Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:25]([NH:27][O:28][P:29]([CH3:32])(=[O:31])[OH:30])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:25]([NH:27][O:28][P:29]([CH3:32])(=[O:30])[OH:31])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NOP(C)(=O)O
Solvent: NCc1ccccc1
Product: CC(C)C[C@H](N)C(=O)NOP(C)(=O)O

Procedure:
In a manner analogous to Example 1(b), starting from the benzylamine salt of [(N-benzyloxycarbonyl-L-leucyl)amino]-methylphosphonic acid there was obtained (L-leucylamino)-methylphosphonic acid of melting point 262°-264° C (decomposition); [α]D20 = +59.7° (c = 0.67% in water).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCO.[Pd]>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH2:8])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCCCN1CCCC1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccncc1NCCCN1CCCC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1.300 g (5.940 mmol) 3-bromo-4-nitro-pyridine-1-oxide and 0.980 g (7.430 mmol) 3-pyrrolidin-1-yl-propylamine was added to a suspension of 0.820 g (5.940 mmol) potassium carbonate in 20 mL DMF and the mixture was stirred for 3 hours at 90° C. The solvent was evaporated i. vac. and the residue purified by column chromatography (Alox (neutral, activity II-III), gradient dichloromethane/MeOH 100:0→95:5 v/v) (0.950 g, 60% of theory). 0.900 g (3.380 mmol) of the intermediate product was added to a suspension of 300 mg Pd/C in 10 mL EtOH and the mixture was hydrogenated for 4.5 hours at RT and 50 psi H2-pressure. The catalyst was removed by filtration and the filtrate evaporated i. vac. The product is present in admixture with the corresponding pyridine-N-oxide and was used in the next reaction step without any further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Brc1ncccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromopyrimidine
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[C:22]3[CH2:30][CH2:29][NH:28][CH2:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:11]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:32][N:28]2[CH2:29][CH2:30][C:22]3[C:21]([NH:20][C:12]4[CH:11]=[N:10][C:19]5[C:14]([CH:13]=4)=[CH:15][CH:16]=[CH:17][CH:18]=5)=[N:26][CH:25]=[N:24][C:23]=3[CH2:27]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: c1ccc2ncc(Nc3ncnc4c3CCNC4)cc2c1
Reactant: BrCC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc2ncc(Nc3ncnc4c3CCN(CC3CCCCC3)C4)cc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 9.4 %

Procedure:
Diisopropylethyl amine(258 mg, 2 mmol) was added to the solution of 5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine (55 mg, 0.2 mmol) and (bromomethyl)cyclohexane (177 mg, 1 mmol) in ethanol (2 ML) and stirred at 80° C. for 48 h. Solvent was removed in vacuo, and the residue was purified by column chromatography to yield the product as a light orange powder (7 mg, 9.5%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2ccccc2C1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCc2ccccc2C1
Temperature: 60 °C

Procedure:
6.5 mmol (1.15 g) 1,2,3,4-Tetrahydro-naphthalene-2-carboxylic acid is dissolved in 20 mL toluene, 20 mL of thionylchloride are added, the mixture is heated to 60° C. in an oil bath for 2 hours. Then the mixture is concentrated in vacuum. Toluene is added to the residue and evaporated again. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O[N:38]=[C:39]([C:41]1[C:42]([CH3:59])=[N:43][C:44]([CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)=[CH:45][CH:46]=1)[NH2:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:40]=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([CH2:47][OH:48])=[N:43][C:42]=3[CH3:59])[N:38]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO
Reactant: CC(C)Cc1ccc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1
Yield: 89 %

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 3-chloro-4-isobutylbenzoic acid (0.11 g, 0.50 mmol) that was obtained in Example 24 (24h), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.53 mmol), N′-hydroxy-2-methyl-6-{[(triisopropylsilyl)oxy]methyl}pyridine-3-carboximidamide (0.16 g, 0.48 mmol) that was obtained in Example 24 (24d), and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.96 ml, 0.96 mmol). Subsequently, the crude product of the tile compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.15 g) in a yield of 89% as a crystalline white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([NH2:28])(=[O:30])=[O:29])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J.Indian Chem.Soc.; 16; 1939; 100, 106) (42%, white solid), MS (m/e): 438.1 (M−H, 100%)
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([CH3:30])=[C:7]([P:23]2(=[O:29])[O:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:9]=1[C:10]([O:12][CH3:13])=[O:11].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:3]([C:4]1[NH:5][C:6]([CH3:30])=[C:7]([P:23]2(=[O:29])[O:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)C1=C(C(OC)OC)NC(C)=C(P2(=O)OCCCO2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C=O)NC(C)=C(P2(=O)OCCCO2)C1c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Dimethylacetal (3.04 g) obtained in Example 1 was dissolved in 30 ml of acetone, 2 ml of 6N hydrochloric acid was dropped therein with ice cooling and stirring, and the mixture was kept at 5° C. in a refrigerator for 4 days. To the reaction solution was added 30 ml of ice water, the mixture was neutralized with sodium bicarbonate, concentrated in vacuo at room temperature, the residual solution was extracted with chloroform, the chloroform layer was washed with sodium chloride solution, evaporated to dryness, the residue was purified by subjecting to a flash column chromatography, and the 1.38 g of resulting crude crystals were recrystallized from etherethyl acetate to give yellow prisms. M.p. 135°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]1[O:8][C@@H:7]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:18])[C@H:6]([OH:19])[C@@H:5]1[NH2:20].[C:22]([O:26][C:27]([NH:29][CH:30]([C:39](O)=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.O>[NH2:18][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[C:15]=1[N:16]=[CH:17][N:9]2[C@@H:7]1[O:8][C@H:4]([C:3]([O:2][CH3:1])=[O:21])[C@@H:5]([NH:20][C:39](=[O:40])[CH:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C@H:6]1[OH:19]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of methyl-1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (294 mg) prepared in Example 62, N-tert-butoxycarbonyl-β-(4-chlorophenyl)-D,L-alanine (300 mg) and N,N'-dicyclohexylcarbodiimide (206 mg) in tetrahydrofuran (15 ml) and water (5 ml) was stirred overnight. The mixture was diluted with water (50 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness. The residue was subjected to column chromatography on silica gel. The elution was carried out with a mixed solvent (chloroform/methanol=97/3). The eluate was evaporated to dryness to give methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (203 mg), mp. 120°-125° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:32]([N:34]([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:22][CH:23]=1)[CH2:35][CH3:36])[CH3:33]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCN(CC)Cc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added diethylamine (36 μL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 37.6 mg of the title compound (67%).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:13][C:12]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:11]=3[NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.ClC(Cl)(Cl)C(O)=O.ClC(Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.C([SiH](CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[NH:29]1[CH:33]=[C:32]([CH2:34][N:10]2[C:11]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:12]=3[CH2:13][N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[C@H:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[N:31]=[CH:30]1
Reactant: O=Cc1c[nH]cn1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2
Agent: CC[SiH](CC)CC
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
In a 500 mL flask was charged (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile (20.0 g, 1 eq.), imidazole-4-carboxaldehyde (5.2 g, 1.1 eq.), and CH2Cl2 (80 mL) at room temperature. Cool to 0-5° C. Add trichloroacetic acid (32 g, 4 eq.) and trichloroacetic acid anhydride (12.2 mL, 1.36 eq.) while keeping the temperature below 20° C. Stir the mixture for 30 min at 0-5° C. Add Triethylsilane (11.6 mL, 1.5 eq.). Agitate the mixture at 20-25° C. for 26 h until the reaction is complete. Add CH2Cl2 (80 mL), then cool to 0° C. Adjust the pH to 8-9 with 10% NaOH. Separate the two phases. Wash the organic phase with H2O (50 mL). Remove most of the solvents, and add EtOH (150 mL); and heat up to reflux and stir at reflux for 10 min. Cool to room temperature in a period of 60 min. Crystals appeared at 65° C. Stir at room temperature for 2 h. Filter and wash the crystals with EtOH (150 mL). Dry at 40° C. in vacuum oven over night to give the product (20.4 g, 85% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH3:20])[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].[CH3:22]I>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH3:20])[CH:19]=[C:13]4[N:12]([CH3:22])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CI
Reactant: CCn1ncc2c3[nH]c4cc(C)nn4c(=O)c3cnc21
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n3nc(C)cc3n(C)c12
Reaction time: 12 h

Procedure:
8.05 g. of 3-ethyl-3,11-dihydro-9-methyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one (0.03 mol.) are refluxed with stirring in 100 ml. of diethyleneglycol dimethylether together with 0.9 g. of sodium (0.04 mol.) for 2 hours. After this time, 14.2 g. of methyl iodide (0.1 mol.) are added and heating is continued for 12 hours. The solvent is removed in vacuo and the residue crystallized with methanol, filtered and washed with water to obtain 3-ethyl-3,11-dihydro-9,11-dimethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]-pyrimidin-6-one, yield 5.2 g. (61%), m.p. 306°-307° (methanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O)=CC=1>CN(C)C=O>[F:28][C:27]([F:30])([F:29])[CH2:26][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Combine 3-hydroxybenzaldehyde (134.3 g), potassium carbonate (304.0 g), 2,2,2-trifluoroethyl p-toluenesulfonate (293.6 g) and dimethylformamide (2 L). Heat the mixture at 90° C. After 15 hours, cool to room temperature, pour on ice-water, and extract with dichloromethane. Combine the organic layers, wash with 1N sodium hydroxide, and then with water. Dry the organic phase over magnesium sulfate, filter, and concentrate to a residue. Dissolve residue in toluene (200 ml), Chromatograph on silica gel eluting sequentially with toluene and then ethyl acetate to give a residue. Distill the reside under reduced pressure using a Claisen flask equipped with a Vigreux column gives title compound: bp 0.8 mm Hg, 84-85° C. Redistilling some fractions using a Claisen flask equipped with a Vigreux column and subsequently an adiabatic column filled with Rasching rings gives title compound: bp 0.9-1.0 mm Hg, 74-76° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=4)[N:12]([CH3:31])[C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(Cl)cc4c3c2C1=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN1C(=O)c2ccc3c(c2C1=O)c1cc(Cl)ccc1n3C
Yield: 60 %

Procedure:
400 mg of N-(2-dimethylaminoethyl)-6-chlorocarbazole-3,4-dicarboximide, 50 mg of 60% sodium hydride and 150 mg of dimethyl sulfate were subjected to the same reaction as in Example 3 (1) to obtain 250 mg (yield: 60%) of N-(2-dimethylaminoethyl)-6-chloro-9-methylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:44][CH3:45])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH3:45][O:44][C:37]1[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 27 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 128 mg of [2-(7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:8]([O:10][CH2:11][CH2:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1)=[O:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.O.[Fe]>[C:30]([C:27]1[CH:26]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:28]=1[OH:29])[C:8]([O:10][CH2:11][CH2:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([NH2:23])[CH:17]=1)=[O:14])=[O:9])([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O
Reaction time: 3 h
Yield: 93 %

Procedure:
Iron metal powder (13.4 g, 0.24 mole) was added portionwise to a solution of the nitro compound (22.9 g, 0.048 mole) from (b) in acetic acid (110 ml) and water (10 ml), heated on a steam bath. Heating was continued for a further 3 hours, after which the suspension was filtered hot through kieselguhr. The filtrate was poured into a mixture of ice/water (1 liter) with rapid stirring and the precipitate was collected by filtration to give the product as a white solid (20 g, 93%). m.p. 122°-124° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([C:10]([CH2:17]Cl)=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][CH2:2][C:3]1[C:4]2[C:9]([C:10]([CH2:17][NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: ClCc1c2ccccc2c(CCl)c2ccccc12
Reactant: CN(C)CCN
Solvent: O
Product: CN(C)CCNCc1c2ccccc2c(CNCCN(C)C)c2ccccc12
Yield: 36.7 %

Procedure:
1.0 g (0.0036 mol) of 9,10-dichloromethylanthracene (0.0036 mol) is refluxed for 20 minutes with 15 g of 2-dimethylaminoethylamine. The reaction mixture is added to water and the precipitate collected by filtration. The dried solid is then recrystallised from ethyl acetate to yield 0.5 g of the title compound as yellow crystals, m.p. 58°-60° C.; λmax (distilled water) (E/cm/M) 248 nm (51760), 372 nm (9030), 392 nm (8305).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccsc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccsc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
To a solution of ethyl 2-(thiophen-3-yl)acetate (20.30 g, 119.25 mmol) in THF (150 mL) was added NBS (21.23 g, 119.25 mmol) during a period of 5 hours at 0° C., and then the mixture was warmed up to room temperature, stirring continuously for 24 hours. The solvent was removed in vacuo, and then the residue as dissolved in EtOAc (150 mL) and washed with brine (4×30 mL). The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave ethyl 2-(2-bromothiophen-3-yl)acetate as a colorless oil (24.00 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=5.4 Hz, 1H), 6.93 (d, J=5.4 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.61 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.37, 133.84, 128.90, 125.93, 111.78, 61.32, 35.30, and 14.43. To a solution of ethyl 2-(2-bromothiophen-3-yl)acetate (24.00 g, 96.32 mmol) and 4-iodo-3-nitrobenzoyl chloride (30.00 g, 96.32 mmol) in anhydrous CH2Cl2 (100 mL) was added AlCl3 (38.53 g, 288.96 mmol) over a period of 4 hours at room temperature. The resulting mixture was stirred for 2 days. The reaction mixture was slowly poured onto 200 g of ice and allowed to warm to room temperature. The aqueous phase was extracted with Et2O (4×30 mL), and the combined organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification of (Hex:EtOAc/4:1) of the residue gave 2 as a light yellow solid (20.00 g, 40%). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.69 (dd, J=2.0, 8.2 Hz, 1H), 7.48 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), and 1.28 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 183.84, 169.61, 153.25, 142.83, 141.87, 138.32, 136.49, 135.94, 133.07, 125.69, 124.50, 91.79, 61.76, 35.20, and 14.42.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[CH3:40][O:41]C1C(OC)=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:39][O:38][C:4]1[C:3]([O:41][CH3:40])=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:32]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1cccc(OC)c1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 2,3-dimethoxyphenylboronic acid (CAS RN 28611-39-4) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow solid (79%). MS (ESI): m/z=245.128 [M+H]+.