Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[CH2:19]([N:22]=[C:23]=[S:24])[CH:20]=[CH2:21]>C(#N)C>[CH3:17][N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:23]([NH:22][CH2:19][CH:20]=[CH2:21])=[S:24])[O:7][C:8]=2[CH:14]=1)[CH3:18]
Reactant: CN(C)Cc1ccc2cc(CSCCN)oc2c1
Reactant: C=CCN=C=S
Solvent: CC#N
Product: C=CCNC(=S)NCCSCc1cc2ccc(CN(C)C)cc2o1

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran (Example 1, Step E) (2.6 g., 0.01 mole) and allyl isothiocyanate (1.1 g., 0.011 mole) in acetonitrile (15 ml.) is kept at 25°-27° C. for 16 hours. The solvent is evaporated and the residual oil chromatographed (silica gel/5% methanol in chloroform) to yield N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N'-(2-propenyl)thiourea.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:5](/[CH:6]=[N:7]/[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[C:4]([F:17])[CH:3]=1.[CH3:18][Mg]Br.CCOC(C)=O.CCCCCCC>C(Cl)Cl.CCOCC>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:5]([C@@H:6]([NH:7][S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:18])=[C:4]([F:17])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(F)c(Br)cc1F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol in CH2Cl2 (200 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (29.6 mL, 89 mmol) in Et2O. Reaction mixture allowed to stir for 5 hours at 0° C. then quenched with the slow addition of a saturated solution of NH4Cl. Aqueous mixture adjusted to pH 8 with HCl (1 N) and extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 30 to 100%) provided (R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (6.86 g, 20.2 mmol, 91% yield) LCMS m/z 342.1 (M+H)+, Rt 0.96 min.
Reaction SMILES: [OH:1][C:2]1([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:2]2([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)[CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OC1(c2cccnc2)CCNCC1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Benzyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (32.7 g, 104.69 mmol) was dissolved in ethanol (350 mL) and hydrogenated over 10% palladium on carbon (3.2 g) at 2 bar pressure at 30° C. After hydrogen uptake was complete, the mixture was filtered through a pad of diatomaceous earth to remove the catalyst and the pad was washed with ethanol. The filtrate was concentrated to dryness under vacuum to give an oil which crystallised on standing overnight. The solid was triturated with MTBE (100 mL), collected by filtration, washed with MTBE (2×50 ml) and dried in a vacuum oven at 40° C. to afford 4-(pyridin-3-yl)piperidin-4-ol (14.9 g, 80%) as a solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:6][CH:5]1[OH:21])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:6][CH:5]1[OH:21]
Reactant: CC1CC(N=[N+]=[N-])C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Temperature: 45 °C

Procedure:
4-Azido-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (0.33 g, 1.06 mmol) was dissolved in THF(50 ml) and H2O (0.2 ml). PPh3 (0.42 g, 1.59 mmol) was added to this solution. The reaction mixture was stirred at 45° C. over night. TLC showed no starting material left. THF was evaperated, azeotroped by toluene (2×100 ml). The resulting thick oil was dissolved in MeOH, treated with HCl in ether to adjust pH to acidic. More ether was added and the solution turned cloudy to give the title compound as a white precipitate (0.21 g, 71% yield) MS (M+H+) 286.0; 1H-NMR (400 Hz, CD3OD); d (ppm): 8.72(d, 1H), 8.14–7.99(m, 2H), 7.68(m, 1H), 3.85–3.69(m, 2H), 3.38–3.22(m, 3H), 3.10–3.04(m, 2H), 2.04(m, 1H), 1.82–1.66(m, 2H), 1.02(d, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[F:20][C:21]([F:28])([F:27])[C:22](=O)[C:23]([O-])=[O:24]>>[NH2:17][C:15]1[C:14]2[N:18]=[C:22]([C:21]([F:28])([F:27])[F:20])[C:23](=[O:24])[NH:19][C:13]=2[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Reactant: O=C([O-])C(=O)C(F)(F)F
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)c(C(F)(F)F)nc12

Procedure:
The sub-titled compound was prepared from the product of Example 2, step (c) (5 g) and trifluoropyruvate (10 ml) using the method of Example 2, step (d).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:34][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][O:33]1
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NCC1CCCO1
Product: COc1cc(NCC2CCCO2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 53 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using rac-tetrahydrofurfurylamine instead of thiomorpholine to the title compound (129 mg, 53%) which was obtained as an off-white solid. MS: m/e=451.2 [M+H]+.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1C2[C:39](=[CH:40][CH:41]=CC=2)[CH2:38][CH2:37]1>C(#N)C>[CH3:26][C:13]1[S:12]/[C:11](=[N:10]\[C:8]([N:5]2[C:4]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:7][CH2:6]2)=[O:9])/[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: c1ccc2c(c1)CCN2
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)N2CCc3ccccc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (62 mg, 0.13 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.16 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added indoline (17 mg, 0.14 mmol) dissolved in acetonitrile (0.7 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [OH-].[Li+].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]([O:13]CC)=[O:12])[NH:8][C:9]=1[Cl:10].Cl>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8][C:9]=1[Cl:10]
Reactant: CCOC(=O)c1cc(Cl)c(Cl)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)[nH]1
Temperature: 50 °C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
A solution of lithium hydroxide in water (2 N, 0.80 ml, 0.16 mol) was added to a stirred solution of a mixture of ethyl 4,5-dichloro-1H-pyrrole-2-carboxylate (Intermediate 59; 7.0 g, 0.033 mol) in THF (15 ml) at room temperature. The mixture was stirred at 50° C. for 8 h over 2 days. The reaction mixture was acidified with 10% HCl solution to a pH ˜2 and partitioned between EtOAc and water. The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound (4.0 g).
Reaction SMILES: Cl.C([O:5][CH2:6][CH2:7][O:8][CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(=O)C>C(O)C>[CH2:16]([O:15][P:10]([CH2:9][O:8][CH2:7][CH2:6][OH:5])([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOP(=O)(COCCOC(C)=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(COCCO)OCC
Temperature: 55 °C
Yield: 81.8 %

Procedure:
15 mL of concentrated hydrochloric acid was added in one portion to a solution of 1-acetoxy-2-(diethylphosphonomethoxy)ethane (76.5 g, 300 mmol) in 600 mL of absolute ethanol and the resulting mixture was heated at 55° C. for 12 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting clear liquid could be used without purification or purified by distillation (1.5 mmHg, 128°-132° C.) to give 52.1 g (82%) of 2-diethylphosphonomethoxy-1-ethanol.
Reaction SMILES: [CH2:1]1[O:17][C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.S(Cl)(Cl)=O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:6][CH2:5]2)[O:17][CH2:1]1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccncc2)CCC2(C1)OCCO2
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone ethyleneacetal dissolved in 40 ml of pyridine, there was added 8 ml of thionyl chloride at -10° C. After stirring the mixture at 0° C., the reaction mixture was poured into ice water. Then, an excess amount of aqueous sodium hydroxide solution was added. The reaction mixture was extracted with methylene chloride and purified. Thus, there was obtained 4 g of 4-(4-pyridyl)cyclohex-3-enone ethyleneacetal.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C>>[C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), acetyl chloride (0.086 mL, 1.2 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) to give 0.31 g to the title compound as a white solid, mp 90–91° C.;
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][NH:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12].[C:15](=O)([O-])[O-:16].[K+].[K+].C(Cl)(Cl)=O.C(OCC)(=O)C>O>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:15](=[O:16])[O:12][C:11](=[O:13])[C:7]2[N:6]1[CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)CCNn1cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(=O)oc(=O)c2cccn21
Temperature: 0 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a solution of 1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid (Example 1d, 0.25 g, 1.27 mmol) in water (2 mL) was added potassium carbonate (0.175 g, 1.27 mmol). The reaction mixture was cooled to 0° C. and phosgene (20% solution in toluene) (0.95 mL, 1.91 mmol) was slowly added dropwise. The resulting yellow solution was stirred for 16 h. Ethyl acetate (4 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexane, 20-50%) to afford the desired product, 4-(3-methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione (0.16 g, 0.72 mmol, 57% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (6H, d, J=6.8 Hz), 1.56 (2H, m), 1.65 (1H, m), 4.16 (2H, t, J=7.2 Hz), 6.50 (1H, m), 7.08 (1H, m), 7.70 (1H, m).
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:55])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([O:30][Si](C(C)(C)C)(C)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:20]([O:38][Si](C(C)(C)C)(C)C)[CH2:19][C:18]=1[O:46][C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:47]([O:46][C:18]1[CH2:19][C@@H:20]([OH:38])[C@H:21](/[CH:22]=[CH:23]/[C@@H:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]=1[S:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:55])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)c2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)c2ccccc2)C[C@H]1O
Yield: 88.3 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.3 ml) and methyl(11R,12S,13E,15S)-9-benzoyloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienoate (239 mg), the same procedure as in Example 2 was performed to obtain methyl(11R,13E,15S)-9-benzoyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoate (144 mg, 86%).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[S:21]([Cl:24])([Cl:23])=[O:22]>C1C=CC=CC=1>[S:21]([Cl:24])([Cl:23])=[O:22].[Cl:23][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Yield: 100 %

Procedure:
Reflux 3.14 gm. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboxylate and 15 cc. of thionyl chloride for 10 minutes. Evaporate excess thionylchloride. Remove traces of thionyl chloride by co-distillation with benzene to obtain the title product (yield 3.35 gm., 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10, 11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257-260° C.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CCCCCC>[CH:12]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH3:11]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(C)NNC(=O)c1ccccc1
Yield: 71.1 %

Procedure:
A solution of benzoylhydrazine (10 g, 73.45 mmol) in hexane (200 ml) was treated with acetone (54 mL, 734.5 mmol) and refluxed overnight. The precipitate was collected by suction filtration to afford a white solid which was treated with TFA (200 ml) and triethylsilane (24 mL, 149.24 mmol) at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the product as a white solid (9.31 g, 71%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:31])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:14]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:31])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:14]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]=1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C2CCCC2)c(C#Cc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1ccc(C2CCCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-cyclopentyl-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate E2e (18 mg, 0.04 mmol) and DCM:TFA (9:1, 2 ml) is stirred at RT for 90 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 13 mg (94%). HPLC-MS: M+H=334; tR=2.09 min (*Method—1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:23][CH3:24])[CH2:9][C@H:10]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][C@@H:10]([CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:23][CH3:24])[C:11]([O:13][CH3:14])=[O:12])[CH2:22][CH2:21]2)=[CH:28][C:27]=1[CH3:34]
Reactant: COC(=O)[C@@H](CCN1CCNCC1)C[C@@H](OC)c1ccc(F)cc1
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](CCN1CCN(Cc2ccc(F)c(C)c2)CC1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-methyl 4-(4-fluorophenyl)-4-methoxy-2-(2-(piperazin-1-yl)ethyl)butanoate (62 mg, 0.11 mmol) and 4-Fluoro-3-methyl-benzaldehyde (19.3 mg, 0.14 mmol) was added NaBH(OAc)3 (32.5 mg, 0.15 mmol) and AcOH (6.6 mg, 6 μL, 0.11 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethylacetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](=O)[CH:14]([CH3:16])[CH3:15].C(=O)C>>[CH2:13]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C=O
Agent: CC=O
Product: CC(C)CN[C@H](Cc1ccccc1)C(=O)O

Procedure:
Starting from 8.25 g (0.05 mole) of D-phenylalanine, and using the procedure described in Example 3, Step A, except that 9.1 ml (0.1 mole) of isobutyraldehyde are used instead of acetaldehyde, 8.7 g (70%) of the product are obtained.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([NH2:26])[CH:20]=1)([O-:18])=[O:17]>CC(C)=O>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][NH:26][C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: CCOC(=O)C(Br)CBr
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc([N+](=O)[O-])ccc2O1

Procedure:
29.2 g of ethyl 2,3-dibromopropionate was added dropwise to a refluxing mixture of 19 g of anhydrous potassium carbonate, 70.9 g of 4-nitro-2-aminophenol and 500 ml of dry acetone. This procedure was repeated thrice. The reaction mixture was refluxed for 17 hours, then filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was washed with dilute sodium hydroxide solution, extracted with ether, then with methylene chloride. The solvent was evaporated separately from each extract. Thin layer chromatographic analysis indicated that the produce from each of the extracts was the same. The products was combined and recrystallized from ether to give 4, as a solid, m.p.: 88°-90° C.
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:25])=[CH:19][CH:20]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CNCCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrazin-2(1H)-one (0.5 g, 1.45 mmol) and Pearlman's catalyst (26 mg; 20% palladium hydroxide on carbon) in methanol (25 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide 1-(4-fluorobenzyl)piperazin-2-one.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:5][CH3:6].Cl[CH2:16][C:17]#[N:18].CCOCC>CN(C=O)C>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][C:17]#[N:18])=[CH:12][CH:13]=1)[CH2:5][CH3:6]
Reactant: N#CCCl
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To prewashed sodium hydride (1.01 g, 42.0 mmol) in 60 ml of DMF at 20° is added 4-(1-methylpropoxy)phenol (7.0 g, 42.0 mmol) in 5 ml of DMF over 30 min. After 1 hour at RT, chloroacetonitrile (3.80 g, 50.4 mmol) in 5 ml of DMF is added dropwise to the mixture at 5°-8° over 15 min. After addition, the reaction is warmed slowly to RT and stirred at RT for 18 hours. The mixture is then poured into ice water and ether and extracted with ether (3X). The combined organic phases are washed with 10% NaOH, with water until neutral and with brine, dried, filtered and solvent removed in vacuo to give 4-(1-methylpropoxy)phenoxyacetonitrile.