Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[CH2:3]1.C[O:16][CH:17](Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([CH3:12])=[C:7]([CH:17]=[O:16])[C:8]=2[CH3:11])[CH2:3]1
Reactant: Cc1cc(C)c2c(c1C)CC(C)(C)C2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1C=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 24.5 g of the 2,2,4,6,7-pentamethylindane in 100 ml of dry dichloromethane was continuously added 18.5 ml of α,α-dichloromethyl methyl ether and 17.6 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 26.8 g of the title compound as yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: Cc1cccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)n1
Yield: 84.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-6-methylpyridine (0.43 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([O:17][CH3:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=2)=[CH:8][CH:7]=1>C(OC(=O)C)(=O)C.O.C(Cl)Cl.C(OCC)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([O:17][CH3:18])[C:15]([C:19]([F:21])([F:22])[F:20])=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]=2[N+:1]([O-:4])=[O:2])=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(OC)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccc(Cl)cc2)n(OC)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Fuming nitric acid (90%, 0.75 mL, 0.0167 mol) is added dropwise to a 5° C. solution of 5-(p-chlorophenyl)-1-methoxy-2-(trifluoromethyl)pyrrole-3-carboxylic acid, ethyl ester (3.27 g, 0.0094 mol) in acetic anhydride. After stirring at room temperature overnight, the reaction mixture is diluted with water and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a thick yellow liquid. Chromatography using silica gel, methylene chloride and 2% ethyl acetate in methylene chloride as eluent gives a solid. Recrystallization from hexanes gives the title compound as a white solid (2.02 g, 55%), mp 90°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:14]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+]>C(O)C.O.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:14]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi Block, Inc., 2.507 g, 14.30 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (5.24 g, 13.62 mmol), Amphos (bis-4-(di-tert-butylphosphanyl)-N,N-dimethylaniline-dichloropalladium, 0.482 g, 0.681 mmol) and potassium acetate (4.10 g, 41.8 mmol) in ethanol (100 mL) and water (10 mL) was purged with argon and heated at 100° C. overnight. The reaction mixture was cooled, concentrated to remove the EtOH and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by ISCO chromatography (hexanes/EtOAc, 15 to 50%) to give 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.62 g, 7.54 mmol, 55.4% yield) as a colorless sticky solid. m/z (ESI, +ve ion) 481.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][N:32]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1)[CH3:33]
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CCl)c1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)Cc1cc(C(=O)Nc2nc(-c3ccco3)c(-c3ccncc3)s2)ccn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
Compound 107 (150 mg, 0.387 mmol) was dissolved in N,N,N′-trimethylethylenediamine (1 mL), followed by stirring at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) and then crystallized from diisopropyl ether to afford the entitled Compound 109 (70 mg, 40%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)[CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrBr>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Cc1ccc2ccc(-c3ccccc3)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
2-Methyl-7-phenylnaphthalene (5.4 g, 25 mmole) and N-bromosuccinimide (4.4 g, 25 mmole) were suspended in CCl4 (60 ml). Benzoylperoxide (0.25 g) and Br2 (20 mkl) were added, the mixture was refluxed for 3 h, filtered, evaporated and dried giving practically pure product. The yield 7.4 g (˜100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH3:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(Br)cc(N)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A heterogeneous reaction mixture of 4-bromo-2-methoxy-6-nitrotoluene (500 mg, 2.032 mmol), acetic acid (20 ml), and iron (1135 mg, 20.32 mmol) was stirred at rt for 24 hr. Ethyl actetate was added, then the mixture was filtered through celite and the filtrate concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with further ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford the title compound. MS m/z: 218.0 (M+H)+.
Reaction SMILES: [OH:1]O.[N+:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C(O)(=O)C>[N+:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N+:15]([O-:1])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Reactant: OO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2cc[n+]([O-])cc2)c1
Temperature: 70 °C

Procedure:
Aqueous hydrogen peroxide (27.5 wt. %, 6.4 ml) was added to a solution of 4-(3-nitrophenyl)pyridine (5 g) in glacial acetic acid (50 ml), and the mixture was heated to approx 70° C. overnight. The mixture was then evaporated and the residue was triturated with ether. The product (6 g), still containing some acetic acid, was used without further purification. Mp 193°-196° C.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Si:27]([O:34][CH:35]([C:41]1([CH2:45][CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42]1)[CH2:36][CH:37]=[CH:38][CH2:39]O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl.CCCCCC>[Br:1][CH2:39][CH:38]=[CH:37][CH2:36][CH:35]([C:41]1([CH2:45][CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42]1)[O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CCCC1(C(CC=CCO)O[Si](C)(C)C(C)(C)C)CCC1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCC1(C(CC=CCBr)O[Si](C)(C)C(C)(C)C)CCC1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Bromine (0.17 mL, 3.22 mmol) was added to a solution of triphenylphosphine (844 mg, 3.22 mmol) and imidazole (219 mg, 3.22 mmol) in CH2Cl2 (11.0 mL) at 23° C. After 0.5 h a solution of the alcohol 7 (838 mg, 2.68 mmol) in CH2Cl2 (2.7 mL) was added. The reaction was stirred for 1 h, diluted with hexane and then filtered through celite. The filtrate was concentrated in vacuo and purified by FCC (silica gel, 100% hex) to give 870 mg (86%) of the bromide 8 as a clear, light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:12]=3[O:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[NH:19][CH:20]=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][C:30](=[O:32])[CH3:31].O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:12]=3[O:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:19]([CH2:29][C:30](=[O:32])[CH3:31])[CH:20]=[O:21]
Reactant: CC(=O)CCl
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2noc3c2CCCC3=O)ccc1N(C=O)CC(C)=O
Temperature: 55 °C
Yield: 33.1 %

Procedure:
To a mixture of N-(2-methoxy-4-(7-oxo-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)phenyl)formamide (2.66 g, 9.28 mmol), Cs2CO3 (5.37 g, 27.9 mmol), and KI (308 mg, 1.86 mmol) in dry DMF (40 ml) was added chloroacetone (7.72 g, 18.57 mmol) dropwise. The reaction was stirred at 55° C. over night. Reaction mixture was worked up with water and DCM, organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and hexanes as the eluent to furnish 1.05 g of the title compound, MS(M+H)+=343.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:13]([NH:20][C:10](=[O:11])[CH2:9][CH2:8][CH:7]([OH:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(c2ccccc2)O1
Solvent: c1ccccc1
Product: O=C(CCC(O)c1ccccc1)NCc1ccccc1
Yield: 71.5 %

Procedure:
A solution of γ-phenyl-γ-butyrolactone (5.17 g, 31.8 mmol) and benzylamine (3.48 ml, 31.8 mmol) in 200 ml of benzene was refluxed under a nitrogen atmosphere for 20 hours. An additional 1.75 ml (16.0 mmol) of benzylamine was added and the solution refluxed for 24 hours. When the reaction was partitioned with 1 N HCl a white solid precipitated. The solid was collected by filtration and dried to give N-benzyl-4-hydroxy-4-phenyl-butyramide (6.12 g, 72%) as a white solid, mp 92-94° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:17][CH2:16]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 80.1 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1,5-naphthyridin-3-yl)ethanone (60 mg, 0.16 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (54 mg, 60%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.91 (s, 1H), 8.46 (d, J=9.1 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H), 8.16 (s, 2H), 4.63 (br s, 2H), 3.70-3.54 (m, 4H), 3.32-3.24 (m, 2H), 3.13-3.03 (m, 2H), 2.67 (s, 3H), 2.22-1.96 (m, 7H), 1.82-1.69 (m, 4H);
Reaction SMILES: [H-].[Na+].[O:3]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][C:10]3[O:3][CH:4]=[CH:5][C:6]2=3)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc2occc2[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2occc2n1Cc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
To a mixture of sodium hydride (0.29 g, 55% dispersion in paraffin liquid) and DMF (10 mL) was added methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (0.5 g) under ice-cooling, followed by stirring for 10 minutes and further 1-(bromomethyl)-4-chlorobenzene (0.81 g) was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1-3/1) to obtain 4-(4-chlorobenzyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.35 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.S(OC)(O[CH3:15])(=O)=O.C(N(CC)CC)C.C1COCC1>C(OCC)C>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH3:15]
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C
Temperature: 60 °C

Procedure:
The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was-distilled under high vacuum to yield a colorless product.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[C:29]([NH:31]C(C)(C)C)=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[S:22][C:21]=3[C:29]([NH2:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(=O)NC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(N)=O)s1
Reaction time: 30 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid was added (2.5 mL) to 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene,2-carboxamide (165 mg, 0.417 mmol, see step (d) above), and one drop (ca. 0.05 mL) of anisol was added to the reaction mixture. The mixture was stirred under a N2 atmosphere for 30 hours and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH2Cl2:MeOH (85:15)) to give the sub-title compound (117 mg, 0.345 mmol) in 73% yield.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH2:6]1.[OH-].[K+]>C(O)(C)C.O>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:9]2[CH2:8][CH:7]3[CH2:6][N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:12][CH:11]3[CH2:10]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CN1CC2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)CN1CC2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A solution of {5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-acetic acid methyl ester (233 mg, 0.55 mmol) in 1:1 isopropanol/water (2 mL) was treated with KOH (62 mg, 1.1 mmol). The reaction stirred at rt overnight. The reaction was acidified to pH 6.5 and extracted with 25% isopropanol/CHCl3 to afford pure acid as a white powder (67 mg, 30%). MS (ESI): Mass calcd for C22H23N3O3S, 409.5; m/z found, 410.2 [M+H]+; 1H NMR (400 MHz, CD3OD): 7.78 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.45-7.35 (m, 3H), 7.34-7.28 (m, 1H), 3.76 (s, 2H), 3.64 (s, 2H), 3.55-3.35 (m, 4H), 3.12-2.97 (m, 2H), 2.94 (d, J=9.9 Hz, 2H), 2.52-2.34 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([Br:30])C(=O)C1>CC#N>[Br:30][C:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:14]=2)[CH:9]=[CH:10][C:11]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(C)(=O)=O)cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccc(S(C)(=O)=O)cc2c1Br
Yield: 92.8 %

Procedure:
A mixture of 202 (2.05 g, 6.38 mmol) and NBS (1.31 g, 7.36 mmol) in MeCN (40 mL) was stirred at reflux for 2 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2, and the solution was washed with 10% aqueous Na2SO3 and water, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2/EtOAc (19:1), followed by recrystallization from MeOH to give tert-butyl 1-bromo-7-(methylsulfonyl)-2-naphthylcarbamate (203) (2.37 g, 93%) as a white solid: mp 166-167° C.; 1H NMR [(CD3)2SO] δ 8.99 (s, 1H), 8.70 (d, J=1.7 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.5, 1.8 Hz, 1H), 7.97 (d, J=8.9 Hz, 1H), 3.32 (s, 3H), 1.50 (s, 9H). Anal. (C16H18BrNO4S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11](OC)=[O:12])[CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.C([Mg]Cl)(C)C.[NH4+].[Cl-]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([NH:30][CH:27]2[CH2:29][CH2:28]2)=[O:12])[CH:7]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(N3CCN(C)CC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Cl)nc(N2CCN(C)CC2)c1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 3-[5-chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 107b) in tetrahydrofuran (6 mL) under nitrogen was added cyclopropylamine (0.15 mL) followed by iso-propylmagnesium chloride (2M in tetrahydrofuran, 0.8 mL), portionwise. After 1 h, sat. aqueous NH4Cl was added and the mixture extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 9 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 5 (9% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.13 and 2.17 (2s, 3H), 2.65 and 2.92 (2t, 2H), 3.50 and 4.05 (2t, 2H), 4.41 and 4.93 (2s, 2H), 6.29-7.00 (4d, 2H), 7.36-7.44 (m, 2H), 7.69-7.79 (m, 1H), 7.86-7.98 (2d, 1H), 8.06-8.18 (m, 2H), 8.37 and 8.44 (2s, 1H), 8.52-8.59 (m, 2H); MS (ESI) m/z 414 ([M+H]+).