Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]2[CH2:13][O:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH2:21]1.[Cl-].[Na+].[CH3:39]CCCCC>CS(C)=O.C(OCC)(=O)C>[F:3][C:4]1[C:14]2[CH2:13][O:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]([CH2:39][C@H:23]3[CH2:24][CH2:25][CH2:20][CH2:21][N:22]3[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reactant: Fc1cccc2c1COc1ccccc1N2
Reactant: CCCCCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)c1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3OCc3c(F)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (35 mg, 0.88 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (5 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 1-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (0.17 g, 0.80 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (R)-3-chloro-1-(4-dimethylaminophenethyl)piperidine (0.18 g, 0.80 mmol) in dimethyl sulfoxide (2 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 6 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (6:4) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-1-fluoro-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)piperidin-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (0.23 g, 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](O)[CH:5]=[CH:4][C:3]1=2.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].[OH-:26].[K+].Cl>ClCCl.O.CS(C)=O>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:18]3([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]3[OH:26])[CH:5]=[CH:4][C:3]1=2
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C3([N+](=O)[O-])C=CC=CC3O)ccc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
DMSO (5 ml) was added to 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol (97 mg, 0.475 mmol), o-chloronitrobenzene (77 mg, 0.48 mmol) and potassium hydroxide (27 mg, 0.48 mmol), and the mixture was stirred at 90° C. for 17 hours and 30 minutes. To the reaction mixture, water, dichloromethane, and concentrated hydrochloric acid (1 ml) were added, and the organic layer was washed with diluted hydrochloric acid and brine. After dryness, the solvent was evaporated under reduced pressure to give a crude product (139.7 mg). This crude product was purified by silica gel column chromatography (AcOEt:n-hexane=1:30) to give o-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtalenyl)-2-nitrophenol (Compound 27, 103.1 mg, 67%, colorless oil)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>CCO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)C1
Yield: 92.4 %

Procedure:
A mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (3.14 g, 0.010 mol) and Methyl acetoacetate (1.28 g, 0.010 mol) in EtOH (30 ml) and Acetic acid (30 ml) is stirred at reflux for one hour. At room temperature the resulting precipitate is filtered with suction to yield the title compound,(3.50 g, 92%) m.p. 149–150° C.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([CH3:9])=[C:7]([N+]([O-])=O)[C:6]([CH3:13])=[CH:5][N+:4]=1[O-:14].Cl.[CH3:16][OH:17]>C(OCC)(=O)C>[CH3:16][O:17][C:7]1[C:6]([CH3:13])=[CH:5][N+:4]([O-:14])=[C:3]([CH3:2])[C:8]=1[CH3:9]
Reactant: CO
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1c(C)c[n+]([O-])c(C)c1C

Procedure:
22.6 g of sodium are dissolved in 4 1 of methanol under argon. 120 g of 2,3,5-trimethyl-4-nitropyridine 1-oxide are then added portionwise thereto and the solution is left to boil under reflux overnight. The pH is adjusted to 7 by means of 5N hydrogen chloride in ethyl acetate while cooling and the mixture is then evaporated in vacuo. The residue is taken up in 1.5 1 of methylene chloride, the solution is filtered throuqh siliceous earth, which is rinsed with 0.5 1 of methylene chloride, the combined filtrates are evaporated in vacuo and the residue is crystallized from petroleum ether. There is obtained 4-methoxy-2,3,5-trimethylpyridine 1-oxide of melting point 48°-50°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:3]=1[NH2:19].S(Cl)(Cl)(=O)=O.[CH2:25]([C:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1)[CH:26]=[CH2:27]>N1C=CC=CC=1>[F:9][C:5]1[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[C:3]([NH:19][S:31]([C:28]2([CH2:25][CH:26]=[CH2:27])[CH2:30][CH2:29]2)(=[O:33])=[O:32])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: C=CCC1(S(=O)(=O)Nc2c(F)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a stirred solution of the amine, i.e., 3,5,6-trifluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine, (1 eq) in anhydrous pyridine (5 ml/mmole) was added the sulfonyl chloride, i.e., 1-allyl-cyclopropanesulfonyl chloride, (1-5 eq). The reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was partitioned with water and EtOAc. The organic layer was washed with brine, dried (MGSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica. 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H), 6.78 (m, 1H), 6.49 (m, 1H), 5.96 (s, 1H), 5.86 (m, 1H), 5.18 (d, 2H), 2.76 (d, 2H), 1.23 (m, 2H), 0.872 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:15])([CH3:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC[CH:18]=[C:19]([CH3:21])[CH3:20].[C:22](=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC)=O>[CH3:14][C:3]([N:2]([CH3:22])[CH2:1][CH:18]=[C:19]([CH3:21])[CH3:20])([CH3:15])[CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(C)(C)CNC(=O)c1ccccc1
Reactant: CC(C)=CCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)=CCN(C)C(C)(C)CNC(=O)c1ccccc1
Yield: 84.1 %

Procedure:
A solution of N[2-methylamino-2-methylpropyl] benzamide (1 g., 0.0052 mole) in methylethyl ketone (MEK) (25 ml.) was added to a solution of 1-bromo-3-methyl-but-2-ene (0.78 g., 0.0052 mole) in MEK (40 ml.) containing sodium carbonate (0.55 g., 0.0052 mole) and a few crystals of sodium iodide. The mixture was heated under reflux for 30 hrs. The inorganic solids were filtered off and the filtrant concentrated by evaporation under reduced pressure to give a liquid residue. This was loaded onto an alumina column and eluted with ethyl acetate. Fractions (25 mls) were collected and concentrated to give N[2-methyl-2[methyl(3-methyl-2-butenyl)amino]propyl]benzamide (1.2 g.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][CH3:24])=C(Cl)[N:15]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:15]=[C:14]([Cl:13])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH2:23][CH3:24])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc2c(c1)OCO2
Product: CCn1cnc2c(Nc3ccc4c(c3)OCO4)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-benzo[1,3]dioxol-5-yl-formamide and 2,6-dichloro-9-ethyl-9H-purine.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH:10]1[CH:15]=[CH:14][C:13]([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1>CC#N.C1(C)C=CC=CC=1>[ClH:2].[Cl-:1].[C:23]1([P+:16]([C:13]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc([P+](Cc2ccncc2)(c2ccccc2)c2ccccc2)cc1
Yield: 93.4 %

Procedure:
step 1—To a suspension of 4-chloromethyl-pyridine hydrochloride (2.72 g, 16.6 mmol) in MeCN (20 mL) was added PPh3 (4.57 g, 17.4 mmol). The mixture was warmed to reflux. After 18 h the mixture was cooled taken up in 20 mL toluene and filtered. The collected solid was washed with toluene and dried in vacuum to afford triphenyl(4-pyridylmethyl)phosphonium chloride hydrochloride (6.61 g, 94%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH:37]=O)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([O:7]C)=[O:6].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH2:37][NH:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52])[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([OH:7])=[O:6]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCCN1CCCC1=O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield following steps 5 and 6 described above, using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 1-(3-aminopropyl)pyrrolidin-2-one as the reactant amine MS: m/e 687.5 (MH+), 1.71 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.91 (s, 3H) 0.96 (s, 3H) 1.05 (s, 3H) 1.08 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 0.85-1.91 (m, 20H) 1.96-2.20 (m, 6H) 2.44 (t, J=8.03 Hz, 2H) 2.47-2.56 (m, 1H) 2.83 (d, J=13.05 Hz, 1H) 3.07 (t, J=7.03 Hz, 2H) 3.21 (d, J=13.05 Hz, 1H) 3.43 (t, J=6.40 Hz, 2H) 3.52 (t, J=7.15 Hz, 2H) 4.62-4.66 (m, 1H) 4.75 (d, J=1.51 Hz, 1H) 5.35 (dd, J=6.02, 1.51 Hz, 1H) 7.22 (t, J=7.65 Hz, 1H) 7.64 (dd, J=9.79, 1.51 Hz, 1H) 7.75 (dd, J=7.91, 1.63 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −114.92 (s, 1 F).
Reaction SMILES: N.C([S:5][CH2:6][CH:7]([CH3:20])[C:8]([N:10]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:9])(=O)C>>[SH:5][CH2:6][CH:7]([CH3:20])[C:8]([N:10]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCC1
Agent: N
Product: CC(CS)C(=O)N(CC(=O)O)C1CCCC1

Procedure:
Ammonia gas was bubbled through a methanolic solution of N-(3-acetylthio-2-methylpropanoyl)-N-cyclopentylglycine (10.4 g, 0.036 mol) for one hour. The reaction mixture was then stoppered and stirred for 30 more minutes and then concentrated. The residue was redissolved in ethyl acetate (400 ml) and was washed with 5% aqueous sodium bisulfate (3×150 ml). The organic portion was then removed, dried (MgSO4), filtered and concentrated. The crude material was further purified by HPLC with ethyl acetate, toluene, hexane, acetic acid (50:25:50:2) as the eluent. The desired product was isolated as a nearly colorelss oil (pale yellowish tinge). 7.9 g (90%) was so obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:8]=2)[NH:3]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)Cl)cc3)ccc2[nH]1
Reactant: NCc1ccccc1
Product: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)NCc4ccccc4)cc3)ccc2[nH]1
Yield: 61.9 %

Procedure:
Reaction of 4-(2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-ylmethyl)benzene-sulfonyl chloride (Preparation 1, 26 mg, 65 μmol) with an excess of BnNH2 (280 mg, 2600 μmol), by the method described for Example 1, generated the title compound (19 mg, 61%): δH ((CD3)2SO)=3.95 (d, 2H), 4.15 (s, 2H), 7.00 (s, 1H), 7.15–7.25 (m, 5H), 7.35–7.45 (m, 3H), 7.50 (d, 1H), 7.55 (s, 1H), 7.70 (d, 2H), 8.05 (t, 1H); m/z (ES+)=514.2 [M+H +MeCN]+.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=[CH:13][CH:14]=2)C=1.[N:19]1C=CC(C#CC2C=C(CCCN)C=CC=2)=C[CH:20]=1.S1C=CC=C1C#CC1C=C(CCCN)C=CC=1.S1C=CC(C#CC2C=C(CCCN)C=CC=2)=C1>>[N:19]1[CH:20]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=[CH:13][CH:14]=1
Reactant: NCCCc1cccc(C#Cc2cccnc2)c1
Reactant: NCCCc1cccc(C#Cc2ccncc2)c1
Agent: NCCCc1cccc(C#Cc2cccs2)c1
Agent: NCCCc1cccc(C#Cc2ccsc2)c1
Product: NCCCc1cccc(C#Cc2ccccn2)c1

Procedure:
3-(3-(pyridin-3-ylethynyl)phenyl)propan-1-amine; 3-(3-(pyridin-4-ylethynyl)phenyl)propan-1-amine; 3-(3-(thiophen-2-ylethynyl)phenyl)propan-1-amine; and 3-(3-(thiophen-3-ylethynyl)phenyl)propan-1-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:38])([F:37])[F:36])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.[Li+].[OH-]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:37])([F:38])[F:36])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(OC)cc4)ccc3C(F)(F)F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(C(F)(F)F)c(NCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-(4-methoxyphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)2,3-dihydro-1H-inden-1-yl]acetate (Example 307) (0.05 g, 0.09 mmol) in THF (1 mL), methanol (1 mL), and water (0.5 mL) was added LiOH (0.02 g, 0.85 mmol). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified to pH ˜5 using H3PO4 (5% aqueous solution). The aqueous solution was then extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the product (0.034 g, 80%). 1H NMR (400 MHz, CD2Cl2) δ 8.03 (d, 2H), 7.68 (d, 1H), 7.07 (dd, 2H), 6.97 (d, 2H), 6.80 (s, 1H), 6.72 (dd, 1H), 5.37 (b, 1H), 4.11 (t, 2H), 3.91-3.81 (m, 5H), 3.56-3.48 (m, 1H), 2.95-2.77 (m, 3H), 2.15-2.37 (m, 2H), 2.23-2.18 (m, 2H), 1.65-1.55 (m, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([NH2:11])([CH3:10])[CH3:9]>>[CH3:9][CH:8]([N:11]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:10]
Reactant: O=C1CCCCC1
Reactant: CC(C)N
Product: CC(C)N=C1CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 600 g. cyclohexanone and 1 l. isopropylamine are added 500 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the excess isopropylamine is removed in vacuo at room temperature. The oily residue is 1-methyl-N-(cyclohexylidene)-ethylamine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:11]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(N)cc1OCC1CC1
Yield: 91.4 %

Procedure:
A mixture of N-(2-(cyclopropylmethoxy)-4-nitrophenyl)methanesulfonamide (0.830 g, 2.90 mmol), iron (0.971 g, 17.39 mmol), and NH4Cl (0.099 g, 1.848 mmol) in EtOH (15 ml) and water (6 ml) was heated to reflux for 30 minutes. The hot reaction mixture was filtered and the filtrate was evaporated. The residue was portioned between EtOAc and water; the organic phase was washed with brine and dried over Na2SO4. The solvent was removed affording N-(4-amino-2-(cyclopropylmethoxy)phenyl)-methanesulfonamide (0.679 g, 2.65 mmol, 91% yield, MS/ESI+ 256.9 [MH]+).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[N:18]=[CH:19][N:20]=[C:21]3[C:28]=2[C:27]2[CH2:26][CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.[Cl:29]CCl>Cl>[ClH:29].[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[N:18]=[CH:19][N:20]=[C:21]3[C:28]=2[C:27]2[CH2:26][CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Reactant: ClCCl
Agent: Cl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-methyl-N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)carbamate (450 mg, 1.12 mmol, 1.00 equiv) in dichloromethane (50 mL), hydrochloric acid (1.0 mL, 12 M) was added and the resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum to provide N-methyl-4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexan-1-amine hydrochloride (350 mg 92%) as a white solid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1)(=O)C.[N+]([O-])(O)=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1
Reactant: COc1ccc(NC(C)=O)cc1F
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1114.4 %

Procedure:
To a cold (15°), stirred solution of 12.8 g (0.0699 mol) of 4-acetamido-2-fluoroanisole in 55 mL of acetic acid and 27 mL of acetic anhydride was added, dropwise, 6.5 g (0.072 mol) of 70% nitric acid (sp. gr. 1.424) at such a rate that the temperature of the reaction mixture did not exceed 16°. The solution was stirred for 1.5 hours at room temperature then poured into 400 mL of ice-water. The aqueous suspension was extracted with methylene chloride (1×300 mL; 1×200 mL), then the combined extracts were concentrated in vacuo to a solid (13 g). The material was chromatographed on a column of silica gel (300 g) using benzene as the eluent. The fractions containing the required product were combined then concentrated in vacuo. The solid residue was dissolved in methylene chloride (400 mL) and the solution was washed with water, dried over anhydrous magnesium sulfate, then concentrated in vacuo; yield, 10.0 g (62.9%). The material was suitable for further transformation. Additional material (169 g; 44.6%) was obtained from 110 g (0.779 mol) of 4-amino-2-fluoroanisole without isolating the intermediate 4-acetamido-2-fluoroanisole (3).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22](=[O:27])[CH:23]([NH2:26])[CH2:24][OH:25].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16]([NH:26][C@H:23]([C:22]([O:21][CH3:20])=[O:27])[CH2:24][OH:25])(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(N)CO
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in a mixture of DCM/DMF (1/1, 10 ml). 2-Amino-3-hydroxy-propionic acid methyl ester (0.2 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in ACN, affording after filtration, Compound (15) as a white powder (54 mg; 39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([C:19]1([NH2:40])[C:25](=[O:26])[N:24]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[N:21]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:20]1=[O:39])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([C:19]2([NH2:40])[C:25](=[O:26])[N:24]([CH2:27][CH:28]3[CH2:29][CH2:30]3)[C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[N:21]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[C:20]2=[O:39])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white solid (melting point=211-212° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.44 (CH2Cl2/EtOAc, 1:1).