Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=4)=[N:16][N:17]([CH3:19])[CH:18]=3)=[O:12])=[C:4]2[N:3]=1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:26][C:22]1[CH:21]=[C:20]([C:15]2[C:14]([NH:13][C:11]([C:10]3[CH:9]=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH:31][CH2:30][CH:27]5[CH2:29][CH2:28]5)=[N:3][C:4]=34)=[O:12])=[CH:18][N:17]([CH3:19])[N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: NCC1CC1
Reactant: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cccc(Cl)c2)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2cnn3ccc(NCC4CC4)nc23)c(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of the above crude 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, cyclopropylmethylamine (0.1 mL, 1.0 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in ethanol (5 mL) was heated at 120° C. by microwave irradiation. After 30 minutes, the reaction mixture was concentrated to dryness, and the resultant crude product was purified by reverse phase HPLC and lyophilized to give 95.7 mg (64%) of N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)-5-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=422.1; 1H NMR (500 MHz, DMSO) δ 9.62 (s, 1H), 8.58 (d, J=7.6, 1H), 8.20 (s, 1H), 8.14 (s, 2H), 7.75-7.59 (m, 2H), 7.46 (t, J=7.8, 1H), 7.42-7.34 (m, 1H), 6.41 (d, J=7.6, 1H), 3.90 (s, 3H), 2.62-2.54 (m, 2H), 0.76 (s, 1H), 0.38-0.24 (m, 2H), −0.14 (m, 2H).
Reaction SMILES: O.[CH2:2]([SH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[CH2:2]([S:10][CH2:14][CH2:13][CH2:12][C:11]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCS
Reactant: O=C1CCCO1
Solvent: CCO
Solvent: O
Product: CCCCCCCCSCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An apparatus was provided including a two liter, 4-neck, round bottom flask equipped with an alcohol thermometer, an overhead mechanical stirrer, a water-cooled condenser and a nitrogen purge. Into this reactor gradually were added 23 g of sodium into 1,200 ml of absolute ethanol previously added. After all of the sodium had reacted the solution was stirred overnight under a slow nitrogen flow. 1-octanethiol, 146.28 g, was added to the mixture and an addition funnel and heating mantel were added to the reactor. In 200 ml of ethanol, 129.13 g of butyrolactone was added dropwise to the ethanol solution at reflux temperature. The resulting mixture was heated at reflux overnight. The ethanol was then removed from the reaction mixture and the residue was dissolved in water. The aqueous solution was washed with methylene chloride. The aqueous solution was then added to an ice/sulfuric acid mixture and the product extracted with methylene chloride. The methylene chloride solution was washed with water, dried with sodium sulfate, filtered and concentrated under vacuum with heating. The liquid product solidified upon cooling to room temperature. There was provided 219 g of 4-(n-octylthio)butyric acid. The solid exhibited a melting point of 33°-34.5° C.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[N+:39]([CH3:42])([O-:41])=[O:40]>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH2:42][N+:39]([O-:41])=[O:40])[CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:26])=[CH:21][CH:22]=2)=[CH:37][CH:38]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(COC(=O)/C=C/c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Product: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1,1,3,3-tetramethylguanidine (0.31 mL, 2.48 mmol) was added to 76.2 (5 g, 12.4 mmol) in nitromethane (20 mL). The mixture was stirred at room temperature for 3 hours, at 50° C. for 3 hours, and at 100° C. for 8 hours. Nitromethane was removed under vacuum and the crude product was purified by flash chromatography to give 76.3 (4.5 g). MS ESI (pos.) m/e: 466 (M+H). 1HNMR (CDCl3) δ 7.37 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 6.92 (m, 6H), 5.01 (s, 2H), 4.97 (s, 2H), 4.68 (m, 1H), 4.59 (m, 1H), 3.96 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.77 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15]Cl)[CH:7]=[C:6]2[CH:17]=[O:18].[I-:19].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][I:19])[CH:7]=[C:6]2[CH:17]=[O:18]
Reactant: [I-]
Reactant: COc1ccc2c(c1)c(C=O)cn2CCCCCl
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)c(C=O)cn2CCCCI
Temperature: 25 °C

Procedure:
A stirred solution of 5-methoxy-1-(4-chlorobutyl)indole-3-carboxaldehyde and sodium iodide in acetonitrile under argon is heated under reflux for 18 h, cooled to room temperature and partitioned between ether and water. The combined organic extracts are washed (aqueous sodium metabisulfite solution, water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=3)[N:15]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][O:38][CH3:39]>>[CH3:39][O:38][N:37]([CH3:36])[C:22]([C:19]1[CH:20]=[C:21]2[C:11]3([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]3)[CH2:14][N:15]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C:16]2=[CH:17][CH:18]=1)=[O:24]
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C(=O)O)ccc43)c21
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2

Procedure:
(R)-tert-butyl 5-(methoxy(methyl)carbamoyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 10, Step 5, substituting (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid with (R)-1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid, and substituting NH4Cl with N,O-dimethylhydroxylamine hydrochloride. LCMS (APCI+) m/z 508.3 [M+H]+; Rt=3.56 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6](O)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[CH3:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6]([Cl:19])[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1
Reactant: Cc1nc2ncnn2c(O)c1C1CCCC1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2ncnn2c(Cl)c1C1CCCC1

Procedure:
A mixture of 5-methyl-6-cyclopentyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyrimidine (17 g, Ex. 2) and POCl3 (50 ml) was heated under reflux for 8 hours. During this operation, some of the POCl3 was distilled off. The residue was poured into a mixture of dichloromethane and water. The organic phase was separated off and dried. Removal of the solvent gave 11 g of the title compound of m.p. 87° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1CCc2c(OC[C@@H](O)CNC3CCN(c4ccc(CC5SC(=O)NC5=O)cc4)CC3)ccc(O)c2N1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (S)-5-(3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one) (which was obtained in Example 12) according to the procedure of Example 73 as a pale yellowish solid; mp>140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.55 (m, 2 H), 1.85–2.00 (m, 2 H), 2.40 (t, J=8.0 Hz, 2 H), 2.60–3.00 (m, 8 H), 3.25 (dd, J=15.9, 3.9 Hz, 1 H), 3.50–3.70 (m, 2 H), 3.80–4.00 (m, 3 H), 4.50 (dd, J=9.7, 3.9 Hz, 1 H), 6.34 (d, J=8.9 Hz, 1 H), 6.61 (d, J=8.9 Hz, 1 H), 6.85 (d, J=8.6 Hz, 2 H), 7.05 (d, J=8.6 Hz, 2 H), 8.76 (s, 1 H), 9.24 (brs, 1 H); MS (ES) m/z: 541.1 (MH+); HRMS Calcd. for C27H33N4N4O6S (MH+): 541.2121. Found: 541.2148.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27]([O:29]CC)=O)[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[NH3:32]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27](=[O:29])[NH2:32])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CCOC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1

Procedure:
The thus-obtained compound (A) is dissolved in a saturated methanol solution of ammonia, and the resultant solution is left to stand, thereby reacting the compound and ammonia to obtain 1-(2,4-difluorophenyl)-1-(4-(4-carbamoylthiazol-2-yl)-thiophen-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (B).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=[O:21])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol produced in Example XV in dry CH2Cl2 at 0 degree C. there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine solution, dried over Na2SO4, and concentrated in vacuo to a yellow oil. Purification by SiO2 column chromatography yielded the p-toluenesulfonate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:11]#[N:12].[OH-:19].[Na+]>S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:14]=[CH:15][CH:16]=[CH:17][N:18]=1)[C:11]([NH2:12])=[O:19]
Reactant: [OH-]
Reactant: N#CC(=C1Nc2ccccc2S1)c1ncccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(=C1Nc2ccccc2S1)c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile (0.1 g, 0.39 mmol) was dissolved in concentrated sulfuric acid (2 mL) and stirred at room temperature for 5 hr. The mixture was cooled to 0° C., poured over ice, and neutralized with 50% aqueous sodium hydroxide. The precipitate that formed was collected by filtration and purified by reverse phase preparative HPLC to give 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide (42 mg, 40% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](=[NH:18])(OCC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.CO>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[NH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(NCC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A white suspension of glycine (3.81 g, 50 mmol) in water (0.9 g) and methanol (16 ml) was stirred at room temperature, adjusted to pH 9.6 by the addition of sodium hydroxide solution and admixed with ethyl benzimidate (7.69 g, 50 mmol). The mixture was heated for 1 hour at 50° C. and allowed to cool at room temperature. The solid was filtered off, washed with toluene and dried at room temperature/30 mbar. The yield of the title compound was 6.81 g (approximately 95 percent pure by H-NMR), 74 percent based on glycine. Other data concerning the title compound was:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Yield: 94.6 %

Procedure:
To a solution of 1-benzyl-3-(4′-ethoxycarbonylphenyl)indazole (1 g, 2.8 mmole) dissolved in 10 mL methanol was added a sodium hydroxide solution (0.56 g in 20 mL water). After the mixture was heated under reflux for 6 hours, the methanol was removed by evaporation. The residue thus obtained was acidified with diluted HCl. After cooling in an ice bath, a solid precipitated and was collected to obtain 0.87 g 1-benzyl-3-(4′-hydroxycarbonyl-phenyl)-indazole in a yield of 94.5%.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[N:21]=3)=[O:19])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].CCO.Cl.[OH-].[Na+]>O>[NH:24]1[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:17][CH:16]=1)=[O:19]
Reactant: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)c2ncccc21

Procedure:
A mixture of [4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl](1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)methanone obtained, EtOH (5 mL), and 6 M HCl aqueous solution (5 mL) was refluxed for 2 h. The reaction mixture was poured into water, alkalized with 1 M NaOH aqueous solution, and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from THF to give the title compound (285 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79.3 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1.[OH:18]OS([O-])=O.[K+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])(=[O:18])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)=O)n2)[nH]n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidin-4-amine (8 g, 31.2 mmol) in methanol (200 ml) at 0° C. was added a suspension of Oxone (44 g, 71.7 mmol) in water (100 ml) portionwise over 10 minutes. The mixture was stirred for 30 minutes at 0° C. then warmed to ambient and stirred for an additional 2 hours. The reaction mixture was filtered and the resulting solid slurried in aqueous sodium bicarbonate. The mixture was filtered and the solid washed with water, then diethyl ether. The solid was slurried in ethyl acetate, filtered and dried. This gave the title product as an off-white solid (7.9 g, 88%); 1H NMR (d6-DMSO) δ 2.24 (3H, s), 3.35 (3H, s), 5.85 (0.5H, brs), 6.50 (0.5H, brs), 6.95 (0.5H, brs), 8.00 (0.5H, brs), 10.95 (1H, s), 12.28 (1H, s); MS ES+288.07, ES−286.25.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>C1CCCCC1>[CH2:2]([C:3](=[N:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:1]
Reactant: CCCCCCC(=O)CC
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCCCC1
Product: CCCCCCC(CC)=NNC(=O)OC(C)(C)C

Procedure:
16.42 g (115 mmol) of 3-nonanone and 15.26 g (115.4 mmol) of tert-butyl carbazate are refluxed for 3 hours in 200 ml of cyclohexane. The solvent is removed in vacuo. This gives 30.54 g (product contains water) of a white solid, Rf=0.49 (cyclohexane/ethyl acetate=3:1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3([C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])=[O:48])[CH2:46][CH2:45]3)=[CH:40][CH:39]=2)O1>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([C:38]3[CH:39]=[CH:40][C:41]([C:44]4([C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])=[O:48])[CH2:46][CH2:45]4)=[CH:42][CH:43]=3)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCOCC3)CC2)n1
Yield: 97 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (from Example 3) (0.536 g, 1 mmol) and morpholine (10 mL) in THF (150 mL) was heated under reflux for 2 hrs. The solvent was removed under vacuum and the residue was diluted with water to give 0.605 g (97% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: 1H NMR (CDCl3) δ 7.86 (d, J=7.9 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.00 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.37 (m, 4H) 3.39 (m, 4H), 3.14 (dd, J=8.3, 6.4 Hz, 2H), 2.84 (dd, J=8.3, 6.3 Hz, 2H), 2.48 (m, 4H).
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:14]>C1(C)C=CC=CC=1.O>[C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: C[C@@H](CC#N)Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](CC(N)=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-phenylamino-butyronitrile (6.06 g, 0.0378 mol) in toluene (150 mL) was added a cooled solution of conc. sulfuric acid in H2O (20.12 mL H2SO4/3 mL)—(The ratio of toluene to acid/H2O is very important and should be followed strictly). Stir the biphasic mixture at room temperature for 0.5 h and warm to 35° C. and stir for 22 h. The reaction was cooled to room temperature and quenched with 13 g of Na2CO3 in water (add slowly some foaming). Separate the organic and extract 2×EtOAc. Combine all the organics and wash the organics with brine, dry over MgSO4, filter and concentrate to give the desired product in 2.11 g (90%)
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([C:25]1[S:26][C:27]([O:30][CH2:31][CH3:32])=[N:28][N:29]=1)[CH3:24]>CC(C)=O>[CH2:31]([O:30][C:27]1[S:26][C:25]([CH:23]([O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH3:24])=[N:29][N:28]=1)[CH3:32]
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CCOc1nnc(C(C)Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccc(C)cc3)cc2)s1
Yield: 73.6 %

Procedure:
0.84 g of 4-(4-methylphenoxy)phenol was dissolved in 5 ml of acetone followed by adding 0.87 g of anhydrous potassium carbonate and 1.0 g of 2-(1-bromoethyl)-5-ethoxy-1,3,4-thiadiazole. The resulting mixture was refluxed with stirring and heating for 2 hours. After cooling, insoluble salts were filtered off, and acetone was distilled off under reduced pressure. The residue was purified by chromatography on silica gel to obtain 1.1 g of the compound No. 10 described in Table 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:13][CH3:12])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc2cc[nH]c12
Reaction time: 3 h
Yield: 88.9 %

Procedure:
Indole-7-carbaldehyde (500 mg, 3.4 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (5.1 mL of 2M solution in methanol, 9.55 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (10 mL). Sodium borohydride (131 mg, 3.45 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the indole was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the tide compound as a yellow oil (484 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.29-7.17 (m, 2H), 7.04 (d, J=3.1 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 3.84 (s, 2H), 2.46 (s, 3H).