Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH3:18])[C:10]2[CH2:19][CH2:20][O:21][C:22]([CH2:25][C:26](O)=[O:27])([CH2:23][CH3:24])[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH3:18])[C:10]2[CH2:19][CH2:20][O:21][C:22]([CH2:25][CH2:26][OH:27])([CH2:23][CH3:24])[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cccc2c3c(n(Cc4ccccc4)c12)C(CC)(CC(=O)O)OCC3
Solvent: C1CCOC1
Product: CCc1cccc2c3c(n(Cc4ccccc4)c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of (9-benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.45 g, 1.2 mmol) in tetrahydrofuran at room temperature was added 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran and it was stirred at 90° C. for 4 hours. The mixture was quenched with 5% HCl solution and stirred at room temperature for 20 minutes. It was extracted with ethyl acetate and washed with saturated sodium bicarbonate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.321 g (74%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.17 (m, 3H), 6.94 (d, 1H), 6.84 (m, 2H), 6.70 (t, 1H), 6.56 (d, 1H), 3.87 (m, 1H), 3.79 (m, 1H), 3.68 (dt, 1H), 3.64 (br, 1H), 3.41 (td, 1H), 2.93 (q, 2H), 2.43 (q, 2H), 2.04 (m, 1H), 1.93 (dt, 1H), 1.86 (m, 1H), 1.77 (m, 1H), 1.49 (m, 1H), 1.38 (m, 1H), 1.17 (t, 3H), 0.70 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>O1CCCC1.CN(C)C1C=CN=CC=1.O.Cl>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cnc(Cl)c(Br)c1
Reaction time: 16 h
Yield: 154.8 %

Procedure:
To a solution of 5-bromo-6-chloronicotinic acid (25.0 g, 106 mmol) in tetrahydrofuran (1.06 L) was added di-tort-butyl dicarbonate (69.2 g, 317 mmol) followed by 4-dimethylaminopyridine (12.9 g, 106 mmol). After 16 h, the mixture was diluted with water and aqueous hydrochloric acid was added (106 mL, 1 M, 106 mmol). The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine (3×), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→10% methanol/dichloromethane) gave the title compound (24.0 g). MS 292.96 (M).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([N:14]([CH2:19][CH:20]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:21][CH2:22]OS(C)(=O)=O)[CH2:15][CH2:16][O:17][CH3:18])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:36]1([C:42]23[CH2:49][CH2:48][N:45]([CH2:46][CH2:47]2)[CH2:44][CH2:43]3)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[Cl-:34].[Cl:35][C:30]1[CH:29]=[C:28]([CH:20]([CH2:19][N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:12](=[O:13])[CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[CH2:21][CH2:22][N+:45]23[CH2:48][CH2:49][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([CH2:43][CH2:44]2)[CH2:47][CH2:46]3)[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: COCCN(CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Reactant: c1ccc(C23CCN(CC2)CC3)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(CC(CC[N+]12CCC(c3ccccc3)(CC1)CC2)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Product: [Cl-]
Temperature: 80 °C

Procedure:
2 g of the product prepared in step 5 and 1 g of 4-phenylquinuclidine are dissolved in 2 ml of dimethylformamide and the reaction mixture is heated at 80° C. for 4 hours. After cooling, the reaction mixture is poured into water and then successively extracted with ethyl acetate, washed with a 5% solution of hydrochloric acid, with a saturated solution of NaCl, dried over Na2SO4 and concentrated under vacuum.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.O.[NH2:19][NH2:20]>CCO>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([C:4]2[C:3]([CH3:17])([CH3:16])[CH2:2][NH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: NN
Reactant: COc1ccc(C(=O)C(C)(C)CCl)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNCC2(C)C)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 3-chloro-1-(3,4-dimethoxy-phenyl)-2,2-dimethyl-propan-1-one (1.3 g, 5 mmol), EtOH (20 mL) and hydrazine monohydrate (0.3 mL, 6 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained: 1170 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 235 (M+H). Step 3
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[CH:10]([NH:12][O:13][CH3:14])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][CH:23]([F:33])[C:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]([CH3:32])[N:25]=1>ClCCl.O>[Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[CH:10]([N:12]([O:13][CH3:14])[C:29]([C:28]2[C:24]([CH:23]([F:33])[F:22])=[N:25][N:26]([CH3:32])[CH:27]=2)=[O:30])[CH3:11])=[CH:4][CH:3]=1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a stirred solution of trans N-{1-[2-(5-Chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.19 g; 0.83 mmol) prepared as described in example P18 and triethylamine (0.16 ml; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.16 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.31 g (97% of theory) of trans 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-methoxy-amide as a resin.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[NH:14][C:13](=[O:15])[O:12][C:10](=O)[C:9]=12)([O-:3])=[O:2].[NH:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1C(O)=O>CS(C)=O.C(O)C>[N+:1]([C:4]1[C:9]2[C:10](=[O:12])[N:16]3[CH2:23][CH2:22][CH2:21][C@H:17]3[C:13](=[O:15])[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCO
Product: O=C1Nc2cccc([N+](=O)[O-])c2C(=O)N2CCC[C@@H]12

Procedure:
10.6 g (50.9 mmol) of 6-nitroisatoic acid anhydride and 6.1 g (50.9 mmol) of L-proline in 70 ml of dimethyl sulphoxide are heated to 90° for 45 minutes, the mixture is subsequently evaporated in a high vacuum and the residue obtained is heated to 140° for 4 hours. The crystalline crude product is taken up in 100 ml of boiling ethanol, left to stand in the cold overnight, the material obtained is filtered off under suction while back-washing with cold ethanol and dried to constant weight. There is obtained (S)-1,2,3,11a-tetrahydro-6-nitro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which has a decomposition point of 235°-237°.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH2:2][CH3:3].[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC.O1CCCC1>[C:14]([O-:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:1]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][NH+:10]([CH3:11])[CH3:12])[CH2:2][CH3:3]
Reactant: O=C(O)c1ccccc1
Reactant: CCCOC(=O)NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCOC(=O)NCCC[NH+](C)C
Product: O=C([O-])c1ccccc1
Reaction time: 2 h

Procedure:
14.1 g (0.075 mole) of N-(dimethylaminopropyl)-carbamic acid propylester are dissolved in 200 ml of ether. While stirring, 9.15 g (0.075 mole) of benzoic acid in 30 ml of tetrahydrofurane are added in drops. Agitation is continued for 2 hours, the solvent is distilled, and the oil dried in vacuum. One obtains 23.1 g (99.4% of the theory) of nD20 = 1.5070.
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH:46]=[O:47])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[C:6]([NH:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([CH:46]([OH:47])[CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:14][CH:13]=1)=[O:19])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 25 mmoles of n-butyllithium in 10 ml of hexane is added dropwise to a solution of 3.19 g of N-tert-butyl 4-bromobenzamide in 250 ml of tetrahydrofuran at -70° under argon. After 30 min, a solution of 3.74 g of 3-(1-tritylimidazol-4-yl)propionaldehyde in 100 ml of tetrahydrofuran is added slowly. The reaction mixture is stirred at -70° for 30 min, allowed to warm to 25°, stirred at 25° for 2.5 h and quenched with excess saturated ammonium chloride solution. The aqueous layer is separated and extracted with methylene chloride (2×100 ml). The combined organic extracts are dried over sodium sulfate and evaporated. The residue is chromatographed on 220 g of silica with 5:1 ether:ethyl acetate to yield 4-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxyprop-1-yl]-1-tritylimidazole as an oil. IR (CH2Cl2): 1660 cm-1.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:34]([C:35]#[C:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:33][N:13]([C@@H:14]2[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])[CH2:15]2)[C:12](=[O:45])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([NH:9][C:10]1[C:34]([C:35]#[C:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:42])([F:41])[F:43])=[CH:33][N:13]([C@@H:14]2[O:32][C@H:22]([CH2:23][OH:24])[C@@H:16]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])[CH2:15]2)[C:12](=[O:45])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1OCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material (15) (140 mg, 0.22 mmol) was dissolved in THF (7.5 ml). TBAF (1M soln. in THF, 0.25 ml) was added slowly and stirred for 2 h at room temperature. Volatile material removed under reduced pressure to yield a brown gel that was purified by flash chromatography (EtOAc:DCM 7:3) to yield the desired product (16) as a light coloured crystalline solid (0.9 g, 76%). 1H NMR (d6 DMSO): δ2.16 (m, 1H, H-2′), 2.22 (m, 1H, H-2′), 3.70 (d, 1H, J=11.5 Hz, H-5′), 3.75 (d, 1H, J=11.3 Hz, H-5′), 4.01 (m, 1H, H-4′), 4.10 (m, 1H, CH2NH), 4.23 (m, 1H, H-3′), 4.76 (s, 2H, CH2S), 5.32 (s, 1H, 5′ OH), 5.99 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.81 (d, 1H, J=7.35 Hz, Ph), 7.95 (s, 1H, H-6), 9.78 (br s, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C22H20F3N7O6 535.44. found 534.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:11]#[N:12].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[Br:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10](=[N:9][O:8][CH3:7])[C:11]#[N:12]
Reactant: CON=C(C#N)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CON=C(C#N)c1ccccc1CBr
Reaction time: 8 h
Yield: 76 %

Procedure:
Benzene (80 ml) was added to (-methoxyimino-2-methylphenylacetonitrile (isomer A)(4.0 g, 23 mmol) and N-bromosuccinimide (4.9 g, 28 mmol), and the mixture was heated under reflux for 1 hour in the presence of 2,2'-azobis(isobutyronitrile) (190 mg, 1.2 mmol) as a radical initiator. After allowing the mixture to stand for cooling, n-hexane (100 ml) was added, and the mixture was allowed to stand overnight, and the resulting insoluble materials were filtered off. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-bromomethyl-α-methoxyiminophenyl-acetonitrile (4.4 g, 76%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N+:19]([O-])=[N:18][C:17]2=[O:28])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.O.[Zn]>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N:19]=[N:18][C:17]2=[O:28])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)nnc3ccc(Cl)cc32)CC1
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of tert-butyl{1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 206) (0.43 g) in acetic acid (8 mL) and water (2 mL) was added zinc dust (0.50 g). After 30 minutes, the solution was filtered and the filtrate concentrated. The residue was then treated with potassium ferricyanide (1.0 g) in water (20 mL). After 2 hours, the reaction was diluted with ethyl acetate. The aqueous layer was collected, the pH adjusted with solid Na2CO3 and extracted with ethyl acetate. The combined organic washes were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel with 0-25% acetone in dichloromethane to yield 66 mg of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:22][CH:23]([CH3:28])[CH2:24][C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][CH:23]([CH3:28])[CH2:24][C:25]([NH:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:26]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)NCC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (3S,4S)-1-amino-3-hydroxy-4-t-butyloxycarbonylamino-5-cyclohexylpentane (30.8 mg, 0.102 mmol) in dry methylene chloride (3 mL) at 0° C. was added 3-methyl-butyroyl chloride (0.123 mmol) and triethylamine (20.0 microliters, 0.143 mmol). The mixture was stirred at 0° C. for 1 hour, evaporated, taken up in methanol (3 mL) and treated with 1M NaOH (1 mL). After stirring for 1 hour, the mixture was diluted with ether, washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution, and brine, and then dried over Na2SO4 and evaporated to afford the desired product.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6](O)[CH2:5][CH2:4]1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.Cl.C(=O)([O-])[O-:18].[K+].[K+]>>[Br:1][CH2:2][C:3]1([O:18][CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1=COCCC1
Reactant: OC1CCC(CBr)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: BrCC1(OC2CCCCO2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromomethylcyclohexanol (C-5) (3.0 g) and dihydropyran (2.6 g) were mixed together and cooled with ice. A tiny drop of 10% hydrochloric acid was added. Exothermic reaction occurred and stirred at ambient temperature overnight. The solution was neutralized with potassium carbonate and extracted with dichloromethane (50 ml). It was filtered and then dichloromethane from the filtrate was evaporated to yield the compound C-6, tetrahydropyranyl bromomethyl-cyclohexyl ether (5.0 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.C(Cl)Cl.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:11]2[N:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2)ncn1

Procedure:
A solution of 2-methoxy-N-(6-(4-nitrophenoxy)pyrimidin-4-yl)acetamide (730 mg, 2.53 mmol) in a mixture of MeOH and DCM (1:1 v/v, 80 mL) containing AcOH (5 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 10% Pt/C, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (100 mL) and saturated aq NaHCO3 solution (25 mL). The organic layer was separated and washed with brine (25 mL) and then dried (MgSO4). Evaporation of the volatiles in vacuo gave the title compound, Intermediate N1, (560 mg, 66%, estimated 82% purity); Rt 0.93 min (Method 2); m/z 275 (M+H)+ (ES+). This material was used directly in the next step without further purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20](=[S:22])=[S:21].[CH3:23]O>>[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[S:22])[S:21][CH3:23])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=C=S
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: CSC(=S)NCCCN1CCN(Cc2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a solution of potassium hydroxide (1.3 g) in methanol (9 ml) was added 3-(4-benzyl-1-piperazinyl)propylamine (4.9 g) and thereto was added carbon disulfide (1.8 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 4 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (20 ml) and washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.0 g) with stirring under ice-cooling over a period of 10 minutes. The resulting mixture was stirred for 4 hours under ice-cooling. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate and the evaporated under reduced pressure to give an oil of methyl N-[3-(4-benzyl-1-piperazinyl)propyl]dithiocarbamate (4.6 g).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11](O[C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[NH3:16]>O>[CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:16][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1
Reactant: N
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Solvent: O
Product: O=C1NC(=O)c2cccc3cccc1c23
Temperature: 70 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
1,8-naphthalic anhydride (50.00 g, 0.252 mol, 1.0 eq), 32.8 ml of 29% aqueous ammonia (29.52% g, or 8.56 g dry, 0.504 mol, 2.0 eq) and water (115 g) were mixed to form a yellow slurry. The yellow slurry was heated with stirring to 70° C. then held at that temperature for 90 minutes for a total heating time of about 2 hours. After the heating period, the mixture was cooled to room temperature and filtered. The product was then washed with 500 to 600 ml of water until the pH of the wash water was neutral (pH 7). The product (i.e. 1,8-naphthalimide) was isolated as a wet filtercake (59.67 g, dry content=82.28%, representing 49.10 g of dry 1,8-naphthalimide, 99% yield), which was suitable for converting to 3, 4, 9, 10-perylenetetracarboxylic diimide. The purity of 1,8-naphthalimide was above 99% as determined by Gas Chromatography with a melting point of about 301-303° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1.Cl[CH2:21][CH2:22][N:23]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[CH2:24][CH2:25]Cl>>[CH2:18]([O:17][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[CH2:25][CH2:24][N:23]([C:27]4[CH:36]=[CH:35][C:30]5[O:31][CH2:32][CH2:33][O:34][C:29]=5[CH:28]=4)[CH2:22][CH2:21]3)[CH:7]=[N:8][C:9]=2[CH:14]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1ccc2c(c1)ncn2CCCCN
Reactant: ClCCN(CCCl)c1ccc2c(c1)OCCO2
Product: CCOC(=O)c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1

Procedure:
Analogously to Example 3, reaction of 1-(4-aminobutyl)-5-ethoxycarbonylbenzimidazole with 6-(N,N-bis(2-chloroethyl)amino)-1,4-benzodioxane ("B") gives 6-[4(4-(5-ethoxycarbonylbenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:20]=[CH:19]C(F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:31]>CN(C=O)C.CCOCC.CO>[ClH:31].[Br:14][C:15]1[CH:20]=[CH:19][C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCNCC1
Yield: 99 %

Procedure:
Using similar reaction conditions as described in (step i of Intermediate-2), tert-butyl piperazine-1-carboxylate (1.5 g, 6.81 mmol) was reacted with 4-bromo-1-fluoro-2-nitrobenzene (1.28 g, 6.81 mmol) in DMF (25 ml) and potassium carbonate (2.35 g, 17.02 mmol) to afford crude product. Using similar reaction conditions as described in Step-ii of example-7, above crude was deprotected in HCl in ether/methanol (10/10 ml). This afforded 2.0 g (99% yield).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27](O)=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:39][NH2:40]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.ClCCl>[CH3:39][NH:40][C:27]([C:22]1[C:21]2[C:20]3[C:19](=[C:32]([CH3:33])[O:31][N:30]=3)[C:18](=[O:34])[N:17]([CH:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:12]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Reactant: CN
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNC(=O)c1cccc2c1c1noc(C)c1c(=O)n2C1CCCC(CNC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of Example 598 (0.05 g, 0.11 mmol) in toluene (1.5 ml) under N2 was added thionyl chloride (0.5 ml) and heated at reflux for 3 h. The solution was concentrated using toluene to azeotrope. The residue was dissolved in dichloromethane (2 ml) under N2 and added methylamine (0.55 ml, 1.1 mmol) and DMAP (0.025 g, 0.22 mmol). The reaction was stirred overnight, diluted with dichloromethane, washed (0.1 N HCl, H2O, and brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, acetone/CH2Cl2 gradient) gave the title compound (0.029 g, 56%). MS(ES+) (m/z) 473.2 [M+1].