Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].[C:8]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:8]1([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]3[NH:4][CH2:5][CH2:6][S:7]3)[CH2:18][CH2:19]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1OCCN1CCN(c2ccccc2)CC1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2.21 g of sodium hydroxide are added to a solution of 5.75 g of cysteamine hydrochloride in 200 ml of ethanol, and a solution of 14.28 g of 2-[2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde in 100 ml of ethanol is added thereto. After the mixture is stirred at room temperature for 2 hours, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is recrystallized from ether. 15.54 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)[C:27]1=[O:52]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:51]=[C:45]7[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]7[N:43]=6)[C:27](=[O:52])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 110 °C
Yield: 74.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 141a (130 mg, 0.38 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (146 mg, 0.38 mmol), Pd(dppf)Cl2 (31 mg, 0.038 mmol), K3CO3 (105 mg, 0.76 mmol), and DMF (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1) to afford 141b as brown solid (160 mg, 74.6%). MS: [M+H]+ 567.3.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[C:13]([N:14]4[C:19]=2[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]4)=[CH:12][C:11]([C:24]([O:26]C)=[O:25])=[CH:10][CH:9]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[C:13]([N:14]4[C:19]=2[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]4)=[CH:12][C:11]([C:24]([OH:26])=[O:25])=[CH:10][CH:9]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)COc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)COc1ccccc1-3
Temperature: 60 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of methyl 11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylate (40 mg, 0.11 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at 60° C. for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with hexane and dried in vacuo to give 11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylic acid (26 mg, yield 68.4%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:19]1(B(O)O)[CH2:21][CH2:20]1>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:19]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2CC2)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of methyl 4-bromo-2-methylbenzoate (5.00 g, 20.7 mmol, 1.00 equiv, 95%) in a mixture of toluene and H2O (20 mL/1 mL) were added potassium carbonate (6.10 g, 44.1 mmol, 2.00 equiv), cyclopropylboronic acid (2.30 g, 26.8 mmol, 1.20 equiv), Pd(dppf)Cl2 (900 mg, 1.23 mmol, 0.05 equiv), and Pd(OAc)2 (250 mg, 1.12 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen and stirred at 80° C. overnight. After cooling to room temperature, the mixture was then concentrated in vacuo. The resulting residue was purified via silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to yield 2.68 g (61%) of methyl 4-cyclopropyl-2-methylbenzoate as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:29][CH2:30][CH2:31][CH2:32][S:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[O:8])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1ccsc1
Yield: 76 %

Procedure:
To a solution of 1.00 g (7.80 mmol) of thiophene-3-carboxylic acid and 1.08 g 10.1 mmol) of N-hydroxysuccinimide in 70 ml of methylene chloride, 1.80 g (9.36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.31 g (7.80 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain 1.65 g of the desired compound (yield: 76.1%, colorless powder).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH:27]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 403.81 g/mol.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[NH:11][CH:12]=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.CCN(CC)CC>COCCOC>[Br:24][C:16]1[CH:15]=[C:14]([CH:10]([N+:11]#[C-:12])[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(C(NC=O)S(=O)(=O)c2ccc(C)cc2)cc(Br)c1OC
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Product: [C-]#[N+]C(c1cc(Br)c(OC)c(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 3b (4.75 g, 10.75 mmol) was suspended in dry DME (100 mL) and cooled to −10° C. POCl3 (3.1 mL, 33.1 mol) was added and a mixture of Et3N (7.5 mL, 53.8 mmol) in DME (10 mL) was dropped slowly to the reaction mixture. After stirring for 2 h at −5° C., the reaction mixture was poured into ice water. The water phase was extracted with ethyl acetate, the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuum. By refrigeration over night a brown solid crystallized from the residue, which was collected and dried in vacuum. Yield: 2.75 g (6.71 mmol, 62%); brown solid of mp 109-110° C.; νmax (ATR)/cm−1 2915, 2135, 1593, 1569, 1489, 1452, 1420, 1325, 1295, 1275, 1238, 1199, 1136, 1081, 1048, 1003, 862, 826, 759, 705, 670; 1H NMR (300 MHz, CDCl3) δ 2.47 (3H, s), 3.81 (3H, s), 3.86 (3H, s), 5.46 (1H, s), 6.81 (1H, d, J=2.2 Hz), 7.01 (1H, d, J=2.2 Hz), 7.35 (2H, d, J=8.3 Hz), 7.64 (2H, d, J=8.3 Hz); 13C NMR (75.5 MHz, CDCl3) δ 321.8, 56.2, 60.7, 75.5, 111.5, 117.8, 123.2, 125.0, 129.9, 130.0, 130.5, 146.9, 148.5, 153.6, 166.6; m/z (EI) 256 (52), 254 (45), 244 (78), 242 (100), 200 (30), 123 (48), 91 (31).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:32][O:33][CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][O:33][CH2:34][CH2:35][NH:36][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)NCCOC)ccc21
Yield: 40.5 %

Procedure:
1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (61.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid (133.0 mg), 2-methoxy-ethylamine (38.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 490. 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, m), 8.38-8.32 (2H, m), 8.07 (1H, m), 7.76-7.68 (2H, m), 7.51-7.45 (1H, m), 7.40-7.39 (2H, m), 7.12-7.10 (1H, m), 4.20-4.17 (2H, m), 3.48-3.42 (3H, m), 3.26 (3H, s), 1.48-1.46 (1H, m), 1.32-1.28 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:16][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cc(Br)c1
Reactant: CC(C)N
Solvent: O
Product: CC(C)NS(=O)(=O)c1cc(Br)cc(Br)c1
Reaction time: 2 h

Procedure:
3.0 G. of 3,5-dibromobenzenesulfonylchloride is added to a solution of 17.7 g. of isopropylamine in 25 ml. of water at room temperature. A complete solution results which is stirred for 2 hours and poured onto 250 ml. of water. The precipitate is filtered, washed with water, and dried affording 3,5-dibromo-N-isopropylbenzenesulfonamide, m.p. 105° to 107° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH3:31])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[N:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38].Cl>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH3:31])[CH2:23][C:24]([OH:26])=[O:25])=[N:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38]
Reactant: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)nc3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)nc3)no2)ccc1-c1ccccc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To tert-butyl N-[(5-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}pyridin-2-yl)methyl]-N-methylglycinate (0.550 g; 1.07 mmol) was added HCl solution in dioxan (4 M; 15 mL) and the reaction mixture stirred at ambient temperature for 2 hours and at 80° C. for 1 hour. The reaction mixture was allowed to cool and the suspension was filtered. The solid was washed with ether and dried under vacuum. The residue was triturated with DCM to afford the title compound as an off-white solid (0.420 g, 74%). 1H NMR (DMSO-d6/D2O, 400 MHz) δ 9.31 (1 H, s), 8.58-8.55 (1 H, dd, J=8, 2 Hz), 8.30 (1 H, J=2 Hz), 8.19-8.16 (1 H, m), 7.77 (1 H, d, J=7.6 Hz), 7.42-7.26 (4 H, m), 7.11-7.10 (1 H, m), 4.65 (2 H, s), 4.26-4.12 (4 H, m), 3.21 (3 H, s), 2.92 (3 H, s), 2.00 (3 H, s). LC/MS: 459 (M+H)+. HPLC (Method D) Rt 8.60 min (Purity: 98.5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(COS(C)(=O)=O)n2)CC1
Temperature: 0 °C

Procedure:
tert-Butyl 4-{[6-(hydroxymethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.34 g, 1.10 mmol) and methanesulfonyl chloride (0.13 mL, 1.64 mmol) were dissolved in DCM (15 mL) and stirred at 0° C. (ice bath). DIPEA (0.57 mL, 3.29 mmol) was added to the reaction mixture and stirred for 2 hours. The resulting mixture washed with water (2×15 mL), dried over a phase separator, concentrated in vacuo and was used directly in the next step.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[C:14]([O:17][CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: C[Si](C)(CCl)Cc1cccc(F)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC[Si](C)(C)Cc1cccc(F)c1
Yield: 40.2 %

Procedure:
Chloromethyldimethyl-3-fluorobenzylsilane (0.85 g, 3.93 mmol) and potassium acetate (0.83 g, 8.45 mmol) are refluxed in acetic acid (10 ml) for 48 hours. The mixture is then cooled, poured into water (50 ml) and extracted with diethyl ether (50 ml). The organic layer is washed with water, brine, dried over MgSO4 and the solvent is removed in vacuo. Chromatography (silica gel, hexane/ether-80/20 affords the title compound as an oil (0.38 g, 40% yield).
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]2[S:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21][CH:22]=2)[CH:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:20]1[S:19][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[N:17]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)Br
Reactant: NCCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C(C)NCCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 2-bromopropanoate (182 mg, 1.09 mmol) was added to a mixture of N-(2-amino-ethyl)-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidin-2-amine (300 mg, 0.99 mmol) and N,N-diisopropylethylamine (153 mg, 1.19 mmol) in 1-methylpyrrolidine (8 mL) at rt. After stirring at rt for 24 h, water (50 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]1([CH3:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C=O.[O-:11][S:12]([O-:14])=[O:13].[Na+].[Na+]>O>[C:1]1([S:12]([OH:14])(=[O:13])=[O:11])([CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]1[CH3:7]
Reactant: Cc1ccccc1C
Reactant: O=S([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CC1C=CC=CC1(C)S(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a similar reactor as described in Example 47, there was charged 106 grams of xylene (1.0 mole). There was added with fast stirring, 150 grams of fuming H1SO4 (20% SO3) at 20°-40° C. over a period of two hours. Next, the reaction was heated at 90°-95° C. for 2.25 hours. It was then cooled to room temperature and 138.0 grams of water was added at 30°-40° C. Then to 200 grams of sulfonation product (0.508 mole) was added 20.5 grams of 37% formaldehyde (0.254 mole) and heated to reflux (110° C.) for eight hours. At the end of this period, all formaldehyde was reacted as determined via standard Na2SO3 titration procedure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:13][CH2:14][N+:15]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[NH2:15][CH2:14][CH2:13][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(CC[N+](=O)[O-])c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCN)c1cccc(Br)c1
Reaction time: 0.02 h
Yield: 83.5 %

Procedure:
To a solution of methyl 2-(3-bromophenyl)-4-nitrobutanoate (3.1 g, 11 mmol) and NiCl2.6H2O (5.4 g, 23 mmol) in methanol (12 mL) was added NaBH4 (1.3 g, 34 mmol). The reaction mixture was stirred for 1 minute and was quenched by adding ice water. The mixture was filtered, and the filtrate was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give methyl 4-amino-2-(3-bromophenyl)-butanoate (2.5 g, 82%) as a white solid, which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)=[N:17][CH:18]=1.Cl[C:38]1[C:43]([CH:44]=[O:45])=[C:42]([N:46]2[CH2:59][CH2:58][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[C:56]([F:57])=[C:48]3[C:47]2=[O:60])[N:41]=[CH:40][CH:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24]([C:38]3[C:43]([CH:44]=[O:45])=[C:42]([N:46]4[CH2:59][CH2:58][N:49]5[C:50]6[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=6[C:56]([F:57])=[C:48]5[C:47]4=[O:60])[N:41]=[CH:40][CH:39]=3)[CH:25]=2)=[N:17][CH:18]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 90 °C
Yield: 25.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 155a (171 mg, 0.35 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (120 mg, 0.35 mmol), K3PO4 (146 mg, 0.69 mmol), PdCl2(dppf) (28 mg, 0.035 mmol), sodium acetate (56 mg, 0.69 mmol), water (5 drops) and acetonitrile (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40/1 dichloromethane/methanol to afford 156a as a yellow solid (60 mg, 25%). MS-ESI: [M+H]+ 681.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH3:14])=[C:5]2[C:15]([OH:17])=[O:16].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>C(OCC)(=O)C>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH3:14])=[C:5]2[C:15]([OH:17])=[O:16])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)O)c2cc(O)ccc2n1C(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)c(C(=O)O)c(C)n2C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 10 g of 5-hydroxy-1-isopropyl-2-methyl-3-indolecarboxylic acid in 100 ml of ethyl acetate was added 15 ml of pyridine, and then to the mixture was added 10 ml of acetic anhydride. The whole mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of ice-cold water. After the mixture was acidified with 10% hydrochloric acid, the precipitated crystals were filtered and washed with water and then ethyl acetate to give 6.4 g of 5-acetoxy-1-isopropyl-2-methyl-3-indolecarboxylic acid. To a suspension of the compound in 100 ml of benzene was added 3 ml of thionyl chloride. After the mixture was refluxed for 3.5 hours, the solvent was distilled off. To the residue was added 50 ml of toluene and the mixture was concentrated. After the excess thionyl chloride was distilled off, the residual oil was dissolved in 100 ml of toluene. To the solution were added 5 g of 4-amino-1-(2-phenylethyl)piperidine and 10 ml of pyridine and the mixture was stirred at room temperature for 4 hours. After the completion of reaction, the crystals were filtered with suction, and washed with water and then ethyl acetate to give 8 g of 5-acetoxy-1-isopropyl-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide hydrochloride, melting at 242°-245° C. with decomposition.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>ClCCl>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([O:15][CH2:14][C:13]([OH:32])=[O:12])[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 100 %

Procedure:
Trifluoroacetic acid (2 mL) is added to a solution of [1-(4-trifluoromethyl-phenyl)-piperidin-4-yloxy]-acetic acid tert-butyl ester (769 mg; 2.14 mmol, prepared in accordance with Example 10) in dichloromethane (2 mL). The reaction mixture is stirred until complete conversion is observed, is then concentrated under reduced pressure and co-evaporated with toluene (10 mL) to yield the desired product (985 mg, 2.14 mmol).