Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3]2.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:18]1([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([OH:17])[CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][N:2]2[CH2:7][CH2:6]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C1CN2CCC1C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C2CCN(C2)C1C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1-azabicyclo[2.2.1]heptan-3-one hydrochloride (1.06 g) and benzophenone (1.82 g) in dry THF (5 ml) at -78° C. under argon was added a solution of lithium bis(trimethylsilyl)amide (18 ml, 1.0M in THF). The solution was stirred at -78° C. for 1 h, allowed to warm to room temperature and stirred for 48 h. The mixture was poured onto water and extracted with dichloromethane (×4). The combined extracts were dried (Na2SO4), evaporated in vacuo, and the residue was purified by chromatography on silica using a gradient elution of 10-30% ethyl acetate in dichloromethane to afford the title compound as a white solid:
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.[CH3:28][N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)N.CC(O)=O.C([O-])([O-])=O.[K+].[K+]>O.[Cl-].[Cl-].[Zn+2]>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:29]([CH3:28])[CH:2]=3)[CH2:11][CH2:12]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: CN(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3cn(C)c4ccccc34)CC2)c1
Temperature: 80 °C
Yield: 18.4 %

Procedure:
A mixture of N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]4-piperidinyl}phenyl)-2-methylpropanamide (100 mg, 0.270 mmol), 1-methyl-1-phenylhydrazine (106 mg, 0.870 mmol), ZnCl2 (119 mg, 0.870 mmol), and HOAc (1.00 mL) was heated for 12 h at 80° C. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was neutralized with saturated K2CO3 solotion (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 3% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 2-methyl-N-(3-{1-[3-(1-methyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)propanamide (20.7 mg, 18.7%): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, 1H, J=8.1 Hz), 7.45 (s, 1H), 7.35 (d, 1H, J=7.4 Hz), 7.26–7.24 (m, 4H) 7.09 (t, 1H, J=7.3 Hz), 6.97 (d, 1H, J=7.3 Hz), 6.86 (s, 1H), 3.75 (s, 3H), 3.11 (d, 2H, J=11.6 Hz, 2.79 (t, 2H, J=7.3 Hz), 2.51–2.50 (m, 4H), 2.12–1.81 (m, 8H), 1.25 (d, 6H, J=7.1 Hz); Anal. Calcd for C27H35N3O+0.225CHCl3: C, 73.57; H, 7.99; N, 9.45. Found: C, 73.93; H, 7.90; N, 9.23; ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[S:6])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCN=C=S
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCNC(=S)NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 6.6 %

Procedure:
A solution of propyl isothiocyanate (0.78 g, 7.72 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.256 g, 7.72 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide a pale orange syrup. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-propylthiourea as a white solid, m.p. 113-116° C. Mass spec M+1=433.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Cl-].[Cl-].[Al+3].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[C:6]([CH2:8][CH2:9][NH2:10])[CH:7]=1
Reactant: N#CCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
140.97 g (0.366 mol) of (5-fluoro-2-{[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methoxy}phenyl)-acetonitrile are dissolved in 701 ml of anhydrous THF under argon and, after cooling to 0° C., 361.6 ml (0.362 mol) of a 1 M solution of lithium aluminum hydride in THF are added. Then 73.2 g (0.55 mol) of aluminum trichloride in 701 ml of THF are slowly added dropwise to the reaction solution. The reaction mixture is stirred at room temperature for 3.5 h. After reaction is complete, the solution is cooled to 0° C. and aqueous sodium hydroxide solution is slowly added. The aqueous phase is extracted three times with ethyl acetate, and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The crude product is purified by chromatography on 10 kg of silica gel (mobile phase: dichloromethane/methanol 6:4). 90.28 g (61% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2].[CH3:11][N:12]([CH3:16])[C:13](=[S:15])[S-:14].C[NH2+]C>C(=S)=S>[CH3:11][N:12]([CH3:16])[C:13](=[S:14])[S:15][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccco1
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccco1

Procedure:
As in Example 17, reaction of 2-(2-nitrovinyl)furan with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave α-(nitromethyl)furfuryl dimethyldithiocarbamate melting at 67°-68° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]([O:13]C)(OC)(=O)=[O:9].S(=O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:13])=[O:9])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)=O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A vertical glass tube having a length of 90 cm and a diameter of 4 cm was packed with glass balls and heated at 70° C. 225 g (2.0 moles) of chlorobenzene, 126 g (1.0 mole) of dimethyl sulfate and 160 g (2.0 moles) of sulfur trioxide were simultaneously fed, dropwise, to the top of the tube at approximately the same rates over 30 minutes. Contrary to the procedure adopted in Example 1, the effluent reaction mixture was not immediately precipitated in dilute sulfuric acid but was continuously recycled to the packed column at a pump rate of 2 l/h. Once all of the starting components had been fed to the reactor, recycling was continued at the same rate for a further half-hour, after which the effluent reaction mixture was precipitated in 1 liter of 5% sulfuric acid. Purification was carried out as described in Example 1 to give 261 g (91%) of bis(4-chlorophenyl) sulfone of 97% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[CH2:32]1COCC1.Cl[Si](C)(C)C.CI>CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH3:32])[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cc(OC)cc(O[C@H](C(=O)O)[C@]2(c3ccccc3)c3ccccc3CCN2C)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in THF (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before methyliodide (30 μl, 0.477 mmol) is added. Stirring at 55° C. is continued for another 16 h. The mixture is diluted with EA and extracted with water. The aqueous phase is acidified with 2 N HCl and extracted with EA. The EA-phase is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC on Rp-C18-silica gel to give (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-methyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (139 mg) as a white powder. LC-MS2: tR=4.03 min, [M+1]+=434.34, [M−1]−=432.32.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:6][C:7](I)=[CH:8][CH:9]=1.[F-].[Cs+].[C:24]([C:28]1[CH:33]=[CH:32][C:31](/[C:34](/[Sn](CCCC)(CCCC)CCCC)=[CH:35]\[C@@H:36]2[N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[O:50][CH3:51])[C:39](=[O:52])[CH2:38][CH2:37]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].O>CN(C)C=O.[Cu](I)I.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.C(OCC)(=O)C>[C:24]([C:28]1[CH:33]=[CH:32][C:31](/[C:34](/[C:7]2[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:21])[F:1])=[C:5]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:6]=2)=[CH:35]\[C@@H:36]2[N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[O:50][CH3:51])[C:39](=[O:52])[CH2:38][CH2:37]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ccc(COc2nc(I)ccc2OC(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2nc(/C(=C/[C@H]3CCC(=O)N3Cc3ccc(OC)cc3OC)c3ccc(C(C)(C)C)cc3)ccc2OC(F)F)cc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
3-(Difluoromethoxy)-6-iodo-2-[(4-methoxybenzyl)oxy]pyridine obtained in Reference Example 4-34 (727 mg), cesium fluoride (270 mg), copper iodide (187 mg) and tetrakis(triphenylphosphine)palladium (103 mg) were added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-26 (609 mg) in N,N-dimethylformamide (6 mL), and the mixture was stirred at 75° C. for two hours. Water and ethyl acetate were added to the reaction solution. After filtration through celite, the organic layer was washed with brine. The organic layer dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-(difluoromethoxy)-6-[(4-methoxybenzyl)oxy]-pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless gum (511 mg).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[C:1]([C:5]1[C:6]([NH:14][C:25](=[O:26])[CH2:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]([CH3:16])[CH3:17])=[CH:19][CH:20]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Product: CC(C)c1ccc(CC(=O)Nc2nn3cccnc3c2C(C)(C)C)cc1

Procedure:
The product from Example 105B and 4-isopropylphenylacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.7 Hz, 3H), 1.39 (s, 9H), 2.82-2.91 (m, 1H), 3.58 (s, 2H), 6.99 (dd, J=7.1, 4.0 Hz, 1H), 7.18-7.23 (m, 4H), 8.48 (dd, J=4.0, 2.0 Hz, 1H), 8.91 (dd, J=7.0, 2.0 Hz, 1H), 9.91 (s, 1H); MS (DCI) m/z 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as tan solid (0.022 g, 23%). MP: 54-75° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.26 (d, 1H, J=8.8 Hz), 8.11 (s, 1H), 8.02-8.00 (m, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.55-6.50 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3 h), 3.57-3.51 (m, 2H), 3.37 (s, 3H), 3.24-3.16 (m, 4H), 2.92-2.83 (m, 4H), 2.77-2.67 (m, 6H), 2.64-2.58 (m, 4H), 2.37 (s, 3H). MS: 582.24 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH:18]=[C:17](B(O)O)[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=3)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: CN1CC=C(B(O)O)CC1
Reactant: Cn1cc(I)c2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC=C(c2cn(C)c3ncc(Br)cc23)CC1
Temperature: 40 °C

Procedure:
To a solution of 5-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.534 mmol) and 1-methyl-1,2,3,6-tetrahydropyridin-4-boronic acid (155 mg, 0.694 mmol) in dioxane (5.4 mL, degassed) was added tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.064 mmol), K2CO3 (369 mg, 2.67 mmol) and water (1.8 mL, degassed). The reaction mixture was heated at 40° C. for 15 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C14H16BrN3: 306.2 (M+H+); Found: 306.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Br)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of 1-bromo-4-methoxy-2-methylbenzene (20 g, 100.00 mmol, 1.00 equiv) in CCl4 (200 mL). Then NBS (19.58 g, 110.00 mmol, 1.10 equiv) and BPO (1.21 g, 5.00 mmol, 0.05 equiv) were added. The resulting solution was heated to reflux for 7 hs in an oil bath. The resulting solids were filtered out. The filtrate was concentrated under vacuum and applied onto a silica gel column with ethyl acetate/petroleum ether (1:500). This resulted in 5.9 g (21%) of 1-bromo-2-(bromomethyl)-4-methoxybenzene as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])=[N:6][CH:7]=1.[OH:15][C:16]([CH3:49])([CH3:48])[CH2:17][C@@:18]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:23][C:22](=[O:24])[N:21]([C@H:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH3:26])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)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>[OH:15][C:16]([CH3:48])([CH3:49])[CH2:17][C@@:18]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:23][C:22](=[O:24])[N:21]([C@H:25]([C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[N:6][CH:7]=3)=[CH:31][CH:32]=2)[CH3:26])[CH2:20][CH2:19]1
Reactant: CN1CCN(c2ncc(Br)cn2)C1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(-c2cnc(N3CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (1 mg) was added to a solution of 1-(5-bromopyrimidin-2-yl)-3-methylimidazolidin-2-one (10 mg), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (38.0 mg), and Na2CO3 (17 mg) in toluene (3 mL), ethanol (2 mL), and H2O (1 mL) under nitrogen at room temperature. The reaction mixture was heated to 100° C. under nitrogen and stirred at this temperature for 2 h. After cooling to room temperature, the mixture was concentrated to afford an oil, which was purified by preparative HPLC to give the title compound. Yield: 2.4 mg (12% of theory); LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=530 [M+H]+; 1H NMR (CD3OD) δ 0.88 (s, 3H), 1.32 (s, 3H), 1.48 (d, 3H), 2.05 (m, 2H), 2.12 (m, 2H), 2.41 (m, 2H), 2.81 (s, 3H), 3.42 (m, 2H), 4.01 (m, 2H), 5.52 (m, 1H), 7.02 (d, 2H), 7.26 (m, 5H), 7.31 (m, 2H), 8.67 (s, 2H).
Reaction SMILES: C([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=O)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[NH:20][C:19]=2[CH3:31])=O)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>O1CCCC1.C(O)(C)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[NH:20][C:19]([CH3:31])=[C:18]2[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH:11]1[CH2:39][OH:44]
Reactant: COc1cc2[nH]c(C)c(C(=O)C(=O)N3CCC(C(=O)c4ccccc4)CC3)c2cc1OC
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cc2[nH]c(C)c(CCN3CCC(c4ccccc4)CC3CO)c2cc1OC
Reaction time: 3 h

Procedure:
A suspension of 20.2 g of 4-benzoyl-1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine in 200 ml of tetrahydrofuran is added dropwise to a stirring solution, under nitrogen at reflux, of 9.6 g of lithium aluminum hydride in 210 ml of tetrahydrofuran. Stirring and refluxing is continued for 3 hours, the mixture is cooled in an ice bath and the excess hydride is destroyed with water. The mixture is filtered and the filtrate is concentrated under reduced pressure, leaving an off-white foam which is triturated with cyclohexane to give an off-white powder. The oxalate salt is prepared by dissolving the free base in isopropanol and slowly adding a solution of oxalic acid in isopropanol. The isoluble oxalate salt is collected and recrystallized from ethanol to give white crystals, mp 152°-154° C., 5,6-dimethoxy-2-methyl-3-[2-(4-phenylhydroxymethylpiperidyl)-ethyl]indole oxalate.
Reaction SMILES: [OH:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([C:16]2[O:17][C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][C:20](=[O:22])[CH:21]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:40])[CH2:38][O:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([C:16]2[O:17][C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][C:20](=[O:22])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(O)c3c2Sc2ccccc2S3)oc(N2CCOCC2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Temperature: 60 °C

Procedure:
To a solution of 2-(4-Hydroxy-thianthren-1-yl)-6-morpholin-4-yl-pyran-4-one (130) (1.20 g, 2.91 mmol) in dimethylformamide (10 ml), under and inert atmosphere, was added powdered potassium carbonate (1.21 g, 8.75 mmol) and methylbromoacetate (0.55 ml, 5.82 mmol). The temperature of the reaction was raised to 60° C. for 48 hours and then cooled to room temperature before the addition of water (20 mL). The mixture was then extracted using ethyl acetate (3×30 ml). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an off white solid (1.40 g, 99%) that was suitably clan and required no further purification. m/z (LC-MS, ESP): RT=4.48 min, (M++1)=484
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH2:14]([N:16]([CH2:27][CH3:28])[CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:15]>>[CH2:5]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:14][CH3:15])[CH2:27][CH3:28])=[CH:26][CH:25]=1)=[O:13])=[CH:5]2)[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(NC(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)cc1

Procedure:
The entitled compound was obtained as a white solid in the same manner as in Example 1-1 but using 5-hydroxyindole-2-carboxylic acid and 4-[2-(diethylamino)ethoxy]aniline.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:21]#[N:22].Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:21]#[N:22]
Reactant: COc1ccc(-c2ccc3c(C#N)c(OC)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1c(O)ccc2cc(-c3ccc(O)cc3)ccc12

Procedure:
The title compound was prepared by reacting 2-methoxy-6-(4-methoxyphenyl)-1-napthonitrile (0.115 g, 0.397 mmol) with-pyridinium HCl (4 g) at 190° C. according to method D to yield 0.025 g (24%) of a tan solid: mp>220° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.37 Hz), 7.28 (1H, d, J=9.07 Hz), 7.63 (2H, d, J=8.42 Hz), 7.88–7.98 (2H, m), 8.12–8.16 (2H, m), 9.63 (1H, s), 11.65 (1H, bs); MS (ESI) m/z 260 (M−H)−