Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:9].[K+].C(Cl)(Cl)Cl.O>C(O)(C)(C)C>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: NC(=O)c1ccccc1

Procedure:
A sample of 3-[(2-dimethylamino)methyl]-1-hydroxycyclohexyl]-benzonitrile (Procedure A, 1.66 g, 6.4 mmol) as a mixture of diastereomers was dissolved in tert-butanol (20 mL), powdered potassium hydroxide (1.8 g, 32.1 mmol) was added, and the reaction was brought to reflux for 1 h. After cooling the reaction, chloroform (50 mL) and water (50 mL) were added. The organic layer was separated, dried (K2CO3), filtered, and concentrated to afford 3-[(2-dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide as a diastereomeric mixture (1.6 g, 93%). The mixture was purified on a reverse phase C-18 column with 0.5% ammonium acetate in water and acetonitrile as eluents. Compound 1, 3-[(1-RS,2-SR)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide, eluted first. Next to elute was Compound 2, 3-[(1-RR, 2-SS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[N:22]=2)=[C:17]([CH3:30])[C:16]=1[CH:31]1[C:44]2[C:43](=[O:45])[CH2:42][C:41]([CH3:47])([CH3:46])[CH2:40][C:39]=2[O:38][C:37]2[CH2:36][C:35]([CH3:49])([CH3:48])[CH2:34][C:33](=[O:50])[C:32]1=2.[BH4-].[Na+].Cl>C1COCC1.O.CN(C=O)C>[OH:28][CH2:27][C:23]1[N:22]=[C:21]([C:18]2[C:17]([CH3:30])=[C:16]([CH:31]3[C:44]4[C:43](=[O:45])[CH2:42][C:41]([CH3:46])([CH3:47])[CH2:40][C:39]=4[O:38][C:37]4[CH2:36][C:35]([CH3:49])([CH3:48])[CH2:34][C:33](=[O:50])[C:32]3=4)[C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COc1ccc(-c2ccnc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(CO)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
1,1′-Carbonyldiimidazole (33.9 mg, 0.209 mol) was added to a suspension of the 4-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyrimidine-2-carboxylic acid obtained in Example 75-4 (90.0 mg, 0.174 mmol) in THF (2.0 mL) at room temperature, and the mixture thus obtained was then stirred at 50° C. for 1.5 hours. Thereafter, DMF (0.5 mL) was added to the resulting solution, and the mixture thus obtained was further stirred at the same temperature as above for 20 minutes. Subsequently, the reaction solution was cooled to 0° C., and sodium borohydride (13.2 mg, 0.348 mmol) and water (0.1 mL) were then added to the reaction solution. The mixture thus obtained was stirred at room temperature for 30 minutes. Thereafter, water and 1 M-hydrochloric acid were added to the reaction solution, and the mixed solution was then extracted with ethyl acetate twice. The organic layer thus obtained was washed with brine, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (dichloromethane:methanol=1:0 to 10:1, v/v), and was then solidified with diethyl ether to obtain the title compound (49.9 mg, yield: 56%).
Reaction SMILES: C([O:3][P:4]([CH3:26])([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Br[Si](C)(C)C.CO>C(Cl)Cl.C(N(CC)CC)C.O>[OH:5][P:4]([CH3:26])([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:3]
Reactant: CCOP(C)(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(C)(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
N-[N-[Ethoxy(methyl)phosphinyl]-L-phenylalanyl]-L-leucine (0.386 g., 1.0 mmole) is thoroughly dried, and then allowed to dissolve in methylene chloride (5 ml.). The solution is flushed with argon and treated with bis(trimethylsilyl)acetamide (0.33 ml., 1.3 mmole), stirred for two hours at room temperature, then concentrated in vacuo (less than 0.3 mm of Hg) and again taken up in methylene chloride (4 ml.). This solution is treated with bromotrimethylsilane (0.29 ml., 2.2 mmole) under argon, stirred overnight at room temperature, then treated slowly with a mixture of methanol (3.1 ml.), water (0.78 ml.), and triethylamine (0.78 ml.). After again stirring overnight at room temperature, the mixture is concentrated to dryness, taken up in water (approximately 3 ml.), and passed through an AG-50W-2 Li+ column (25 ml. settled bed). Fractions of approximately 8 ml. each are collected and those containing the product (fractions numbered 1 to 4) are pooled and concentrated to a small volume (approximately 2 ml.). This material is applied to a column of HP-20 and eluted with water. Fractions of approximately 8 ml. each are collected and those containing the product (fractions numbered 11 to 19) are pooled and concentrated to approximately 20 ml. and lyophilized to a white powder (0.168 g.). A sample of this powder (0.04 g.) is taken up in water, filtered (millipore) and relyophilized to give an analytical sample (0.039 g.) of N-[N-[hydroxy(methyl)phosphinyl]-L-phenylalanyl]-L-leucine, dilithium salt; m.p. greater than 250° (turns pink at 210°). Tlc (isopropanol/water/con. NH4OH, 7:2:1) single spot Rf is 0.51. [α]D25 =-36.6° (c=1.0, water).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([O-:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:17]([O-])=O.[K+]>CCO.O.[Pd]>[C:1]([C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C(=O)[O-]
Reactant: O=C[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol) in water (1 mL), followed by the addition of 20 mg of 10% Pd—C. The reaction mixture was refluxed for additional 40 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give methyl 2-tert-butyl-5-aminobenzoate (E-6) (76 mg, 95%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.6 Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.7 Hz, 1H), 3.86 (s, 3H), 1.34 (s, 9H); HPLC ret. time 2.19 min, 10-99% CH3CN, 5 min run; ESI-MS 208.2 m/z (MH+).
Reaction SMILES: O=S(Cl)[Cl:3].[Br:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16]O)=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[Br:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16][Cl:3])=[CH:12][N:11]=[CH:10]1
Reactant: OCCCc1cncn1Cc1ccccc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCCc1cncn1Cc1ccccc1Br

Procedure:
To a solution of SOCl2 (0.55 mL, 7.54 mmol) in CH2Cl2 (15 mL) at 0° C. is added 3-[3-(2-bromobenzyl)-3H-imidazol-4-yl]propan-1-ol in portion and the resulting white suspension is refluxed for 1.5 h. The mixture is cooled with ice and collected to give a buff-colored solid, which is partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic layer is washed with brine, dried over anhydrous Na2SO4, and concentrated to give an oil. MS (ESI) m/z 313 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[NH2:8].[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=O)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:26]([CH3:44])=[N:25]1>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:41]([CH2:40][C:37]3[CH:38]=[CH:39][C:34]([S:31]([NH:30][C:27]4[C:26]([CH3:44])=[N:25][N:24]([CH3:23])[C:28]=4[CH3:29])(=[O:32])=[O:33])=[CH:35][CH:36]=3)[NH:1][C:2]=2[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Reactant: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4c(C)nn(C)c4C)cc3)nc21

Procedure:
Prepared from 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfamoyl)-phenyl]-acetic acid. 4-[3-Butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide was obtained as a colorless solid; 1H NMR (DMSO-d6, 300 MHz) δH 13.48 (s, 1H), 8.94 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.38 (d, J=7.7 Hz, 2H), 7.30–6.90 (m, 4H), 5.03 (s, 2H), 4.10 (s, 2H), 3.88 (t, J=7.1 Hz, 2H), 3.45 (s, 3H), 1.71 (s, 3H), 1.60–1.45 (m, 2H), 1.42 (s, 3H), 1.25–1.10 (m, 2H), 0.79 (t, J=7.5 Hz, 3H); FAB-HRMS m/e calculated for C29H32FN7O4S (M+H)+ 594.2299, found 594.2281.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[N:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]3=[N:8][C:7]=2[NH:16]C(=O)C(F)(F)F)[CH2:5][CH2:4]1.CO.O1CCCC1>O>[CH:3]1([C:6]2[N:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]3=[N:8][C:7]=2[NH2:16])[CH2:5][CH2:4]1
Reactant: O=C(Nc1nc2ccc(F)cn2c1C1CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc(F)cn2c1C1CC1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
6.00 M of Sodium hydroxide in water (1.0 mL) was added to a solution of N-(3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (compound e, 0.197 g, 0.000617 mol) in Methanol (2.00 mL, 0.0494 mol) and Tetrahydrofuran (2.0 mL, 0.0246 mol) and the reaction mixture was stirred at 55° C. for 36 hours. The reaction mixture concentrated in vacuo to dryness and crude product purified by column chromatography (5% methanol/dichloromethane) as a yellow solid. Rf 0.41, 5% methanol/dichloromethane; MS m/z 192 (M+H).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][CH2:5]2)[O:3]C1.C([O-])(O)=O.[Na+]>CO.Cl>[CH2:11]([O:10][CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(OCc2ccccc2)CC1

Procedure:
A solution of 4-benzyloxy cyclohexanone ethylene ketal 40 (5.0 g, 20.1 mmol) in methanol (20 mL) and 1N HCl (0.5 mL) was stirred overnight at 25° C. (Step 37). The mixture was neutralized by addition of 1N NaHCO3 (0.5 mL), solvent removed by roto-evaporation, and the residue chromatographed on silica gel using 15:85 ethyl acetate/hexane. Yield of the ketone 41 was 2.7 g (67%); Rf=0.35; 1H NMR (CDCl3) δ 2.3 (m, 8H, ring--CH2) 3.6 (m, 1H, CH--O), 4.6 (s, 2H, CH2 --O).
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.[CH3:47][N:48]([CH3:57])[CH2:49]CC1CCCCN1>>[CH3:47][N:48]([CH3:57])[CH2:49][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: CN(C)CCC1CCCCN1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CN(C)CCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B8 was prepared following the procedure reported for B4 using A1 and rac-2-(2-(dimethylamino)ethyl)piperidine and obtained as a white crystalline solid; yield: 230 mg (61%). MS (ES) C19H29N7O2S requires: 419. found: 420 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].ClCCl.[OH:8][N:9]=[C:10]([CH3:25])[CH2:11][N:12]([S:21]([CH3:24])(=[O:23])=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>C(N(CC)CC)C>[C:1]([O:8][N:9]=[C:10]([CH3:25])[CH2:11][N:12]([S:21]([CH3:24])(=[O:23])=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(CN(c1c(C)cccc1C)S(C)(=O)=O)=NO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON=C(C)CN(c1c(C)cccc1C)S(C)(=O)=O

Procedure:
Acetyl chloride (0.9 ml) was added to a dichloromethane (20 ml) solution of N-[2-hydroxyiminopropyl]-2',6'-dimethylmethanesulphonanilide (2.6 g) and triethylamine (1.6 ml). The mixture was stirred and boiled under reflux for 3 hours, then filtered, and the filtrate evaporated to a clear yellow oil. A solution of this oil in chloroform was percolated through a short column of silica gel, and the eluate evaporated to give analytically pure N-[2-(acetyloxyimino)propyl]-2',6'-dimethylmethanesulphonanilide. Yield 1.9 g (63%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(N(CC)CC)C.C1C=CC=CC=1.[Cl:27][C:28]([Cl:33])([Cl:32])[C:29](Cl)=[O:30]>O>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:29](=[O:30])[C:28]([Cl:33])([Cl:32])[Cl:27])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(NC(=O)C(Cl)(Cl)Cl)c(C)c1

Procedure:
To a slurry of 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole), triethylamine (1.11g., 0.011 mole), and 25 ml. of benzene was added trichloroacetyl chloride (2.0g., 0.011 mole) dropwise. After refluxing for one hour, the reaction mixture was poured into water and the resulting solid product was filtered (3.05g., m.p. 185°-87° C.).
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[NH2:15][C@H:16]([CH2:30][F:31])[C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[OH:18]>CO>[F:31][CH2:30][C@@H:16]([NH:15][C:3](=[O:4])[CH:2]([Cl:1])[Cl:7])[C@@H:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH2:28][F:29])(=[O:27])=[O:26])=[CH:23][CH:24]=1)[OH:18]
Reactant: COC(=O)C(Cl)Cl
Reactant: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1)C(Cl)Cl
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Methyl dichloroacetate (23.2 g, 5 eq ) and triethylamine (33.0 g, 10 eq) was added to a solution of 17 (8.64 g) in 50 ml of MeOH at room temperature. The reaction mixture was stirred overnight. Methanol was removed in vacuo. The residue was dissolved in 250 ml of ethyl acetate and washed with 1N HCl. The organic layer was washed with a 10% solution of sodium bicarbonate and brine and dried over sodium sulfate and concentrated to dryness. After purification via a column, 11.7 g of the desired product was obtained as a white solid.
Reaction SMILES: N#N.C(OC([C@@:13]1([C:30]([NH2:32])=[O:31])[CH2:17][C@@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][N:14]1[C:26]([CH3:29])([CH3:28])[CH3:27])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:22]([O:21][C:19]([NH:18][C@H:16]1[CH2:15][N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:13]([C:30]([NH2:32])=[O:31])[CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(C)(C)C)[C@@](C(N)=O)(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(N)=O)N(C(C)(C)C)C1
Yield: 106.6 %

Procedure:
0.25 g of N2 -(benzyloxycarbonyl)-4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide was dissolved in ethanol and hydrogenated over 0.1 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 4 hours. The catalyst was filtered off and the filtrate-was evaporated to give 0.17 g of 4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide as a glass which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:31][CH2:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a stirred solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 10 ml of methylene chloride is added 0.46 g of triethylamine and 36 mg of dimethylamino-pyridine followed by the slow addition of 0.42 g of chloroacetyl chloride in 5 ml of methylene chloride. The resulting mixture is stirred at room temperature for 3 hours then partitioned with 10 ml of 50% NaHCO3 and the methylene chloride evaporated in vacuo. The remaining suspension is filtered, washed with 50% NaHCO3, H2O, EtOAc (2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beige solid. MS(CI): 380(M+H).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.O.[NH2:32][NH2:33]>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:32][NH2:33])=[O:30])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3)CC2)cc1
Yield: 63 %

Procedure:
A mixture of 3.2 parts of phenyl{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}carbamate, 50 parts of hydrazine hydrate and 100 parts of 1,4-dioxane is stirred and refluxed for 3 hours. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and crystallized from N,N-dimethylformamide, yielding 1.7 parts (63%) of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide; mp. +300° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:26][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1cncc(-c2c3ccccc3cc3ccccc23)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Brc1c2ccccc2c(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 26 h
Yield: 55.4 %

Procedure:
In a 200 mL three-necked flask were placed 1.0 g (4.0 mmol) of 3-(9-anthryl)pyridine and 25 mL of carbon tetrachloride. Under a nitrogen stream, 10 mL of a carbon tetrachloride solution containing 0.83 g (5.1 mmol) of bromine was dripped into this solution, followed by stirring at room temperature for 26 hours. After a predetermined time has passed, 100 mL of a 1.0 M sodium thiosulfate solution was added to this mixture. The aqueous layer of this mixture was extracted with chloroform. The obtained extract and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and with saturated brine, and dried with magnesium sulfate. This mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. A chloroform solution of the obtained solid was suction filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to give a solid. Recrystallization of this solid from a mixed solvent of ethyl acetate and hexane gave 0.74 g of a pale yellow powder in 53% yield, which was the desired substance.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1[C:16]([NH2:17])=[N:15][C:13](=[O:14])[N:12]([C@@H:18]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@@H:19]2[OH:26])[CH:11]=1.CN(C=[O:31])C>C(Cl)Cl>[C:18](=[O:22])([O-:31])[NH2:12].[CH:10]1[C:16]([NH2:17])=[N:15][C:13](=[O:14])[N:12]([C@@H:18]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@@H:19]2[OH:26])[CH:11]=1
Reactant: CN(C)C=O
Agent: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (60 μL, 0.35 mmol) is added to a mixture of SC-PEG 40 kDa (4, 1.0 g, 0.025 mmol) and 1 (0.15 g, 0.5 mmol) in DCM (10 mL) and DMF (10 mL) and the mixture is stirred overnight at room temperature. The solvent is removed in vacuo and the residue is recrystallized from IPA to give PEG-carbamate-Ara-C (5).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([CH:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].C[Si]([C:26]#[N:27])(C)C>>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([CH:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:26]#[N:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: CCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-ethoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 88%).
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33](O)[CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:11]([O:19][CH2:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:37][CH:36]=2)=[CH:32][CH:31]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: CC(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cccnc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCCc1ccc(OCc2ccc(Cl)cc2)cc1)c1cccnc1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
Benzenesulfonyl chloride (10.6 g, 0.06 mole) is dropped with stirring at 60° C. to a nicotinic acid in 30 ml of pyridine to yield uniform solution. After the solution was stirred at 50°-60° C. for ten minutes, 4-(4-chlorobenzyloxy)phenyl ethanol (13.1 g, 0.05 mole) is added to the solution, and the mixture is stirred for 45 minutes at room temperature. The reaction mixture is poured into 300 ml of ice water to give crystals. The crystals are dissolved into 300 ml of chloroform, the chlorofrom layer is washed with 5% pottassium carbonate solution and water. The chloroform layer is dried over sodium sulfate, and the chloroform is evaporated to give crude crystals. The crude crystals are recrystallized from isopropanol to obtain 15.5 g (84.3%) of a title compound.