Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Reaction time: 0.67 h
Yield: 45.2 %

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (1.18 g, 5.24 mmol) in THF (20 mL) cooled at −78° C. was dropwise added a 1.60 M solution of n-butyllithium in hexane (3.4 mL). After being stirred for 40 min; a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.0 mmol) in THF (3 mL) was added and the solution stirred for 1 h at −78° C. The reaction was quenched with saturated ammonium chloride. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated to give 0.78 g of a white solid which was used for the next reaction without purification. MS calculated for C17H22F3NO3: (M+H) 346; found 246.0 (M-Boc+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1)#[N:12].[CH:23]([NH2:25])=O>CN(C=O)C>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:18]=[C:17]([C:16]3[CH:21]=[CH:22][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[N:25]=[CH:23]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: NC=O
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCCc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCCc1ccc(-n2cnc(-c3ccc(C#N)cc3)c2)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
4-Propylaniline (2.70 g, 20 mmol) was added dropwise to a solution of 4-cyanophenacyl bromide (2.20 g, 10 mmol) in DMF (5 mL). This solution was then added to hot (180° C.) formamide (20 mL) over 5 min, and the combined solution was allowed to stir at 180° C. for 2 h. The cooled solution was then poured onto ice (100 mL), and extracted with ether (2×75 mL). After drying and concentrating, the resulting dark oil was purified by chromatography (3:1:2 hexanes:EtOAc:CH2Cl2). The first product (510 mg) was identified as 4-(5-propyl-1H-indol-3-yl)-benzonitrile, mp 140° C. The second fraction (275 mg) was identified as the desired imidazole: mp 133° C.; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=6 Hz, 2H), 7.90 (s, 1H), 7.70 (d, J=6 Hz, 2H), 7.68 (s, 1H), 7.38 (d, J=4 Hz, 2H), 7.31 (d, J=4 Hz, 2H), 2.69 (t, J=8.9 Hz, 2H), 1.68 (m, 2H), 0.98 (t, J=7.5 Hz, 3H); ESIMS m/z 288.1 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]([CH2:35][C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH:3]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]([NH:1][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:8]1=[O:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)C(c2ccccc2)Sc2ccccc21
Agent: [BH]C#N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2SC1c1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1.2 g of the compound obtained in Example 20 was mixed with 2.0 g of ethyl benzylpyruvate, 20 ml of ethanol and 1 ml of acetic acid and dissolved therein by warming to 40° C. The resulting reaction mixture was stirred for 3 hours. Thereafter, a solution of 400 mg of sodium boron cyanide hydride in 10 ml of ethanol was slowly added dropwise to the reaction mixture, which was then allowed to stand overnight. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was fractionated and purified by silica gel column chromatography using a 9:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.66 g of the desired compound.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16]Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(C(C)=O)C>[C:1]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH2:16][N:33]2[CH2:34][CH2:35][C:30]3([N:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)[CH2:27][NH:28][C:29]3=[O:36])[CH2:31][CH2:32]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(N2CNC(=O)C23CCNCC3)cc1
Reactant: BrCCCN(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(N2CNC(=O)C23CCN(CCCN(c2ccccc2)c2ccccc2)CC3)cc1

Procedure:
A mixture of 940 mg. (0.00325 moles) of 3-[N,N-diphenylamino)-1-bromopropane (prepared according to the procedure of Example 2) and 850 mg. (0.00325 moles) of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 400 mg. of sodium carbonate and 100 mg. of sodium iodide in 15 ml. of methyl ethyl ketone is refluxed for about 16 hours. The preparation of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one is described in United States Pat. No. 3,155,670 to Janssen, issued Nov. 3, 1964. Solvent is evaporated and the residue is dissolved in chloroform, washed with water and chromatographed on a column of silica gel. The product fractions are evaporated and the residue is recrystallized from isopropyl alcohol and again from ethanol, giving 470 mg. of 8-[3-diphenylamino)propyl]-1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, mp. 156.5°-157.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][NH:41][CH3:42]>CO.C1COCC1>[CH3:40][N:41]([CH2:28][C@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1)[CH3:42]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C[C@H]1C[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 60 °C

Procedure:
A mixture of trans-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (30.0 mg, 0.0555 mmol), dimethylamine in MeOH (2 M, 2 mL) and THF (5 mL) was heated to 60° C. overnight in a sealed tube. The material was concentrated in vacuo, purified by prep TLC (eluting with 5% MeOH in DCM). MS (ES+): m/z 414.19 (100) [MH+]. HPLC: tR=0.65 min (polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[Cl:20])=[O:28]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(F)c(Oc3cc(Cl)cc(C#N)c3)c2Cl)[nH]1
Yield: 68.3 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(aminomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (40 mg, 0.129 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (20.64 mg, 0.129 mmol), EDC (27.4 mg, 0.143 mmol) and HOBT (27.3 mg, 0.178 mmol) in DMF (3.0 ml) to give the title compound as a white solid (40 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.42 (1H, br. s.) 7.46-7.54 (0H, m) 7.31-7.41 (2H, m) 7.16-7.23 (2H, m) 7.14 (1H, d, J=2.1 Hz) 7.00 (1H, s) 4.72 (2H, d, J=6.2 Hz) 2.41 (3H, s). LCMS: m/z 453 (M+1).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH2:42]/[CH:43]=[CH:44]/B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:44]=[CH:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)/C=C/Cc1ccccc1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(C=CCc4ccccc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-3-phenyl-1-propen-1-ylboronic acid (49 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(3-phenyl-propenyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20]2)=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][N:14]([CH3:13])[N:15]=3)[CH:20]=2)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3nn(C)cc3c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3nn(C)cc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((2-methyl-2H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 16).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33]([I:35])[S:34][C:27]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[CH:32]=[C:33]([I:35])[S:34][C:27]=34)=[C:19]([F:24])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Cn1c(NCc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cn1c(NCc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O

Procedure:
A mixture of 2-(benzylamino)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one (0.036 g, 0.112 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.030 g, 0.102 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.025 g, 0.20 mmol) in bromobenzene (1.5 mL) under nitrogen was stirred at 150° C. for 3 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible. MeOH was added to the residue and a brown solid precipitate was filtered and discarded. The filtrate was concentrated and then purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (15.7 mg; 27%) as a yellow solid. LRMS (APCI pos) m/e 585 (M+1).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@H:12]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.C1(S)C=CC=CC=1.O>CN(C)C=O>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][C@@H:12]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)C2(O)CCCC2)cc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)C2(O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a mixture of 4a (3.65 g, 11.9 mmol) and triethylamine (2.5 mL) in N, N-dimethylformamide (18 mL) was added thiophenol (1.8 mL) in one portion. The mixture was stirred at ambient temperature overnight. The mixture was poured into water, and extracted with diethyl ether. The combined organic layers were washed with sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 3.26 g of an oily material, which was purified by column chromatography (silica gel 40 g, ethyl acetate in n-hexane, 2.5-20%) to give 2.06 g (73.3%) of 5a, as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 19.7 %

Procedure:
At 0° C., a solution of N-methyl-2-(2-nitrophenyl)acetamide (7.00 g, 36.05 mmol) in tetrahydrofuran (410 ml) was added dropwise to a suspension of sodium borohydride (1.63 g, 43.25 mmol) in tetrahydrofuran (110 ml). A solution of iodine (4.57 g, 18.02 mmol) in tetrahydrofuran (150 ml) was added dropwise. The reaction mixture was warmed to reflux for 16 h. It was cooled to 0° C. Methanol (310 ml) was added dropwise. The solvent was removed in vacuo The residue was dissolved in 20% aqueous sodium hydoxide solution (300 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (160 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.28 g of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19].[OH-].[K+].I[CH3:23]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])=[CH:4][C:3]=1[CH2:17][CH2:18][O:19][CH3:23]
Reactant: C[Si](C)(C)CCOCOc1ccc(Br)c(CCO)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCCc1cc(OCOCC[Si](C)(C)C)ccc1Br
Reaction time: 16 h
Yield: 59 %

Procedure:
{2-[4-Bromo-3-(2-methoxy-ethyl)-phenoxymethoxy-ethyl}-trimethyl-silane: 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g, 6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and the solution stirred for 16 h. The reaction was diluted with water (50 mL) and extracted with ether (2×40 mL). Organics were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (10% ether/hexanes) gave 1.28 g of {2-[4 bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.7 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](C(C)=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)c(I)cc21
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1I)C(=O)CC2

Procedure:
The product of Example 60 was added to methyl ethyl ketone (50 ml), K2CO3 (5 g) and methyl iodide (5 ml) then heated at reflux for 41/2 hrs. The reaction was cooled, H2O added, followed by an EtOAc extraction. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and evaporated. Trituration of the residue afforded the desired compound after filtration, m.p. 129°-30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH:24]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:21]([CH3:20])[CH:22]=2)[CH2:16][CH2:15]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: Cc1ccc(C=O)cc1C
Product: Cc1ccc(CN2CCC(Nc3cc(=O)oc4ccc(Cl)cc34)CC2)cc1C

Procedure:
Prepared from 6-Chloro-4-(piperidin-4-ylamino)-chromen-2-one and 3,4-dimethyl benzaldehyde in a manner analogous to that described above. MS (ESI) m/e 397.1 (M+H)+. 1H NMR (500 MHz, MeOD-d4) δ ppm 8.12 (d, 1H), 7.60 (dd, 1H), 7.21-7.34 (m, 4H), 5.44 (s, 1H), 4.27 (s, 2H), 3.83-3.87 (m, 1H), 3.55-3.60 (m, 2H), 3.16-3.20 (m, 2H), 2.30-2.38 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 1.89-1.96 (m, 2H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:14][CH:15]=1)=[O:10].[CH2:25]=O>CCOCC.C(O)CCC>[ClH:1].[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[O:12][C:11]([C:9](=[O:10])[CH2:8][CH2:25][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:15][CH:14]=1)([O-:24])=[O:23]
Reactant: CC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reactant: C=O
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCO
Product: O=C(CCN1CCCCC1)c1ccc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
Concentrated HCl (16 ml.) is added to a stirred solution of 17 g. (0.20 mole) of piperidine in 100 ml. of n-butanol. To this solution is added 23 g. (0.10 mole) of 5-(o-nitrophenyl)-2-furyl methyl ketone and 6.0 g. (0.20 mole) of paraformaldehyde. The solution is heated under reflux for 3 hr. and the solvent is removed on a rotary evaporator. The residual semi-solid is partitioned between ether and water, the layers are separated, and the ether layer is dried over MgSO4. The solvent is removed on a rotary evaporator to give a residual oil. The oil is dissolved in anhydrous ether and is treated with ethereal HCl. The solid is collected by filtration and is dissolved in 300 ml. of CH3CN. The solution is concentrated and cooled in ice to give solid which is collected by filtration. Recrystallization from CH3CN and then recrystallization with absolute ethanol-anhydrous ether mixture gives 6.5 g. (28%) of product, m.p. 160°-162°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[C:15]1[CH:23]=[CH:22][C:21]2[N:20]([CH3:24])[C:19]3[CH2:25][CH:26]4[NH:30][CH:29]([C:18]=3[C:17]=2[C:16]=1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27]4>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH:26]5[NH:30][CH:29]([C:18]=4[C:17]=3[C:16]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27]5)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)[O-])cc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc31)C1CCC(C2)N1
Yield: 54 %

Procedure:
Intermediate 12 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 1:1 hexane/ethyl acetate) to give tert-butyl 2-(4-nitrophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (150 mg, 54%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.27-8.31 (m, 2H), 8.19 (s, 1H), 8.09-8.11 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 5.26 (br s, 1H), 4.70 (br s, 1H), 3.62 (s, 3H), 3.40 (br s, 1H), 2.50 (d, J=16.2 Hz, 1H), 2.17-2.31 (m, 2H), 1.89-1.97 (m, 1H), 1.54-1.65 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([C:13]1[CH:14]=[C:15](O)[CH:16]=[CH:17][CH:18]=1)[CH3:12].N1CC[O:23][CH2:22]C1>[B].CO>[CH2:11]([C:13]1[CH:14]=[C:15]2[C:16]([C:22](=[O:23])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][O:10]2)=[CH:17][CH:18]=1)[CH3:12]
Reactant: O=C(O)Cc1ccccc1
Reactant: C1COCCN1
Reactant: CCc1cccc(O)c1
Agent: [B]
Solvent: CO
Product: CCc1ccc2c(=O)c(-c3ccccc3)coc2c1
Temperature: 80 °C
Reaction time: 21 h
Yield: 12.2 %

Procedure:
This compound was prepared by the same method described for the synthesis of analog 23. To a solution of 6.51 g of phenylacetic acid (47.81 mmol) in 50 ml of boron trifluroide diethyl etherate was added 6.5 ml of 3-ethylphenol (53.20 mmol). The mixture was stirred at 80° C. for 21 hours, cooled to RT, and then washed with aqueous K2CO3 and water until the pH of wash approached neutrality. The product was extracted with ethyl acetate and concentrated. Residue was dissolved in 50 ml of 2-propanol and 8 ml of triethyl formate (48.1 mmol) and 3 ml of morpho line were added. The mixture was stirred at 80° C. for 7 hours and solvent was removed by flash evaporation. The syrup obtained was dissolved in 30 ml of methanol, stirred at 50° C. for 30 min, cooled to room temperature, and kept at 4° C. overnight. Crystals were collected by filtration and washed with small portions of acetone to give 790 mg of analog 35, a yield of 12.2% (based on 3-ethylphenol, w/w): mp 103-104° C. 1H NMR (DMSO-d6) δ 1.35 (t, 3H, —CH3), 2.78 (q, 2H, —CH2—), 7.38 (m, 4′-H), 7.39 (dd, 1H, J=8.10, 1.91 Hz, 6-H), 7.44 (t, 2H, J=7.77 Hz, 3′, 5′-H), 7.52 (d, 1H, J=2.0 Hz, 8H), 7.59 (dd, 2H, J=7.35, 1.38 Hz, 2′, 6′-H), 8.05 (d, 1H, J=8.54 Hz, 5-H), 8.51 (s, 1H, 2-H). 13C NMR (DMSO-d6) δ 14.9 (—CH3), 28.2 (CH2—), 116.7 (C-6, 8), 121.8 (C-10), 123.8 (C-3), 125.4 (C-1′), 125.8 (C-7), 127.8 (C-5), 128.1 (C-3′, 5′), 128.9 (C-2′, 6′), 131.9 (C-4′), 154.4 (C-2), 155.9 (C-9), 174.9 (C-4). MS (m/z), 251.4 (M+H)+, 273.2 (M+Na)+, 249.3 (M−H)−. Anal. (C17H14O2) for C, H. Cacld: 81.58, 6.91; found: 80.92, 6.87.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1)(C(C)(C)C)(C)C.[I-:17].[Na+].[C:19](Cl)(=[O:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[I:17][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=1.[I:17][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:9][O:8][C:19](=[O:21])[CH3:20])[CH:15]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Cl)ccn1
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCc1cc(I)ccn1
Product: Cc1cc(I)ccn1
Yield: 45 %
Yield: 22 %

Procedure:
2-(((Tert-butyldimethylsilyl)oxy)methyl)-4-chloropyridine (600 mg, 2.33 mmol), dry sodium iodide (5 g) and freshly distilled acetyl chloride (0.7 mL, 9.78 mmol) in 6 mL of anhydrous acetonitrile were refluxed under nitrogen for 33 hours. Aqueous 10% K2CO3/5% NaHSO3 was added and the mixture extracted three times with chloroform. After drying (Na2SO4) and evaporation of the chloroform, flash chromatography (hexane/EtOAc 9:1) yielded 110 mg (22%) of 4-Iodo-2-methylpyridine as a white solid and 290 mg (45%) of (4-iodo-2-pyridyl)methylacetate as a white solid.