Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(Br)cc1
Yield: 72.8 %

Procedure:
A solution of (3-(4-bromophenyl)propionic acid (387 mg, 1.68 mmoles) and benzoic acid N′-isopropyl-hydrazide (300 mg, 1.68 mmoles) in DMF (10 mL) was treated with triethylamine (0.70 mL, 5.05 mmol), HOBT (273 mg, 2.02 mmoles) and EDCI (387 mg, 2.02 mmoles) at room temperature for 72 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated to afford the product as a solid (476 mg, 73%). The product was not further purified.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][C:34](F)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>CS(C)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=3)=[CH:35][CH:36]=2)=[O:38])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
Tert-butyl 2-(4-hydroxyphenyl)acetate (200 mg, 0.960 mmol) was diluted with DMSO (4 mL) followed by the addition of K2CO3 (133 mg, 0.960 mmol) and N-(4-chlorophenethyl)-4-fluorobenzamide (267 mg, 0.960 mmol). The reaction was stirred at 85° C. overnight, and then stirred at 138° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (4:1) to yield tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetate (20 mg, 4.47% yield) as an off white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OCc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCc1cccnc1)n1ccnc1
Yield: 80.6 %

Procedure:
A solution of (pyridin-3-yl)methanol (2 g, 18.32 mmol) and di(1H-imidazol-1-yl)methanone (5.94 g, 36.65 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was washed with water, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate (3 g, 81%). LC/MS: m/z 204.1 (M+H)+ at 0.39 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (s, 1H), 7.81 (m, 1H), 7.44 (s, 1H), 7.38 (m, 1H), 7.09 (s, 1H), 5.46 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[N:10]1.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:18]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[N:10]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccnn1-c1ccccc1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnn1-c1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
To a solution of methyl 1-[2-(bromomethyl)phenyl]pyrazole-5-carboxylate (1.30 g, 4.40 mmol) in 10 mL of N,N-dimethylformamide was added sodium azide (2.86 g, 44.0 mmol). This mixture was stirred at ambient temperature for 48 h and then was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated to afford 0.80 g (71%) of the title compound which was used directly without purification. LRMS (ES+): 280.1 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 22: (+)-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol), triethylamine (13.1 μL, 0.093 mmol), tetrahydrofuran (2 ml) and iodoethane (5.6 μL, 0.07 mmol). The crude product analyzed by GCMS. Analysis showed 92% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 6), 226 (46), 211 (23), 141 (43), 71 (bp).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[N:39]([CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[C:40]=[O:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:40]([NH:39][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:41])[CH:29]=3
Reactant: O=C=NC1CCCC1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)NC1CCCC1
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and isocyanatocyclopentane as the starting materials in 39% yield. LCMS for C24H26ClN6O (M+H)+: m/z=449.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[CH3:10].[H-].[Na+].C(O)C>CCOCC>[CH3:15][N:14]([CH3:16])[C:13](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:17]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=Cc1ccccc1)N(C)C
Yield: 60 %

Procedure:
Benzaldehyde, N,N-dimethylglycine ethyl ester and sodium hydride were reacted in ether with the addition of a catalytic amount of ethanol according to the method described in Lieb. Ann. Chem. 703 (1967) 37-43 to give ethyl α-dimethylaminocinnamate. This compound was then reacted according to the method described in Tetrahedron Letters, 46, (1978) 4573-4574 with oxalyl chloride and hydrazine in 60% yield to give ethyl 4-phenyl-3-pyrazolecarboxylate, melting point 164°-165° after recrystallization from ethanol/diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:7][C:6]=2[CH:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].P(OCC)(OCC)[O:37]CC>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([OH:37])([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:25]=1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (15 g, 41.7 mmole) in 780 ml of tetrahydrofuran was cooled to -78° C. and 147 ml (167 mmole in tetrahydrofuran) of potassium hexamethyldisilazide solution was added. After stirring for 1 hour, 28.7 ml of triethyl phosphite (166.7 mmole) was added and anhydrous oxygen gas was rapidly bubbled through the resulting solution. The reaction temperature was then raised to 0° C. and allowed to stir for an additional hour. Oxygenation was then discontinued and the reaction was quenched by the addition of 50 ml of acetic acid. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate, and brine and then dried over anhydrous sodium sulfate. Concentration of the dried organic solution afforded a solid which, upon trituration in hexane, gave 14.8 g of the title compound.
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]1([C:11]2[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[C:5]1([C:11]2[S:12][C:13]([C:16]([O:18][CH3:1])=[O:17])=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cnc(-c2ccccc2)s1
Solvent: CO
Product: COC(=O)c1cnc(-c2ccccc2)s1

Procedure:
2.5 ml of acetyl chloride were added to a solution of 4.77 g of the acid of Stage B in 160 ml of methanol, and the mixture was refluxed for 18 hours. After evaporating to dryness under reduced pressure, the residue was taken up in ethyl acetate. The mixture was filtered and concentrated to a reduced volume. The crystals were separated off and the mother liquors were washed with sodium hydroxide. Extraction was carried out with ethyl acetate, followed by washing with water and evaporating to dryness. The 2 crystallized fractions were combined to obtain 4.54 g of the desired product melting at 108° C.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].N(C(OC[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O)[C@H](C(NCC(N)=O)=O)C>CO>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH2:3][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Solvent: CO
Product: NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Z-D-Ala-Gly-NH2 (21) (Richman et al., Int. Peptide Protein Res., 25:648-662 (1985), which is hereby incorporated by reference): 1H and 13C NMR data are identical to (8). HRMS (FAB+) MH+ calcd 280.1297 found 280.1298; [α]27D+10.5 (c 0.72, MeOH); lit. [α]D=+10.5.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[C:8]([C:17]([NH2:19])=[O:18])[CH:9]=[CH:10][C:11]=3[Br:16])[NH:6][C:5]=2[CH2:4]1.[Br:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1.C(Cl)Cl>[Br:16][C:11]1[CH:10]=[CH:9][C:8]([C:17]([NH2:19])=[O:18])=[C:7]2[C:12]=1[C:13]1[CH2:14][CH2:15][CH:3]([CH2:2][NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Br:20])[CH2:4][C:5]=1[NH:6]2
Reactant: NCC1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CNC(=O)CCCBr)CC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.1 %

Procedure:
Step 4 A suspension of 2-(aminomethyl)-5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (130 mg, 0.403 mmol) and TEA (0.067 mL, 0.484 mmol) in THF (2 mL) was treated with 4-bromobutanoyl chloride (74.8 mg, 0.403 mmol). The mixture was stirred at rt for 20 min, diluted with DCM, washed with NaHCO3 (aq), dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc) to provide 5-bromo-2-((4-bromobutanamido)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a white solid (80 mg, 42%). Mass spectrum m/z 470, 472, 474 (M+H)+.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][O:16][C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][C:22](=[O:27])[CH2:21]1>O1CCCC1>[CH3:15][O:16][C:17]([CH3:28])([CH3:29])[CH2:18][CH2:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]([OH:27])[CH2:21]1
Reactant: COC(C)(C)CCC1CC(=O)CC(C)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Reaction time: 16 h

Procedure:
A solution of lithium tri-sec-butylborohydride (267 mL of a 1M solution in tetrahydrofuran, 0.27 mol) was added to a cooled (-65~C.) solution of 3-(3-methoxy-3-methylbutyl)-5 methylcyclohexan-1-one (48.6 g, 0.22 mol) dissolved in tetrahydrofuran (350 mL). The solution was stirred at 25~C. for 16 hours and was quenched by addition of sodium hydroxide (10% aqueous, 165 mL) followed by hydrogen peroxide (30% aqueous, 170 mL). Workup yielded 3-(3-methoxy-3-methylbutyl)-5-methyl cyclohexan-1-ol as a mixture of diastereoisomers (ratio 90.1:7.2:2.7), bp0.75 120-122~C. (40.7 g). This compound and mixtures of diastereomers possess strong, tenacious, sandalwoody, musky notes. NMR(CDCl3) δ 0.6 (q,1H), 0.9(d,3H), 1.0-1.1(m,2H), 1.1(s,6H), 1.2-1.3 (m,2H), 1.4-1.6(m,2H), 1.6-1.9(m,5H), 2.2(brs,1H), 3.2(s,3H), 4.1(m,1H). IR(neat) 2400, 2975, 2925, 1460, 1385, 1365, 1210, 1090, 1015 cm-1 ; MS(m/e) 43, 73, 93, 111, 149, 167, 182, 199, 200.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8]Br)[CH3:2].NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][SH:15])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2,2-dimethylpentanoic acid ethyl ester (2.41 g, 10 mmol) in ethyl alcohol (5 mL) was added thiourea (0.77 g, 10 mmol) and the mixture was refluxed for 3 h under a nitrogen atmosphere. A solution of sodium hydroxide (0.62 g, 15 mmol) in deionized water (2.5 mL) was added and stirring was continued for another 2 h at reflux temperature. The mixture was cooled to rt and the ethanol was distilled off under reduced pressure. Diethyl ether (20 mL) was added and the layers were separated. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-mercapto-2,2-dimethylpentanoic acid ethyl ester (1.41 g, 74%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 4.12 (q, J=7.0 Hz, 2H), 2.57-2.43 (m, 2H), 1.69-1.45 (t, 4H), 1.25 (t, J=7.0 Hz, 3H), 1.17 (s, 7H). 13C NMR(75 MHz, CDCl3/TMS): d (ppm): 177.55, 41.0, 39.24, 25.07, 24.90, 14.18.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][S:10][CH3:11])[NH:5][C:6](=[O:8])[CH3:7].O.[NH2:14][NH2:15]>C(O)C>[CH3:11][S:10][CH2:9][C@@H:4]([C:3]([NH:14][NH2:15])=[O:2])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](CSC)NC(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSC[C@H](NC(C)=O)C(=O)NN
Yield: 58 %

Procedure:
In 20 ml of ethanol were dissolved 1.70 g (8.9 mmole) of S-methyl-N-acetyl-L-cysteine methylester and 6 ml of aqueous 80% hydrazine hydrate solution and the solution was heated at reflux for 2 hours. After the reaction solution was concentrated in vacuo, a small amount of water was added to the residue and then distilled off in vacuo and this procedure was repeated three times to give white crystals. The crystals were washed with small amount of ethanol and dried to give 0.99 g (58% yield) of S-methyl-N-acetyl-cysteinylhydrazine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1.[OH:21]O>C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[S:3]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:21]
Reactant: O=C1c2cc(SC(F)(F)F)ccc2CCn2cccc21
Reactant: OO
Solvent: CC(=O)O
Product: O=C1c2cc(S(=O)C(F)(F)F)ccc2CCn2cccc21

Procedure:
A solution of 3 gm. of 9-trifluoromethylthio-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 25 ml. of acetic acid containing 3 ml. of 50% hydrogen peroxide is stirred at 25° C. for 6 hr. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride. The solution is washed with 2 × 25 ml. of 5% Na2CO3 solution, dried and evaporated. Chromatography of the residue on silica gel yields 9-trifluoromethylsulfinyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.COC[CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: COCCOCCOCCOCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A suspension of 362 (0.90 g, 2.3 mmol), amine 363 (0.93 g, 5.7 mmol) [amine 363 has been synthesized according to the procedures used for the synthesis of amines 322 (scheme 18) and 326 (scheme 20)] and acetic acid (0.26 ml, 4.6 mmol) in dichloromethane (50 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (1.45 g, 6.85 mmol) was added and the mixture was stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.5 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N HCl. The organic phase was discarded. The aqueous phase was basified (pH=13) with 3M NaOH, and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 364 (0.72 g, 58%) as a yellow solid. LRMS (M+H): 542.4
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:23][CH2:24]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:38][C:36]3[N:37]=[C:32]4[N:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Reactant: Cc1cnc2nc(C=O)nn2c1
Solvent: CO
Product: Cc1cnc2nc(CC3C(=O)CC(CCc4ccc(C5(C#N)CC5)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour before it was cooled to −10° C. for 2 hours. The precipitate was removed by filtration, and the filtrate was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 1:3->1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid): (81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (146 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 1.41–1.64 (m, 8 H), 1.84–1.88 (m, 2 H), 2.22–2.28 (m, 2 H), 2.42 (s, 3 H), 2.49–2.59 (m, 4 H), 2.65–2.74 (m, 3 H), 3.97–4.05 (m, 2 H), 6.72–6.82 (m, 2 H), 7.05–7.10 (m, 1 H), 8.55 (s, 1 H), 8.67 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]2[NH:1][N:14]=[CH:13][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(Br)ccc(N)c1C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)ccc2[nH]ncc12
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (5.44 g, 22.3 mmol) in acetic acid (110 mL) was added a solution of sodium nitrite (1.69 g, 24.5 mmol) in water (11 mL) at room temperature, and the mixture was stirred for 20 hr. The organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→30/70) to give the title compound (4.86 g, yield 86%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:13][O:14][NH2:15]>N1C=CC=CC=1>[CH3:13][O:14][N:15]=[C:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CON
Reactant: O=C1CCc2c(Br)cccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromoindan-1-one (5.08 g, 24.1 mmol) was added to a mixture of methoxyamine hydrochloride (2.21 g, 26.5 mmol) in pyridine (40 mL) under nitrogen atmosphere and stirred overnight at ambient temperature. The reaction mixture was concentrated, added ethyl acetate (200 mL), washed with 3N hydrochloric acid (200 mL), dried with brine and anhydrous sodium sulfate, and concentrated. Obtained 4-bromoindan-1-one O-methyloxime (5.66 g, 98%) as an orange liquid. MS (DCI/NH3) m/z: 239.94 [M+H]+. 1H NMR (DMSO-d6) □: 2.83 (m, 2H), 2.96 (m, 2H), 3.91 (s, 3H), 7.25 (t, 1H), 7.56 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[Br:13][C:14]1[O:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:19]([C:17]2[O:18][C:14]([Br:13])=[CH:15][CH:16]=2)=[O:20])[CH:6]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
Methyl ester (15) (1 g, 6.06 mmol) was coupled to 5-bromo-furan-2-carboxylic acid (1.16 g, 6.07 mmol) using Method C to give the title compound