (commercially available) in CH2Cl2 was added Et3N (2 eq.) and methyl-chloroformate (1.05 eq.). Stirring was continued overnight at RT. The reaction was quenched by addition of H2O, the product was extracted with CH2Cl2 and the organic phase washed with aq. HCl 1M. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The residue was dissolved in MeOH and a 2M KOH aq. solution was added. The reaction was stirred at RT 4 hours, aq. HCl was added until ph=6, and then the product was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to afford the title product as a white foam which was used in the next step without further purification.
Reaction SMILES: [CH:1](OCC)=[O:2].[OH:6][C@@:7]1([CH3:27])[CH:12]=[CH:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.[H-].[Na+].Cl>O1CCCC1.C1(C)C=CC=CC=1>[OH:6][C@@:7]1([CH3:27])[CH:12]=[CH:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])/[C:19](=[CH:1]\[OH:2])/[CH2:20]1)[CH2:15][CH2:14]3
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@]12C/C(=C/O)C(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
At room temperature, 4.6 ml of ethyl formate is added to 4.6 g of 17β-hydroxy-17α-methylandrosta-4,15-dien-3-one in 40 ml of tetrahydrofuran and 70 ml of toluene. Then 3.5 g of sodium hydride (60% paraffin suspension) is added in small portions. After 6 hours, the reaction mixture is gently stirred into ice/water which contains hydrochloric acid, the precipitated product is suctioned off, washed with water, dissolved in methylene chloride, dried, and concentrated under vacuum. After chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient, 2.4 g of (Z)-17β-hydroxy-2-hydroxymethylene-17α-methylandrosta-4,15-dien-3-one is obtained, mp 176° C. (from acetone/hexane).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH3:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:39][CH2:38][C:27]2[N:28]=[C:29]([C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(C4(C)CCCCC4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-(1-methylcyclohexyl)-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H, J=8.60 Hz), 6.92 (d, 1H, J=8.60 Hz), 6.73 (d, 2H, J=8.99 Hz), 6.64 (d, 1H, J=2.35 Hz), 6.57 (dd, 1H, J=8.21 Hz, J=3.13 Hz), 4.06 (t, 2H, J=6.25 Hz), 3.14 (d, 1H, J=14.08 Hz), 3.04 (d, 1H, J=14.08 Hz), 2.85 (t, 2H, J=6.25 Hz), 2.19 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.07-2.01 (m, 2H), 1.53-1.28 (m, 8H), 1.36 (s, 3H), 1.20 (s, 3H); MS (ES+) calcd for C31H40NO5: Found m/e 506.3 (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([OH:28])[CH:22]=2>>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:28][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH:22]=2
Reactant: COC(=O)Cc1cc2ccc(O)cc2[nH]c1=O
Reactant: CC(C)(C)OC(=O)NCCCCBr
Product: COC(=O)Cc1cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2[nH]c1=O

Procedure:
The title compound is prepared according to the procedure of Example 75 except that (4-bromobutyl)-carbamic acid tert-butyl ester is used in place of (3-bromopropyl)-carbamic acid tert-butyl ester and that (7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester is used in place of (7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([CH2:16][CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2].O.[Cl-].[Na+].CS(C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)CCc1ccc(C#N)cc1S2)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc2c(c1)CCc1ccc(C#N)cc1S2

Procedure:
A mixture of ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropanoate (4.025 g; 4.84 mmole), water (354 mg; 19.7 mmole), sodium chloride (576 mg) and dimethylsulfoxide (100 ml) are heated together under argon in an oil bath at 200°-205° C. for 3 hours. The cool reaction mixture was diluted with methylene chloride and the solution was extracted with water (3×100 ml), then dried (MgSO4) and evaporated to an oil (3.223 g; 97%). The pure title compound was obtained by short path distillation of the crude product (oven temperature 200° C./0.05 Torr).