Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: NC1CCc2c(Br)cncc21
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Yield: 94 %

Procedure:
In analogy to the procedure described for the preparation of example 4, (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (intermediate A-3 [C]) and ethanesulfonyl chloride gave the title compound as a grey solid in 94% yield. MS: 304.99 (M+H+, 1Br).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:14])=[O:13]>C([O-])(O)=O.[Na+].ClCCl.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([CH3:11])(=[O:14])=[O:13])(=[O:23])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
A mixture of orcinol monohydrate (1.68 g, 12 mmol) and 2-methylsulfonylbenzenesulfonyl chloride (3.0 g, 11.8 mmol) in saturated aqueous NaHCO3 (25 mL) and dichloromethane (25 mL) was stirred vigorously at room temperature for one week. The reaction mixture was diluted with 50 mL of water and extracted into dichloromethane (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was treated with dichloromethane and ether to initiate crystallization. The mixture was filtered to provide 1.05 g of a white solid. 1H-NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 3.45 (s, 3H), 5.20 (s, 1H), 6.51 (t, 1H), 6.54 (s, 1H), 6.61 (s, 1H), 7.74 (td, 1H, J=1.4, 7.7 Hz), 7.87 (td, 1H, J=1.3, 7.7 Hz), 8.12 (dd, 1H, J=0.66, 7.8 Hz), and 8.44 (dd, 1H, J 0.52, 7.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][O:29][CH2:30]Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:28][O:29][CH3:30])[C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccc(Cl)cc2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A solution (0.20 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF was treated at 0° C. with NaH (1.5 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 45 min then cooled again to 0° C., and treated with chloromethyl methyl ether (5 eq.). The reaction mixture was stirred at RT for 1.5 h then was cooled at 0° C. and quenched with aqueous NaHCO3 (saturated solution) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:9 acetone/toluene) to afford methyl 5-(4-chlorophenyl)-6-cyclohexyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (100%). This compound was dissolved in THF/MeOH (2:3), and the resulting solution (0.08 M) was treated at RT with aqueous NaOH (2N solution, 5 eq.). The mixture was heated at 85° C. for 1.5 h. After cooling down, the reaction mixture was concentrated and acidified to pH 1 with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent under reduced pressure afforded the title compound (96%) as a solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:20][CH3:21])[C:6](=[O:19])[C:7]1[C:12]([CH:13]=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:4]>C(O)C.CCOCC>[CH2:20]([N:5]([CH2:3][CH3:4])[C:6](=[O:19])[C:7]1[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:15]([CH3:17])([CH3:16])[CH3:18])[CH3:21]
Reactant: CCN(CC)C(=O)c1c(C=O)cccc1[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCN(CC)C(=O)c1c(CO)cccc1[Si](C)(C)C
Yield: 74 %

Procedure:
Sodium borohydride (1.0 g, 26.4 mmol) was added to a solution of N,N-diethyl-2-trimethylsilyl-6-formylbenzamide, prepared in Example 97, (5.54 g, 20 mmol) in absolute ethanol (100 mL). After 3 h the mixture was diluted with ether, extracted three times with brine, dried (MgSO4), concentrated, and recrystallized from 1:1 ethyl acetate/hexanes to afford 4.12 g of N,N-diethyl-2-trimethylsilyl-6-hydroxymethylbenzamide as a white solid, a 74% yield. m.p. 81-82.5° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(O)cc3)CC2)CC1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OC(C)=O)cc3)CC2)CC1

Procedure:
8 g of acetyl chloride is added to a solution of 30 g of trans-1-p-hydroxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane and 20 ml of pyridine in 300 ml of toluene and the mixture is warmed to 80° for 1 hour. After cooling and customary working up, trans-1-p-acetoxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane is obtained.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[NH:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)c2nc3ccccc3[nH]2)cc1
Temperature: 100 °C

Procedure:
A mixture of diphenylacetaldehyde (2-1, 1.64 mL, 9.25 mmol, 1 equiv), 1,2-diaminobenzene (0.787 mL, 9.25 mmol, 1.00 equiv) and sodium metabisulfite (2.11 g, 11.1 mmol, 1.20 equiv) in DMF (10 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to 23° C. and filtered. The filtrate was suspended with sonication in a 1:1 mixture of saturated aqueous sodium chloride solution and saturated aqueous sodium carbonate solution then extracted with ethyl acetate (6×150 mL). The combined organic layers were dried voer sodium sulfate and concentrated. The residue was suspended in ethyl ether (50 mL), filtered, washed with ethyl ether (2×50 mL) and air dried to give 2-(diphenylmethyl)-1H-benzimidazole (2-2) as a white solid. 1H NMR (300 MHz, DMSO) δ 12.3 (br s, 1H), 7.50 (m, 2H), 7.34 (m, 8H), 7.24 (m, 2H), 7.08 (m, 2H), 5.74 (s, 1H). LRMS m/z (M+H) 235.0 found, 335.1 required.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][N:25]([C:33](=[O:34])[CH2:32][C:30]#[N:31])[CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: N#CCC(=O)O
Reactant: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CCC2(CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a solution of 5-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine hydrochloride (270 mg, 0.6159 mmol) in a mixture of DCM and DMF (6 mL/2 mL) were added TEA (253.2 mg, 2.502 mmol), cyanoacetic acid (52.1 mg, 0.733 mmol), HOAT (124.8 mg, 0.9169 mmol) and EDCI (177.5 mg, 0.9259 mmol). The reaction mixture was stirred at rt for 1.5 h then quenched with water (30 mL), and extracted with DCM/MeOH (10/1, 80 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1). The crude product was recrystallized from MeOH (10 mL) to give the title compound as a white solid (106.6 mg, 36.91%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][NH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[F:37])[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:28]=1[CH3:45]>CCOC(C)=O>[F:37][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:36]=1[C:27]([N:12]1[C:11]3[CH:18]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=[CH:9][C:10]=3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1)=[C:28]([CH3:45])[C:29]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])=[N:30]2
Reactant: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl
Reactant: O=S1(=O)CCNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a N2 atmosphere, 6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide (0.0800 g, 0.298 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol). Sodium hydride (0.0143 g, 0.596 mmol) was added and the reaction was allowed to stir at rt for 10 minutes. 4-Chloro-5-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.0950 g, 0.328 mmol) was added and the reaction was heated to 140° C. for 2 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate, then brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase chromatography to afford 4-(5-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide. Mass Spectrum (ESI) m/e=522.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:30]([C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2ccc(Cl)s2)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
To a mixture of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.100 g, 0.3 mmol), 5-chlorothiophene-2-carboxylic acid (0.049 g, 0.3 mmol), and HATU (0.114 g, 0.3 mmol) in DMF (4 mL), DIEA (0.157 mL, 0.9 mmol) was added, then the reaction mixture stirred at room temperature overnight. The crude product was purified by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 333 as a brown solid in 15.1% yield. LCMS m/z (%)=481.2 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.41 (s, 1H), 9.95 (bs, 1H), 7.90-7.87 (m, 2H), 7.66 (s, 1H), 7.63 (d, J=2.6 Hz, 1H), 7.31-7.23 (m, 2H), 4.48-4.27 (m, 2H), 3.66 (s, 3H), 3.81-2.87 (m, 10H and water).
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:15][C:16]([CH3:19])=[N:17][N:18]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)(=O)C.O>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:15][C:16]([CH3:19])=[N:17][N:18]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(-c3nnc(C)o3)cc12
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(-c2cc3c(O)cccc3s2)o1
Temperature: 80 °C
Yield: 119 %

Procedure:
2-(4-(Methoxymethyloxy)benzo(b)thiophen-2-yl)-5-methyl-1,3,4-oxadiazole (1.4 g) was dissolved in a mixed solvent (10 ml) of acetic acid-water (1:1) and the mixture was heated at 80° C. for 4 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily compound (1.4 g).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>C(N(CC)CC)C.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Yield: 95.7 %

Procedure:
A solution of 1-(difluoromethoxy)-4-iodobenzene (12.7 g, 50 mmol) in triethylamine (175 mL) was treated with tetrakis(triphenylphosphine)palladium (4.0 g, 3.5 mmol), copper iodide (925 mg, 4.85 mmol), and a solution of ethynyl(trimethyl)silane (6.9 mL, 50 mmol) in acetonitrile at room temperature, stirred for 1 h at 60° C. and concentrated in vacuo. The resultant residue was dissolved in Et2O, filtered and the filtrated was concentrated in vacuo. This residue was purified by chromatography (silica gel, EtOAc/hexane:5/95) to give {[4-(difluoromethoxy)-phenyl]ethynyl}(trimethyl)silane (11.5 g, 96%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[C:19]([CH3:20])=[O:21]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)COc1ccc(Cl)cc1C(=O)O

Procedure:
To a solution of 5.16 g. (0.3 mole) of 5-chlorosalicylic acid in 60 ml. of ethanol and 40 ml. of water containing 1.2 g. (0.03 mole) of sodium hydroxide is added 2.8 g. (0.03 mole) of chloroacetone and the solution heated to reflux for 5 hours. The resulting solution is cooled in an ice bath and the precipitated product filtered, dried and recrystallized from ether, 800 mg., m.p. 90°-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:11][CH2:10]1.N[C:28](N)=[O:29].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:18](=[O:26])[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:28]2=[O:29])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2N)CC1
Reactant: NC(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Yield: 92.1 %

Procedure:
1-(2-Methoxyphenyl)-4-[2-(2-aminobenzoyl)aminoethyl]piperazine (3.54 g) and urea (1.2 g) were dissolved in dimethylformamide (20 ml) and the resulting solution was heated at an external temperature of 140° to 180° C. for 5 to 8 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture and the resulting crystal was filtered off. Upon recrystallization from dioxane, 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]2,4-(1H,3H)-quinazolinedione (3.5 g) was obtained as needles. Its physicochemical data was the same as that of the product obtained in (a).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15](OCC)=[O:16])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C([Mg]Cl)(C)C>C1COCC1>[CH3:24][O:23][N:22]([CH3:21])[C:15]([C:10]12[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:14][CH2:13]1)[CH2:8][CH2:9]2)=[O:16]
Reactant: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C12CCC(c3ccccc3)(CC1)CC2
Temperature: -20 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a mixture of ethyl 1-phenylbicyclo[2.2.2]octane-4-carboxylate (Intermediate 4; 15 g, 58.06 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.87 g, 89.99 mmol) in anhydrous THF (130 mL) cooled to −20° C. was added isopropylmagnesium chloride (2M solution in THF; 87 mL) dropwise over 30 mins maintaining the internal temp at −10° C. The mixture was stirred at −10° C. for 1 hr and then quenched by adding 20% ammonium chloride solution. The mixture was extracted into EtOAc (2×200 mL), the organic phase was separated and dried and evaporated to leave a white solid. This was purified on a 330 g Crawford silica cartridge, loading in DCM and eluting with 20-40% EtOAc-isohexane, to provide the title compound as a white solid (8.66 g, 31.67 mmol, 55%); 1H NMR (CDCl3) δ 1.75-1.90 (6H, m), 2.01-2.06 (6H, m), 3.19 (3H, s), 3.70 (3H, s), 7.15-7.20 (1H, m), 7.28-7.36 (4H, m); GC-MS EI+ m/e 243 (M−CH2O), MH+ not seen
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>C(O)C>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:13]1)[CH3:35]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)c(N(CC)CC)c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 10.7 g (0.043 mole) of 90 percent active N,N,N',N'-tetraethyl-m-phenylenediamine and 6.0 ml of acetic anhydride was stirred at room temperature for seventeen hours. The reaction mixture was diluted with 26.0 ml of ethanol, stirred and filtered. The separated solid was washed with diethylether and dried to yield 11.8 g of 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indoly)phthalide (Formula III: R°=R1 =R2 =R3 =Y1 =H; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3), a white crystalline material which melted at 139°-140° C. The infrared spectrum showed a significant band at 1760 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure. A solution of this product in benzene developed a deep blue-black color when spotted on silica gel.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=N1.[I:19]I>>[I:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: II
Agent: c1ccc2[nH]ncc2c1
Product: Ic1c[nH]c2ccccc12

Procedure:
Compounds of formula VIII may also be prepared directly from an indole or indazole of formula XVII by reacting the formula XVII substrate with iodine to give the 3-iodoindole or -indazole of formula XVIII; coupling the formula XVIII compound with an appropriate thiol of formula XIX to give the 3-thioindole or -indazole of formula XX and oxidizing said formula XX compound with a conventional oxidizing agent such as H2O2, m-chloroperbenzoic acid, or the like to afford the desired formula VIII intermediate. The reaction is shown in flow diagram IV.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1>ClCCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)=[O:27]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: NC(=O)n1c(-c2ccc(N)cc2)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cccc(C(=O)Nc2ccc(-c3cc4ccccc4n3C(N)=O)cc2)c1
Temperature: 60 °C

Procedure:
To the solution of 2-(4-amino-phenyl)-indole-1-carboxylic acid amide (125.5 mg, 0.5 mmol, 1 eq) and m-toluic acid (68.8 mg, 0.5 mmol, 1 eq) in anhydrous DCE (4 mL) was added DMAP (12.2 mg, 0.2 eq) and EDC (115.2 mg, 1.2 eq). The reaction mixture was heated at 60° C. for 1.5 hours. It was then cooled to room temperature, diluted with ethyl acetate, washed subsequently with aqueous NH4Cl, saturated aqueous NaHCO3, brine, and lastly dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was treated with EtOAC-Hex(2:1) with stirring. 2-{4-[(3-methylbenzoyl)amino]phenyl}-1H-indole-1-carboxamide was obtained as slightly brown solid upon filtration in amount of 165 mg (89%).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:12][C:11]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:2]([O:6][C:7]([N:9]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37% w/w, 40 μL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (45 mg, 84%).