Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9]C)=O)[CH:3]=[N:2]1.[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([C:7](=[O:9])[CH2:6][C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[C@@H:26]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)Cc1cn[nH]c1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cn[nH]c3)[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Yield: 58 %

Procedure:
Prepared by the method outlined for Example 275 using methyl 1H-pyrazol-4-ylacetate and (S)-1-(3-cyclobutoxy-4-methoxyphenyl)-3-(4-fluorobenzyl)piperazine as starting materials. Product was obtained as a colorless solid (58%). LC/MS 3.44 min, [M+1]+ 479.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)=[CH:8][C:6]=2[N:7]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(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.O>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[N:11][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:39]4[CH:40]=[N:41][C:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:37][CH:38]=4)=[N:7][C:6]=3[CH:8]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Reactant: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(-c4cnc(NC(=O)OC(C)(C)C)nc4)nc3c2)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a 50 mL sealed tube, N-(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-phenyl)acetamide (1.30 g, 0.0033 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (1.21 g, 0.0050 mol), potassium phosphate (K3PO4) (1.43 g, 0.0067 mol), DMF (35 mL) and water (9 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.274 g, 0.00023 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 105° C. for 2 hours. The reaction mass was cooled and added to ice cold water. The precipitate was obtained and was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 3% methanol in chloroform) to provide the title compound (1.6 g, 87.4%). NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 10.15 (s, 1H), 9.47 (s, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.17 (s, 1H), 7.63 (t, J=8.4 Hz, 2H), 7.49 (t, J=7.8 Hz, 1H), 4.56 (br s, 4H), 3.85 (t, J=3.9 Hz, 4H), 2.10 (s, 3H), 1.49 (s, 9H): LC-MS (ESI): Calculated mass: 542.2; Observed mass [M+H]+: 542.9. (RT=1.39 min).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[O:13][C:14]4[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][C:15]=4[C:16](=[O:19])[C:17]=3[OH:18])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(Cl)(Cl)Cl.CO>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[O:13][C:14]4[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][C:15]=4[C:16](=[O:19])[C:17]=3[O:18][CH2:12][C:8]3[CH:9]=[CH:10][CH:11]=[CH:6][CH:7]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(O)c(=O)c2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(OCc3ccccc3)c(=O)c2c1
Yield: 55 %

Procedure:
Prepared analogously to Example 5.d, starting from 2-[(3-(imidazol-1-yl)-phenyl]-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 55%; TLC (85/15 Chloroform/Methanol) Rf: 0.64; 1H-NMR (d6-DMSO): 10.28 (s broad, 1H), 8.44 (d, 1H), 8.23-8.16 (m, 2H), 8.04-7.9 (m, 2H), 7.85-7.65 (m, 4H), 7.27 (m, 4H), 7.14 (m, 1H), 5.17 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][CH2:30][CH2:29][CH:28]([CH3:33])[CH3:27])[CH:7]=1
Reactant: CC(C)CCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CC(C)CCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 4-methylpentan-1-ol (100 μl; 0.789 mmol), example 47 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH:49]([CH3:51])[CH3:50])[C:42](Cl)=O>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]3[N:19]=[C:42]([C:41]4[CH:45]=[CH:46][C:47]([O:48][CH:49]([CH3:50])[CH3:51])=[C:39]([Cl:38])[CH:40]=4)[O:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.3 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 264 mg, 0.629 mmol) in dioxane (4 ml) was added triethylamine (0.263 ml, 1.89 mmol) followed by dropwise addition of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 33; 176 mg, 0.755 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 90 min, followed by heating at 100° C. for 24 h. The mixture was cooled to room temperature, most of the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound as a pale yellow oil (80 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4ccccc34)c2c1
Yield: 58 %

Procedure:
2-Methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 298 mg of 2-naphthaleneboronic acid, 20 ml of dimethylformamide, 1.9 ml of a saturated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of 2-methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 186° C. (analysis C24H19N3O4S2 % calculated C, 60.36; H, 4.01; N, 8.80; O, 13.40; S, 13.43. % found C, 59.78; H, 4.05; N, 8.76; S, 13.34).
Reaction SMILES: [C:1]([N:5]([C:14]1[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:19])=[CH:16][CH:15]=1)[O:6][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[C:1]([N:5]([C:14]1[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:19])=[CH:16][CH:15]=1)[OH:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)N(O)c1ccc(C(=O)Nc2ccccn2)cc1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of 0.95 g (2.37 mmol) of compound 5 in THF (3 mL) was added 2.84 mL (2.84 mmol) of 1 M solution of tetrabutylammonium fluoride in THF at room temperature, and the solution was stirred for 1 hour. After completion of the reaction, 2 mL of water was added to quench the reaction. Ethyl acetate and sat'd NaHCO3 solution were added to the mixture, and the organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc=10:1) to give 0.44 g of compound 6 in 65% yield.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([Cl:35])[CH:34]=1)[CH2:31][C:30](=O)[CH2:29][CH2:28]2>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][CH:30]2[CH2:29][CH2:28][C:27]3[C:32](=[C:33]([Cl:35])[CH:34]=[C:25]([Cl:24])[CH:26]=3)[CH2:31]2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Product: CCCC(NC1CCc2cc(Cl)cc(Cl)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Dichloro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 25.9, 26.0, 28.5, 29.4, 34.0, 34.6, 36.5, 52.7, 53.4, 55.5, 58.9, 60.9, 67.5, 68.9, 104.6, 126.7, 127.2, 127.3, 131.2, 131.4, 131.8, 137.4, 139.9.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(F)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A solution of 2-fluoro-5-methylbenzaldeyde (1.80 g, 12.3 mmol) in 3:1 tetrahydrofuran:methanol (82 ml total) at 0° C. was treated with sodium borohydride (0.93 g, 24.6 mmol). The reaction was slowly warmed to ambient temperature and stirred for about three hours. The reaction was quenched with water, transferred to a separatory funnel, and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by high performance liquid chromatography to yield 1.3 grams (76%) of a clear oil.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][C@H:7]([NH2:9])[CH3:8])[NH:3][CH:2]=1.[CH2:10]=O.[OH-].[Na+]>P([O-])([O-])([O-])=O.C(O)C>[CH3:8][C@H:7]1[NH:9][CH2:10][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH2:6]1
Reactant: C=O
Reactant: C[C@@H](N)Cc1cnc[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1Cc2[nH]cnc2CN1
Temperature: 37 °C
Reaction time: 12 h

Procedure:
0.5 g (R)-2-(3H-imidazol-4-yl)-1-methyl-ethylamine are dissolved in 50 mL phosphate buffer (pH 7) and combined with 1.35 mL formaldehyde. The pH is adjusted to 8 by the addition of 1 N NaOH and the reaction solution is stirred for 12 h at 37° C. Then by the further addition of 1 N NaOH the pH is adjusted to 12, the solvent is eliminated in vacuo, the residue is suspended in ethanol and filtered to remove any undissolved constituents. After elimination of the ethanol in vacuo a crude product is left which is further used directly for the following reactions.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[O:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A solution of 26.28 g (0.141 mol) of 4-bromobenzyl alcohol and 19.1 g (0.28 mol) of imidazole in 100 mL of methylene chloride was treated dropwise with a solution of 21.18 g (0.14 mol) of t-butyldimethylsilyl chloride in 50 mL of methylene chloride. The reaction mixture was stirred at room temperature for 30 minutes then transferred to a separatory funnel and washed with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum giving 41 g of the product as a colorless, viscous oil. 1H NMR (200 MHz, CDCl3): 0.09 (s, 6H), 0.93 (s, 9H), 4.67 (s, 2H), 7.18 (d, 8 Hz, 2H), 7.43 (d, 8 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:21][N:20]=1>C1(C)C=CC=CC=1>[C:25]1([C:23]2[C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][N:20]=[C:19]([NH:7][CH2:8][CH:9]3[CH2:10][CH2:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC1CCC(C(=O)O)CC1
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=C(O)C1CCC(CNc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
550 mg (1.69 mmol) of cesium carbonate were added to a suspension of 133 mg (0.84 mmol) of 4-aminomethylcyclohexanecarboxylic acid in 5 ml of toluene, and the mixture was stirred at room temperature. After 30 minutes, 150 mg (0.56 mmol) of 2-chloro-4,5-diphenyl-pyrimidine were added, and the mixture was stirred at 120° C. for 31 hours. The solvent was removed in vacuo and the residue was mixed with dichloromethane and water. The resulting precipitate was filtered off with suction. 135 mg (62%) of the desired product were obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([OH:10])[CH:7]=2)[O:2]1.[Br:11]Br>C(O)(=O)C>[Br:11][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[OH:10]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1cc2c(cc1Br)OCO2
Temperature: 0 °C

Procedure:
To a solution of 0.18 mol (25 g) of 4,5-methylenedioxyphenol in 125 ml of glacial acetic acid, a solution of 0.16 mol (29 g) of bromine in 145 ml of glacial acetic acid is added slowly, the temperature of the reaction medium being maintained at between 15° and 25° C. When the addition is complete, the reaction medium is poured into 1.5 liters of ice-cold water. The expected product precipitates. After being drained, it is washed with water until the solvent has been removed. After being dried under vacuum in the presence of potassium hydroxide, it is recrystallized from a petroleum ether/ethyl acetate mixture or from cyclohexane. It melts at 84° C. (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:8])=[CH:5][C:4]=1[CH3:23])#[N:2].[H-].[Na+].I[CH3:27]>CN(C=O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[CH3:27])=[O:8])=[CH:5][C:4]=1[CH3:23])#[N:2]
Reactant: Cc1cc(C(=O)Nc2ccccc2-c2ccco2)ccc1C#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)c2ccccc2-c2ccco2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-cyano-N-(2-furan-2-ylphenyl)-3-methylbenzamide from Example 21B (222 mg, 0.734 mmol) in DMF (8.0 ml) was added sodium hydride (60%, 44 mg, 1.10 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 45 min. Iodomethane (68 μl, 1.10 mmol) was added and the mixture was stirred for 18 h. The mixture was evaporated in vacuo and the residue was taken up in EtOAc, washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant pet.ether:EtOAc 80:20) to give a brown solid; yield 198 mg, 85%.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:43][C:38]1[CH:37]=[C:36]([C:34]([CH3:35])=[CH:33][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)CCN(C)C2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.7 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (63 mg, 0.31 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol), K3PO4 (134 mg, 0.63 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 45 mg of 9-(2-(3,4-dichlorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (CD3OD) TFA SALT 7.82 (d, 1H), 7.58 (d, 2H), 7.36 (d, 1H), 7.15 (m, 2H), 7.0 (s, 1H), 4.65 (m, 1H), 4.40 (m, 1H), 3.85 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:37]2[C:38]([Cl:42])=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,6-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 47%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:28]([Si:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 878.8 %

Procedure:
To 4-(tert-butyl-diphenyl-silanyloxy)-piperidine-1-carboxylic acid tert-butyl ester (54 mg, 0.124 mmol) was added 4M HCl/dioxane (2 mL) and CH2Cl2 (5 mL). The reaction mixture was stirred at RT for 2 h. 4M HCl/dioxane (3 mL) added and reaction stirred for a further 1 hr. The reaction mixture was concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with CH2Cl2 and increasing the polarity to 10% MeOH/CH2Cl2 to obtain 4-(tert-butyl-diphenyl silanyloxy)-piperidine as a cream foam (370 mg, 79%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:36]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (bromomethyl)benzene (0.67 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 51%).