Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
MeOSuc-Phe-Gly-Leu-OH was prepared from Z-Phe-Gly-Leu-OH, as described above in Procedure C. Z-Phe-Gly-Leu-OH (4.00 g, 8.52 mmol) was dissolved in 100 mL of methanol and hydrogenated in the presence of 1.0 eq of anhydrous HCl and 0.50 g of 10% Pd on carbon overnight in a Parr apparatus. The resulting reaction mixture was filtered and solvent was evaporated to yield 3.1 g of H-Phe-Gly-Leu-OH as a foam.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([F:24])[C:21]([CH3:25])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([F:24])[C:21]([CH3:25])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1cc(N)c(Cl)cc1F
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C)c(F)cc1Cl
Yield: 84 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (4.35 g, 21.0 mmol) and 2-chloro-4-fluoro-5-methylaniline (3.02 g, 18.9 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (5.54 g, 76%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:14])[CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CCCCCC>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C1CC1)C(O)c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
After 15 minutes 1-(4-chlorophenyl)-2-cyclopropylpropan-1-ol (44.72 g, 212 mmol) in dry dichloromethane (330 ml) was added over approximately 35 minutes. After 75 minutes triethylamine (154 ml), 1105 mmol) was added and the mixture allowed to warm to room temperature. Hexane was added and the mixture washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (100:0) to (90:10)] gave 1-(4-chlorophenyl)-2-cyclopropylpropan-1-one (38.0 g, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Reaction time: 17 h
Yield: 92.1 %

Procedure:
To a solution of 12.5 (53 mg, 0.116 mmol) in CH2Cl2 (2 ml) was added trifluoroacetic acid (3 ml) and the mixture was stirred for 17 h and concentrated. The crude product was purified by semi-preparative HPLC (gradient elution: 50 to 100% CH3CN/H2O+0.1% TFA) to afford 43 mg (72%) of 12.6. HRMS (ESI) calc'd for C25H27N2O3 403.2022, found 403.2026 (M+H+); 1H NMR (300 MHz, CDCl3) δ 7.59–7.56 (m, 3H), 7.46–7.34 (m, 6H), 7.13 (d, J=8.4, 2H), 6.74 (d, J=15.7, 1H), 5.12 (s, 2H), 4.20–4.11 (m, 1H), 2.07–2.03 (m, 2H), 1.95–1.89 (m, 2H), 1.75–1.71 (m, 3H), 1.28–1.25 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](N(OC)C)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>ClCCl.CCCCCC>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]2)=[O:28])[N:3]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 100.2 %

Procedure:
Dissolve 2,6-dibromopyridine (3.6 g, 15.3 mmol) in anhydrous dichloromethane (90 mL) under nitrogen atmosphere. Cool the reaction mixture to −78° C. Add a solution of n-butyl lithium in hexane very slowly via a syringe (1.6 M, 10.5 mL, 16.9 mmol). After the addition is complete, stir the reaction at −78° C. for 1 hr. Add a solution of 4-(methoxy-methyl-aminocarbonyl)-piperidine-1-carboxylic acid tert-butyl ester (2 g, 7.3 mmol) in anhydrous dichloromethane (10 mL) dropwise to the reaction mixture. Stir the reaction at −78° C. for 2 hrs., then allow it to slowly warm to room temperature overnight. Quench the reaction with 0.1 N aqueous NaOH. Dilute the solution with dichloromethane (100 mL), transfer into a separation funnel and shake with 0.1 N NaOH (60 mL). Separate the organic layer and dry it over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel column (10%-30% ethyl acetate/hexane) to obtain 2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (2.7 g, quantitative yield). Mass spectrum (ion spray): m/z 370 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:24][CH2:23]3)=[CH:20][S:19][C:18]=2[CH:34]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.O1CCN(N=C=N)CC1>CN(C=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:12])[CH2:24][CH2:23]3)=[CH:20][S:19][C:18]=2[CH:34]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Agent: N=C=NN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Add indole-2-carboxylic acid (507 mg, 3.15 mmol) to a solution of 4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazapan-1-yl]butylamine (Example 6) (920 mg, 2.86 mmol), diisopropylethylamine (2.5 mL, 14.3 mmol), 1-hydroxy-1H-benzotriazole (503 mg, 3.72 mmol) and morpholinocarbodiimide (1.39 g, 3.29 mmol) in DMF (10 mL), and stir the solution overnight at room temperature. Remove the solvent under vacuum and dissolve the residue in EtOAc. Wash the organic phase with ether and saturated sodium chloride solution, and dry over MgSO4. Evaporate the solvent under vacuum and purify the crude product by column chromatography (EtOAc/MeOH 7:3) to obtain 716 mg of a colorless solid LC/MS, (LiChrospher 5μ, RP-18, 250 mm CH3CN/Water-gradient 20%→100% (25 min), Flow: 1.5 mL/min) tR=19.89 min, m/z=464.3.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>O1CCOCC1>[O:16]=[C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:3]=[C:2]([NH:1][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:13]=2[NH:12]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reaction time: 16 h
Yield: 92 %

Procedure:
Prepared from 2-amino-6(5H)-phenanthridinone 3 and succinic anhydride. To a solution of 2-amino-6(5H)-phenanthridinone (150 mg, 0.71 mmol) in dioxane (30 mL) was added a solution of succinic anhydride (87 mg, 1.1 mmol) in dioxane (5 mL) over 5 minutes. The mixture was stirred for 16 hours and a yellowish precipitation was formed. Purification of the precipitation by crystallization in dioxane gave a light white solid (92% yield), mp 224-228° C. 1H-NMR (400 MHz DMSO-d6), 11.7 (s, 1H), 10.1 (s, 1H), 8.67 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.87 (t, J=7.0 Hz, 1H), 7.66 (t, J=7.44 Hz, 1H), 7.60 (t, J=8.7 Hz, 1H),7.30 (d, J=8.7 Hz, 1H), 2.60 ((d, J=5.4 Hz, 2H), 2.56 (d, J=5.4 Hz, 2H). Anal. (C17H24N2O4 .0.1 H2O), C H N.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13]OC1C=CC(B(O)O)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]CCCC(O)=O)=[CH:29][CH:28]=1)([OH:26])[OH:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][CH2:12][CH2:13][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([B:24]([OH:26])[OH:25])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCc1ccc(B(O)O)cc1
Reactant: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Agent: BrCc1ccccc1
Product: O=C(CCCCc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 79 %

Procedure:
Using a procedure analogous to that used to prepare 1B, 5B (250 mg, 1.13 mmol) was reacted with benzyl bromide to afford 5C (226 mg, 79%) as a clear oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH:6]2C.C[OH:17]>[Ni].C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:17])[CH2:6]2
Reactant: CO
Reactant: CC1C(=S)Nc2ccc(C(F)(F)F)cc21
Agent: [Ni]
Solvent: ClCCl
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1

Procedure:
A mixture of 4.0 g. of 5-trifluoromethyl-3-methylthio-oxindole, 20 g. of Raney Nickel and 100 ml. of methanol is refluxed for 4 days, cooled, treated with methylene chloride, filtered to remove the Raney Nickel and the filtrate concentrated in vacuo to obtain 5-trifluoromethyl-oxindole, m.p. 188°-190° C.
Reaction SMILES: FC(F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].CN(C)C=O.[Br:19][C:20]1[N:21]=[C:22]2[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]2=[N:24][C:25]=1[CH3:26]>ClCCl>[Br:19][C:20]1[N:21]=[C:22]2[C:29]([CH:3]=[O:4])=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:23]2=[N:24][C:25]=1[CH3:26]
Reactant: Cc1nc2c(ccn2COCC[Si](C)(C)C)nc1Br
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(nc1Br)c(C=O)cn2COCC[Si](C)(C)C
Yield: 84.8 %

Procedure:
Trifluoroacetic anhydride (10.2 mL, 60.8 mmol) was added dropwise, with cooling (ice bath), to N,N-dimethylformamide (24 mL) under an argon atmosphere. The cooling bath was removed for 15 min to facilitate stirring and then replaced. A solution of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (3.47 g, 10.1 mmol) in dichloromethane (5 mL) was added dropwise. The cooling bath was removed; the mixture was stirred for 15 min, then set in a bath at 45° C. and stirred for 16 h. The mixture was cooled, then poured onto ice water (200 mL) containing sodium carbonate (13 g) and extracted four times with ether. The combined ether extracts were washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on (silica, 20% ethyl acetate in hexanes) gave 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.17 g, 84%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 9H), 0.85 (t, J=8.0 Hz, 2H), 2.71 (s, 3H), 3.58 (t, J=8.0 Hz, 2H), 5.68 (s, 2H), 8.87 (s, 1H), 10.04 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:15])=[O:5])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:18]1[CH:19]=[CH:20][C:21]([Si:23]([CH3:25])([CH3:24])[CH3:26])=[CH:22][C:17]=1[F:16])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CCOC(=O)c1[nH]c2ccncc2c1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A degassed solution of 3-amino-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (200 mg, 0.98 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (324 mg, 1.02 mmol), Pd2dba3 (44 mg, 0.048 mmol), Xantphos (56 mg, 0.098 mmol) and Cs2CO3 (636 mg, 1.95 mmol) in toluene (6 ml) was subjected to microwave irradiation at 150° C. for 20 minutes. The reaction mixture was cooled to ambient temperature then diluted with EtOAc (100 ml). The resultant solution was washed with water (60 ml), dried (Na2SO4) and concentrated in vacuo to give a black oil. The oil was purified by flash chromatography (Si-PPC, cyclohexane:EtOAc, gradient 90:10 to 20:80) to provide the title compound as a brown solid (152 mg, 42%). LCMS (method B): RT=2.65 min, M+H+=372.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[CH:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>O1CCCC1>[CH2:1]([S:5][CH:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccc(C(Cl)Cn2cncn2)c(Cl)c1
Reactant: CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCSC(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
12.55 parts by weight of butylmercaptan is dripped into a suspension of 3.33 parts by weight of sodium hydride in 180 parts by weight of tetrahydrofuran. A solution of 27.5 parts by weight of 1-[2-chloro-2-(2,4-dichlorophenyl)-ethyl]-1,2,4-triazole in 50 parts of tetrahydrofuran is then dripped in and the mixture is stirred for 3 days at room temperature. The mixture is concentrated, stirred with water, and extracted with dichloromethane. The resulting dichloromethane solution is dried and evaporated. There is obtained 29.5 parts of crude 1-[2-n-butylmercapto-2-(2,4-dichlorophenyl)-ethyl]-1,2,4-triazole, which is dissolved in ethyl acetate. When hydrogen chloride is passed into the ethyl acetate solution, 25.9 parts of 1-[2-n-butylmercapto-2-(2,4-dichlorophenyl)-ethyl]-1,2,4-triazole hydrochloride, m.p. 143° C., precipitates out.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].O.[NH2:11][NH2:12]>>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH:11][NH2:12])=[C:7]([CH3:8])[CH:6]=1
Reactant: NN
Reactant: Cc1cc(Cl)nnc1Cl
Solvent: O
Product: Cc1cc(Cl)nnc1NN
Temperature: 80 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
A mixture of 3,6-dichloro-4-methylpyridazine (5 g, 30.7 mmol) in hydrazine hydrate (30.4 mL, 153 mmol) was heated up and stirred at 80° C. for 24 hr. The reaction was cooled down to RT; the resulting solid was filtrated off, washed with water and dried under reduced pressure. Recrystallization in hot EtOH followed by trituration in EtOH and ultra sounds afforded the title product (721 mg, 4.55 mmol, 14.8% yield) as white solid. tR: 0.34 min (LC-MS 2); ESI-MS: 159 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:10])[CH:5]([Br:9])[CH2:6][CH2:7]Br.[H-].[Na+].BrC(CCBr)C(Br)=O>C1C=CC=CC=1>[CH3:1][O:2][N:3]1[CH2:7][CH2:6][CH:5]([Br:9])[C:4]1=[O:10]
Reactant: CONC(=O)C(Br)CCBr
Agent: O=C(Br)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CON1CCC(Br)C1=O
Yield: 36 %

Procedure:
130 g of the above-obtained oil containing N-methoxy-2,4-dibromobutyric acid amide were dissolved in 500 mL of benzene. To the resultant solution, 12 g of sodium hydride were gradually added while cooling the solution to 15° C. to 20° C. After the completion of the addition, ice was added to the resultant reaction solution to decompose excessive sodium hydride. The resultant solution was washed with a saturated saline, followed by drying the solution by magnesium sulfate. The solution was concentrated under a reduced pressure and purified by silica gel-acetone/benzene column chromatography. Consequently, 39 g (0.2 mol) of N-methoxy-2-bromo-4-butyrolactam (with a yield of 36% from 2,4-dibromobutyric acid bromide) was obtained.
Reaction SMILES: Br.COC1C=CC(C[O:9][CH2:10][C:11]2[N:15]3[C:16]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=4[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:19][CH2:20][C:14]3=[N:13][N:12]=2)=CC=1.[OH-].[Na+]>C(O)(=O)C>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[C:17]2[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:16]=2[N:15]2[C:11]([CH2:10][OH:9])=[N:12][N:13]=[C:14]2[CH2:20][N:19]=1
Reactant: COc1ccc(COCc2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2Cl)=NC3)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.92 h

Procedure:
An amount of 72 ml of 48% aqueous hydrobromic acid is added to 20° to a solution of 9.7 g of 1-[ (p-methoxybenzyloxy)-methyl]-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 90 ml of glacial acetic acid. The reaction mixture is stirred for 55 minutes; it is then neutralised with 30% sodium hydroxide solution and extracted with methylene chloride. The organic phase is separated, washed with water, dried over sodium sulphate and concentrated by evaporation. Crystallisation of the residue from ethyl acetate/petroleum ether yields 6-(o-chlorophenyl)-8-chloro-4 h-s-triazolo[4,3-a] [1,4]benzodiazepine-1-methanol, M.P. 235°-237°.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:11][N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: CNc1ccccc1
Reactant: O=C1CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C1=CCc2ccccc21)c1ccccc1

Procedure:
Into a dry flask equipped with a Dean-Stark trap and a reflux condenser were placed 1-indanone (10.0 g, 75.7 mmol). N-methylaniline (15.1 g, 141 mmol) and toluene (200 mL). A catalytic amount of p-toluenesulfonic acid (0.1 g) was added and the mixture was refluxed under N2 for 96 hours. The reaction was cooled and the toluene was removed under reduced pressure before the remaining material was distilled under vacuum. The highest boiling fraction (6.8 g; bp 150-2° C./0.7 mm Hg) was collected as a yellow oil which solidified to a yellow-orange solid on standing. This material was stored in a glove box. Analysis by NMR indicated ca. 10 percent N-methylaniline in the product. However, further distillation on another sample of distilled enamine was not successful in lowering the amount of unwanted amine in the product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10]C.O=CC1C=CC(O)=C(OCC)C=1.C1OC2C=CC(C=O)=CC=2O1.C(OC1C=C(C=CC=1O)C=O)C.OC1C=C(C=CC=1OC)C=O.OC1C(OC)=CC=CC=1C=O.OC1C=CC(O)=CC=1C=O.C(C1C=C(C=O)C=C(OC)C=1O)=O>>[OH:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Agent: CCOc1cc(C=O)ccc1O
Agent: COc1cc(C=O)cc(C=O)c1O
Agent: COc1ccc(C=O)cc1O
Product: O=Cc1ccc(O)c(O)c1

Procedure:
4-hydroxy-3-methoxybenzaldehyde; 3,4-dimethoxybenzaldehyde heliotropin; 3,4-methylenedioxybenzaldehyde bourbonal; 3-ethoxy-4-hydroxybenzaldehyde; 3-hydroxy-4-methoxybenzaldehyde; 2-hydroxy-3-methoxybenzaldehyde; 2,5-dihydroxybenzaldehyde; and 2,4-diformyl-6-methoxyphenol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH3:18])[CH2:19][OH:20])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 83.5 %

Procedure:
The procedure of Example 1 was repeated except that 93 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carbaldehyde was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 78 mg of 1α,3β-diacetoxy-20-methylpregna-5,7-diene-21-ol.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][N:23]=[CH:24]3)(=[O:18])=[O:17])[CH2:10]1)=O)(C)(C)C.Cl>CO>[CH:24]1[C:25]2[C:20](=[C:19]([S:16]([NH:15][CH:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10]3)(=[O:17])=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(NS(=O)(=O)c2cccc3cnccc23)C1
Agent: Cl
Solvent: CO
Product: NC1CCCC(NS(=O)(=O)c2cccc3cnccc23)C1
Yield: 108.4 %

Procedure:
Intermediate 54 (6 g) obtained above was added to a 10% hydrogen chloride solution in methanol (50 ml) and stirred under reflux by heating for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in a mixed solvent of dichloromethane and ethanol, added with saturated aqueous potassium carbonate and vigorously shaken. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (4.9 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].Cl.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: NCc1ccc(-c2nccs2)cc1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccccn1
Yield: 75.2 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 2-pyridylsulfonyl chloride (see Heterocycles, 28, 1115 (1989)) (220 mg, 1.24 mmol) in place of 3-pyridylsulfonyl chloride, and using 4-(thiazol-2-yl)benzylamine hydrochloride (300 mg, 1.14 mmol) obtained in Reference Example 4-(d) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (284 mg) as a white solid. (Yield: 75%)