Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[CH:10]=1)([O-])=O.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]3[NH:21][C:20]4[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]5[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cc(O)cc(O)c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1cc(O)cc(O)c1

Procedure:
Compound 425 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(3,5-dihydroxybenzoyl)aniline and 4-morpholinobenzaldehyde. [M+H]+ calcd for C24H22N4O4: 431.17; found: 431.18.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.O[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[O:6][C@@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: O[C@H]1CCOC1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O[C@@H]2CCOC2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a stirred solution of (3S)-tetrahydrofuran-3-ol (403 mg, 4.57 mmol), methyl 4-hydroxy-3-methoxy-benzoate (1.00 g, 5.49 mmol) and triphenylphosphane (1.44 g, 1.27 mL, 5.49 mmol) in THF (13 mL) at 0° C. was added DIAD (1.11 g, 1.06 mL, 5.49 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then at 55° C. for 4 h. The mixture was diluted with EtOAc and was washed with sat. aq. NaHCO3 (×2) and brine (×2). The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield (R)-methyl 3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate (0.97 g, 84%) as a viscous liquid. ESI-MS m/z calc. 252.1. found 253.3 (M+1)+; Retention time: 1.72 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[I:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([I:18])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(I)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2cccc(I)c2)n1
Temperature: 120 °C
Yield: 0 %

Procedure:
A solution of 2,4-dichloropyrimidine (3.0 g, 20 mmol) and N,N-diisopropylethylamine (4.2 mL, 24 mmol) in N-methylpyrrolidinone (20 mL) was treated with 3-iodoaniline (2.4 mL, 20 mmol) dropwise and heated at 120° C. for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), and washed with water (150 mL). The aqueous layer was separated and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (3.2 mg, 48%) as a tan solid. LCMS for C10H8ClIN3 (M+H)+: m/z=331.9.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[C:21]([I:22])=[CH:20][C:13]([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:12][C:11]=2[I:23])=[CH:5][CH:4]=1.N[C@H:25](C(O)=O)CC1C=C(I)C(OC2C=C(I)C(O)=C(I)C=2)=C(I)C=1.C([O-])(O)=O.[Na+]>CO>[CH3:25][O:18][C:17](=[O:19])[C@H:15]([CH2:14][C:13]1[CH:12]=[C:11]([I:23])[C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[C:21]([I:22])[CH:20]=1)[NH2:16]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Yield: 87 %

Procedure:
A 6 M solution of HCl in MeOH (8 mL; 4.8 mmol) was added to a suspension of O-(4-hydroxyphenyl)3,5-diiodo-L-tyrosine (2.12 g; 5 mmol) (prepared according to: Chalmers J. R., Dickson G. T., Elks J. and Hems D. A., “The Synthesis of Thyroxine and Related Substances”, Part V., J. Chem. Soc. (1949), 3424-3433) in MeOH (12 was stirred for 4 days at 20° C. Then a NaHCO3 saturated aqueous solution was added to the mixture until pH 7 was reached, obtaining a precipitate which was filtered by concentration of the solution a second crop of precipitate was obtained. The two samples were combined and dried (50° C.; 1.3 kPa) 3.7 mmol). Yield 87%.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:24]C)[CH:8]=[CH:9][C:10]=2[CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[CH2:13]2)[C:5](=O)[C:4]1=O)[CH3:2].B.O1CCCC1.N>O1CCCC1>[CH2:1]([N:3]1[C:11]2[C:10]([CH:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=4)[CH2:13]3)=[CH:9][CH:8]=[C:7]([OH:24])[C:6]=2[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCN1C(=O)C(=O)c2c(OC)ccc(C3CCc4cc(OC)ccc4C3)c21
Agent: B
Agent: N
Solvent: C1CCOC1
Product: CCn1ccc2c(O)ccc(C3CCc4cc(O)ccc4C3)c21
Temperature: 0 °C
Yield: 5.2 %

Procedure:
A mixture of 1-ethyl-4-methoxy-7-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-indole-2,3-dione (160 mg), borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (1.8 ml) and tetrahydrofuran (10 ml) was refluxed for 1 hour. After dilution with ice water, ammonia solution was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system), the resulting 1-ethyl-4-methoxy-7-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-indole (58 mg) was used according to an analogous synthetic method to Example 364 described below to provide the title compound (7 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCCc1ccc(N)cc1
Product: CCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 88.9 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (11 g) and 4-propylaniline (10 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-propylphenyl)amine (17.6 g) was obtained. melting point: 74–76° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][N:18]=[C:19]([C:23]1[N:24]=[C:25]([NH:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:26][CH:27]=1)[C:20]([OH:22])=O.[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][N:58]1[C:63](=[O:64])[C:62](=[O:65])[NH:61][NH:60][C:59]1=[S:66])=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(OCC)(=O)C>[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][N:58]1[C:63](=[O:64])[C:62](=[O:65])[NH:61][N:60]=[C:59]1[S:66][C:20](=[O:22])[C:19](=[N:18][O:17][CH3:16])[C:23]1[N:24]=[C:25]([NH:28][C:29]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:26][CH:27]=1)=[O:54])([CH3:51])([CH3:49])[CH3:50]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NCCn1c(=S)[nH][nH]c(=O)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)Sc1n[nH]c(=O)c(=O)n1CCNC(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
N,N'-Dicyclohexylcarbodiimide (1.11 g) is added to a suspension, cooled to +4° C., of 2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetic acid, syn isomer (2.17 g) and 4-(2-tert.-butyoxycarbonylamino-ethyl)-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (1.05 g) in ethyl acetate (50 cc). The mixture is stirred for 4 hours at 20° C., filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is taken up in methylene chloride (20 cc) and the solution is poured into diisopropyl ether (250 cc). After filtration and drying, 4-(2-tert.-butoxycarbonylamino-ethyl)-5,6-dioxo-3-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetylthio]-1,4,5,6-tetrahydro-1,2,4-triazine (syn isomer) (0.73 g) is obtained in the form of a yellow powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:27].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][S:24]([CH3:23])(=[O:26])=[O:25])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 53.9 mg (470 μmol) methanesulfonic acid chloride are dissolved in 5 ml DMF under argon and while cooling with ice, 152 mg (1.18 mmol) N,N-diisopropylethylamine are added and the mixture is stirred overnight at RT. The reaction mixture is then purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=1[CH2:24]O>C(Cl)Cl>[Cl:3][CH2:24][C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CO)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (available from Aldrich) (4.46 g, 37.5 mmol) was added to a solution or 66.63A in DCM (6 mL). The reaction mixture was stirred at room temperature for 2 hours and then at 50° C. for 3 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:9 EtOAc/hexane) and gave 66.69A (386 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:6]2=[O:13].[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]2=[O:13]
Reactant: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CC2Cc3c(C)cc(C)c(O)c3C2=O)cc1

Procedure:
16.09 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one was dissolved in a mixed solvent of 150 ml of ethyl acetate with 100 ml of acetic acid, this solution was let subjected to catalytic reduction at room temperature under 3 atmospheric hydrogen gas pressure in the presence of 1.5 g of palladium black as the hydrogenation catalyst. After the catalytic reduction, the catalyst was removed by filtration, and the filtrate was concentrated by removing the solvent under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane: ethyl acetate =9:1) to obtain 8.5 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzyl)-1H-inden-1-one as in the form of colorless oily substance.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[C:3](=[O:21])[O:4][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][C:7]=2[OH:8])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1
Reactant: CC(C)c1cc(Cl)ccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)c1cc(Cl)ccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-chloro-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 95-96° C.). 1H NMR (DMSO-d6) δ 1.16 (d, 6 H), 3.23 (m, 1 H), 3.73 (bs, 2 H), 5.60 (d, 1 H), 6.45 (d, 1 H), 7.14 (d, 1 H), 7.32-7.48 (m, 10 H).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])[CH:12]=[C:11]([F:35])[N:10]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CO>[F:35][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])[CH:14]=[C:9]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:10]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(F)nc(F)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(F)nc(N2CCOCC2)c1
Temperature: 55 °C

Procedure:
To a solution of triethylamine (3.0 equiv.) and N-(3-(2,6-difluoropyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) at RT in MeOH (0.12 M) was added morpholine (2.0 equiv) in one portion, the resulting mixture was then heated at 55° C. for 8 hours. LCMS analysis indicated 90% conversion to the desired product (M+H=460.1, Rt=0.43 min/non-polar). Water was then added, and the mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield N-(3-(2-fluoro-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide as a light brown solid (>100%). LCMS (m/z) (M+H)=460.1, Rt=0.43 min/non-polar.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)CCC2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g-see Preparation 3), 5-(2-bromoethyl)indane (0.24 g-see Preparation 6), anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.23 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:7]=1.[ClH:24]>CCOCC>[ClH:24].[ClH:24].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccs3)n2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1csc(-c2nc(N3CCNCC3)no2)c1
Yield: 78 %

Procedure:
A solution of tert-butyl 4-(5-(2-thienyl)-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (2.2 g) in 2M HCl in Et2O (50 mL) was stirred at RT for 6 hours. The solvent was removed under vacuum to give 1.6 g (78%) of The title compound as a solid. TLC—CHCl3/MeOH (8/2): Rf=0.2. HPLC purity >98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5](=[CH:10][CH:11]=1)[CH2:6][C:7]([OH:9])=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:19]2[C:7](=[O:9])[CH2:6][C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[C:12]2=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1C(=O)O
Reactant: Nc1cccc(Cl)c1
Product: O=C1Cc2ccc(Cl)cc2C(=O)N1c1cccc(Cl)c1

Procedure:
A mixture of 4-chlorohomophthalic acid (54.0 g., 0.25 mole) and m-chloroaniline (31.8 g., 0.25 mole) is heated by an oil bath until molten for two hours. When removed from the oil bath, the reaction mixture solidifies and is recrystallized twice from ethanol/ethyl acetate, giving 2-(m-Chlorophenyl)-7-chloroisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[C:13]=2[Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:8]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc(-c2cn3c(n2)CCC3)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccc(OC)cc2)nc2n1CCC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To an ice cold (0° C.) solution of [16.8 g, 0.078 mol] 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole in 200 ml of dry tetrahydrofuran under argon was added dropwise over 20 minutes 35 mL [0.0858 mol] of a 2.5M solution of n-butyl lithium in hexane. Once the addition was complete, the deep-red solution was stirred in the cold for five minutes and then a solution of the tributyltin chloride [26.4 g, 0.0975 mol] in 50 ml of dry tetrahydrofuran was added over 20 min. The reaction mixture was stirred at ice-bath temperatures for 1.5 hours and then saturated ammonium chloride was added. The layers were shaken together and separated and the organic extract was washed an additional time with saturated ammonium chloride and then dried with anhydrous potassium carbonate. The solvent was removed in vacuo to give 50 g of a crude oil, which was taken up twice in cold hexane, filtering off the unreacted 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole each time. The product was purified on a column of silica, eluting with 1:1 ethyl acetate/hexane in the presence of 1% diethylamine, to give 19.2 g (49% of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[CH3:18][C:19]1([O:22][CH2:21]1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[C:6]=2[N:14]=1
Reactant: CC1(C)CO1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Yield: 70.1 %

Procedure:
2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 200 mg, 0.884 mmol), isobutylene oxide (0.196 mL, 2.21 mmol) and cesium carbonate (460 mg, 1.40 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at 100° C. under microwave irradiation for 10 min. The volatiles were removed in vacuo then the crude residue was adsorbed onto silica gel using methanol and purified by silica gel chromatography (5-10% methanol in methylene chloride gradient) to afford the title compound (43, 185 mg, 70%). NH4OAc standard conditions. DAD Retention time=5.93 min. M+H=299. 1H NMR (300 MHz, MeOD-d4): 8.64 (d, J=4.9 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.34 (dd, J=7.6, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 5.49 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:4][CH:3]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[CH3:35][CH2:34][NH:36][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[C:14]=3[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:24][CH:23]=3)[NH:19]4)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:6][CH:7]=1)=[O:38]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN(C)C)cc4)cc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4ccc(CN(C)C)cc4)cc23)cc1

Procedure:
Following the procedure described in Example 48 using 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine and ethyl isocyanate provided the title compound. ESMS (M+H)+: 508.4
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13])([O-])=O.[H][H].[S]>C(O)C.[Ni]>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:6]=1
Reactant: CSc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: [S]
Solvent: CCO
Product: CSc1ccc(N)c(C(F)(F)F)c1

Procedure:
2-Nitro-5-methylthiobenzotrifluoride (190 g, 0.85 mole) in ethanol (1 l.) is reduced over Raney nickel at about 45 psi of hydrogen gas. After hydrogen uptake is complete the catalyst is deactivated with elemental sulfur, the mixture is filtered, and the filtrate evaporated under reduced pressure to afford the desired product as an oil. IR 2.9μ (strong NH band).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]([O-])=[O:20].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[N:19][OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CSc1nccc(CC(=O)c2cccc(Br)c2)n1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nccc(C(=NO)C(=O)c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12.75 g (39.5 mmol) C1 were dissolved in a mixture of 173 ml glacial acid, 136 ml tetrahydrofurane and 17 ml water. After cooling to 5° C. a solution of 3.24 g (47.0 mmol) sodium nitrite in 25 ml water was added keeping the temperature between 5° C. and 10° C. The cooling was removed and the mixture stirred for 6 hours at room temperature. After removal of the solvent in vacuo 320 ml water and 320 ml ethyl acetate were added. The pH was adjusted to 8 with 3 N NaOH. The phases were separated and the aqueous layer was extracted with 50 ml ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was treated with diethylether, filtered off and dried. Yield: 8.33 g (60%) D1, m.p. 156–158° C.