Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18]>Cl>[CH3:9][C:4]1[CH:5]=[C:6]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccccc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(C)(C)CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
To 2-methoxytoluene (146.7 g, 1.2 mol), aluminum chloride (44 g, 0.33 mol) and 3-methylcrotonic acid (30 g, 0.3 mol) were added, and the mixture was stirred at room temperature for 24 hours, and thereafter the reaction was stopped by the addition of six normal (6-N) hydrochloric acid aqueous solution (300 ml) thereto. Subsequently, from the thus-obtained mixture, the organic material was extracted with diethyl ether (150 ml). After that, one normal (1-N) caustic soda aqueous solution (100 ml) was added to the organic layer for extraction of the carboxylic acid(s). The thus-obtained alkaline mixture was acidified by the addition of hydrochloric acid (HCl) aqueous solution, and the mixture was extracted with diethyl ether and the solvent therein was removed by distillation. The thus-obtained residue was re-crystallized with hexane to obtain 3-(3-methyl-4-methoxyphenyl)-3-methylbutyric acid (39.6 g, yield: 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[S:8][C:7]=2[CH:21]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:19][C:18](=[O:20])/[CH:17]=[CH:16]/[C:9]2[S:8][C:7]3[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[C:10]=2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCCc1c(/C=C/C(=O)O)sc2cc(OC)ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)sc2cc(OC)ccc12
Yield: 82.8 %

Procedure:
As in Example 113, (E)-3-(6-methoxy-3-pentylbenzo[b]thien-2-yl)-2-propenoic acid (7 g) was reacted with 4-nitrophenol (3.6 g) in dichloromethane (70 mL) in the presence of 1,3-dicyclohexylcarbodiimide (4.8 g). The crude reaction product was crystallized from dichloromethane-2-propanol to give 8.1 g of (E)-3-(6-methoxy-3-pentylbenzo[b]thien-2-yl)-2-propenoic acid 4-nitrophenyl ester, mp 111°-113° C. Anal. Calcd for C23H23NO5S: C, 64.92; H, 5.45; N, 3.29; S, 7.54 Found: C, 64.64; H, 5.35; N, 3.27; S, 7.67
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][N:14]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COC(=O)CCCCC(C)=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: COC(=O)CCCCc1ccc2cccnc2n1

Procedure:
A mixture of 1-2 (1.4 g, 9.04 mmol), 1-3, 2-amino-3-formylpyridine (552 mg, 4.52 mmol) (for preparation, see: J. Org. Chem., 1983, 48, 3401), and proline (260 mg, 2.26 mmol) in absolute ethanol (23 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 80% ethyl acetate/hexane, then ethyl acetate) to give ester 1-4 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:15](=[O:17])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:21][CH2:20][C:5]1=2)[CH3:23]
Reactant: CCN
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: CCNC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and ethylamine (1 ml) was heated at 120° C. for 15 h to obtain N-ethyl-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide (CD23) after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.S(Cl)([Cl:14])=O.O1CCOCC1>CN(C)C=O>[Cl:14][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=S1(=O)N=Cc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2ccccc21
Reaction time: 8 h

Procedure:
100 g (545 mM) of benzisothiazole-1,1-dioxide 100 ml. of thionyl chloride, 4 ml. of dimethylformamide (catalyst) and 400 ml. of dioxane are refluxed overnight. Thionyl chloride (50 ml.) and dimethylformamide (1 ml.) are added to the reaction mixture which is again refluxed overnight. The reaction mixture is evaporated to dryness and the residue recrystallized from toluene to obtain 73.4 g of 3-chloro-1,2-benzisothiazole-1,1-dioxide, m.p. 140°-145°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzyloxybutyric acid (54.8 g, 0.282 mol) in methanol (1.4 L), was added sulfuric acid (concentrated, 1.4 mL) dropwise and it was stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (700 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated, washed with brine (2×100 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil that was used in step B without further purification.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[C:16]([F:15])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1c(F)cccc1F
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1c(F)cccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,6-difluorophenol:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][CH2:37][C:38](N(OC)C)=[O:39]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[CH2:37][Cl:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)CCl
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)CCl)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2-chloro-N-methoxy-N-methylacetamide.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]3[S:34][C:30]([CH3:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)s1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)s1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 5-methyl-thiophene-2-carbaldehyde. MS (ESI) m/z 489.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:12][NH2:13]>>[F:11][C:7]1[C:5]2[NH:6][C:2]([NH:13][CH3:12])=[N:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Fc1cccc2nc(Cl)[nH]c12
Reactant: CN
Product: CNc1nc2cccc(F)c2[nH]1
Temperature: 160 °C
Yield: 74.7 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES−) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17]C(Cl)Cl>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]([CH:16]=[O:17])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1O)CCCC2
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c2c(c1O)CCCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Stannic chloride (36.71 g, 0.141 mole) was added to a solution of 2-tert-butyl-5,6,7,8-tetrahydro-1-naphthol (16.0 g, 0.0783 mole) in dry dichloromethane (150 ml) at -10°. To the stirred solution was added 1,1-dichloromethyl methyl ether (13.45 g, 0.118 mole) dropwise at 0°. After 10 minutes, the reaction mixture was treated with ice-water and extracted with ethyl acetate (2×200 ml). The organic extract washed with aqueous saturated sodium chloride and dried over magnesium sulphate. The solvents were removed in vacuo and the solid residue was triturated with n-pentane:diethyl ether (4:1) mixture to give a grey white crystalline solid which was filtered off and air-dried to yield 10.15 g (55.7%), m.p. 193°-94°.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[CH:39])[CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1>C(#N)C.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[C:39][C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCOCCCCCCN(Cc1ccccc1)C[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: NS(=O)(=O)c1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(C#CCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c(NC=O)c2)c1
Yield: 51 %

Procedure:
A stirred solution of 5-((1R)-2-{benzyl[6-(but-3-ynyloxy)hexyl]amino}-1-hydroxyethyl)-2-(benzyloxy)phenylformamide (500 mg) and 3-iodobenzenesulfonamide (340 mg) in acetonitrile (10 ml) and triethylamine (10 ml) with cuprous iodide (50 mg) and bis(triphenylphosphine) palladium dichloride (100 mg) was stirred at ambient temperature under nitrogen for 2 h. The mixture was evaporated in vacuo and the residue was purified by chromatography on Biotage (40 g) cartridge eluting with light petroleum 40-600/ethyl acetate (9:1) to give the title compound (330 mg). LCMS RT=3.04 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C.[C].[Pd]>[CH3:17][Si:2]([CH3:1])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: C[Si](C)(C)C#CCCCCCCCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
At the same time, 11-trimethylsilyl-10-undecynoic acid (0.23 g) was dissolved in ethyl acetate (5 ml), and palladium-carbon (10 mg) was added to the solution. After the air within the reactor was purged with hydrogen, the mixture was stirred at room temperature for 12hours. Then, the mixture was filtered, and the filtrate was concentrated to give 11-trimethylsilylundecanoic acid (0.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)[NH:12][C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 39.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-cyano-1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.32 g, 0.62 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.2 g, 1.1 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.14 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:16]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:15][CH2:14][N:17]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: NCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2nc(CN(CCN(Cc3ccc4ccccc4n3)Cc3ccc4ccccc4n3)Cc3ccc4ccccc4n3)ccc2c1
Yield: 89.6 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (1.07 g, 5 mmol), ethylenediamine (75.0 mg 1.25 mmol), potassium carbonate (2.07 g, 15 mmol) and acetonitrile (10 mL) was refluxed by heating for 48 hours. The solvent was evaporated under reduced pressure, and then the residue was separated by phase separation using chloroform and water. The organic layer was dried, and the solvent was evaporated. The residue was washed with acetone to obtain the objective compound as white powder (0.70 g, 89%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27]C)=[O:26].O.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate (7.56 g, 17.6 mmol) in a mixture of THF/water (2/1 v/v, 180 mL) was added lithium hydroxide monohydrate (1.48 g, 35.2 mmol). The resulting mixture was stirred at ambient temperature overnight and concentrated in vacuo followed by the addition of water (150 mL). The mixture was extracted with of ethyl acetate/hexanes, 1/3 v/v, 50.0 mL). The water layer was acidified with 1 N HCl solution until the pH value reached 2. The precipitate was filtered and dried to give the title compound (7.30 g, 100%) as a white solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.95 (dd, 1H), 7.49 (dt, 1H), 7.37 (t, 1H), 7.24-7.16 (m, 2H), 7.11-6.98 (m, 2H), 6.80 (d, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.91 (s, 2H), 5.37-5.19 (m, 2H), 4.88-4.68 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 168.8, 156.0, 148.8, 143.0, 142.3, 137.6, 133.1, 132.1, 131.5, 129.9, 129.4, 127.7, 126.5, 124.2, 123.6, 120.1, 109.8, 103.8, 101.9, 93.8, 80.5, 58.0, 42.6.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@:10]2([OH:27])[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.[N+]([O-])(O)=O.[C:32](N1C(C)=CC(C)=N1)(=[NH:34])[NH2:33]>C(O)C>[NH:1]([CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@:10]2([OH:27])[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)[C:32]([NH2:34])=[NH:33]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/OCCN)CC[C@]12O
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/OCCNC(=N)N)CC[C@]12O
Yield: 36 %

Procedure:
A solution of 0.95 g of (E)-17β-(2-aminoethoxyimino)methyl-5β-androstane-3β,14β-diol (I-ab) and 1.05 g of 1-amidino-3,5-dimethylpyrazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness under reduced pressure. The residue was ground with di-iso-propyl ether/ethanol to give 0.38 g of the title compound (I-ag), as a nitrate, white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].CN(C)[CH:25]=[O:26]>O1CCCC1>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:25]=[O:26]
Reactant: COc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(Br)ccc(F)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
1.6 M Solution of n-butyllithium in hexanes (3.35 mL, 5.36 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.960 mL, 6.85 mmol) in tetrahydrofuran (10 mL) at −78° C. and the resultant reaction mixture was stirred at −78° C. for 10 min. A solution of 1-bromo-4-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. N,N-dimethylformamide (0.412 mL, 5.32 mmol) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. Reaction mixture was quenched with saturated ammonium chloride, warmed to 20° C., and diluted with ether and 1M aqueous solution of HCl. Layers were separated and the aqueous layer was and re-extracted with ether. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (727 mg, 64%) as a yellow solid. LCMS calculated for C8H7BrFO2 (M+H)+: m/z=233.0, 235.0. found: 233.0, 234.8.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=O.N1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:24][C:16]1[NH:17][C:18]2[C:23]([C:15]=1[CH3:14])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 5-acetyl-2-oxindole (70 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum to give 83 mg (75% yield) of 5-acetyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.