Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:7][C@@H:28]2[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:22])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
Aluminum chloride (2.15 g, 16.12 mmol) was added to a stirred mixture of 1,2-dimethoxybenzene (2.03 g, 14.65 mmol) in anhydrous methylene chloride (20 ml) in an ice bath. Then a solution of 4-methoxybenzoyl chloride (2.50 g, 14.65 mmol) in anhydrous methylene chloride (50 ml) was added. The mixture was allowed to warm up to rt, then refluxed overnight. After cooling down to rt, the mixture was poured to ice water (50 ml), stirred for 20 min., and extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with sat. NaHCO3 (3×50 ml), H2O (2×50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane) to give (3,4-dimethoxy-phenyl)-(4-methoxy-phenyl)methanone as an off-white solid (3.66 g, 92%); 1HNMR (CDCl3) δ 7.80 (d, J=8 Hz, 2H, Ar), 7.44 (d, J=1 Hz, 12H, Ar), 7.37 (dd, J=1 Hz and 8 Hz, 1H, Ar), 6.97 (d, J=8 Hz, 2H, Ar), 6.90 (d, J=8 Hz, 1H), 3.96 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.89 (s, 3H, OCH3). The product was carried over to the next step.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)C(C)C)(C)C.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[C:7]([O:6][C:4]([C@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:2][NH:1][C:46]([NH:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47])=[O:5])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN)C(=O)OC(C)(C)C
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CNC(=O)Nc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.8 g of 2(R)-[2-amino-1(R)-(tert-butoxycarbonyl)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide prepared as described in Example 33, part (i), 0.325 ml of N,N-diisopropylethylamine and 0.21 ml of phenyl isocyanate in 10 ml of dimethylformamide was stirred at 60° C. under nitrogen for 2.5 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate solution was separated and washed with sodium hydrogen carbonate solution and with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether and there was obtained 0.705 g of 2(R)-[1(R)-(tert-butoxycarbonyl)-2-(3-phenylureido)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>ClCCl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To 4-(methylthio)aniline (1 mL, 8.19 mmol) in dichloromethane (20 mL) was added pyridine (2 mL, 24.6 mmol). The resulting solution was cooled to 10-15° C. and 4-chlorobenzoyl chloride (1.14 mL, 9.00 mmol) was added over 5 min. The mixture was stirred at room temperature for 90 min. The precipitate was filtered off, washed with dichloromethane, 1M aqueous sodium hydroxide solution and 1M aqueous hydrochloric acid solution to afford 2.12 g (93%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.C[Al](C)C.C.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25](=O)[O:26]C)[N:18]=1>C(Cl)Cl.C(O)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25]([NH:10][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[O:26])[N:18]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: COC(=O)Nc1nc(C)cc(C)n1
Agent: C
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2)n1
Reaction time: 66 h

Procedure:
To a slurry of 3-pyridinesulfonamide (1 m mole) in methylene chloride is added 2 m mole of trimethylaluminum. Following methane evolution, the reaction mixture becomes homogeneous, whereupon 1 m mole of methyl (4,6-dimethylpyrimidin-2-yl)carbamate is added, and stirring is continued for 66 hours. Aqueous acetic acid is added and the product is extracted into methylene chloride. The solvent is evaporated and the product is isolated by trituration on chromatography.
Reaction SMILES: C([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:36][CH2:35][C:30]4(OCCO4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH:38][C@@H:39]([CH2:52][NH2:53])[CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1.CNC1SC(=CC2C=CC(N3CCC(=O)CC3)=CC=2)C(=O)N=1.NCC(C1C=CC(O)=C(NS(C)(=O)=O)C=1)O>>[OH:38][C@H:39]([CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)[CH2:52][NH:53][CH:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:20]=[C:16]3[S:15][C:14]([NH:13][C@@H:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:3])=[O:37])=[N:18][C:17]3=[O:19])=[CH:22][CH:23]=2)[CH2:36][CH2:35]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1)C(=O)OCC
Agent: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: O=C(O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester (which was obtained in Intermediate 34) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedures of Intermediate 18, Example 1 and Example 9 as a yellowish solid; mp >270° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.70 (m, 2 H), 1.80-4.30 (m, 17H), 6.50-6.80(m, 2 H), 6.80-7.10(m, 3 H), 7.23(d, J=8.4 Hz, 2 H), 7.37 (s, 1 H), 10.61(brs, 1 H), 11.01 (brs, 1 H); MS (ES) m/z: 320.3 ((M+2 H)2+, 100%); 639.4 (MH+, 60%); HRMS Calcd. for C30H35N6O8S (MH+): 639.2231. Found: 639.2233.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:16]\[N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(C[N+](=O)[O-])c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CN(C)/C=C(\C(=O)c1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 1-(4-bromophenyl)-2-nitroethanone (5.38 g, 0.022 mol, Seter J. et al., Isr. J. Chem., 4, 7 (1966)) and N,N-dimethylformamide dimethylacetal (2.9 g, 0.024 mol) and catalitic amount of p-TsOH in THF (100 mL) was refluxed for 10 h. The mixture was cooled to room temperature and concentrated in vacuo. The reaction mixture was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give title compound (2.8 g, 43%).
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[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([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[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure II, 1-{6-chloro-4-[trans-4-(dimethylamino)cyclohexyl amino)-1,5-naphthyridin-3-yl)ethanone (61 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 (76 mg, 90%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.36 (d, J=8.9 Hz, 1H), 8.10 (s, 2H), 5.65-5.55 (m, 1H), 3.52-3.43 (m, 1H), 2.91 (s, 6H), 2.76 (s, 3H), 2.66-2.56 (m, xH), 2.33-2.26 (m, 2H), 1.88-1.71 (m, 4H). ESI MS m/z 473 [M+H]+; HPLC>99% (AUC), tR=9.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:22]3[CH2:21][CH2:20][CH:19]([N:18]4[C:17]5[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=5[NH:15][C:14]4=[O:13])[CH2:24][CH2:23]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 34.8 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1: 0.186 g), 4-(2-keto-1-benzimidazolinyl)piperidine (Aldrich; 0.201 g), triethylamine (0.094 g), and dichloromethane (4 mL) is stirred at 45° C. for 20 h, after which time the mixture is cooled. Dichloromethane and aqueous sodium bicarbonate are added and the solids collected and dried. Additional material is obtained by concentration of the organic layer. Crystallization from methanol/dichloromethane/hexane gives 0.123 g of the title compound; mp 210-211 (decomp)°C; IR (mineral oil) 1695, 1486, 1338, 736, 1074 cm-1. 1H NMR (DMSOd6) δ1.63, 2.19, 2.38, 3.08, 3.66, 4.12, 6.96, 7.23, 7.54, 7.87, 8.80, 10.84.
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10]C(C)(C)C)=[O:9])=[CH:6][C:5]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)OC(C)(C)C)cc1Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)O)cc1Oc1ccccc1
Yield: 81.3 %

Procedure:
To a solution of tert-butyl 4-isopropyl-3-phenoxybenzoate (150 mg, 0.48 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The resultant mixture was stirred at room temperature for 30 minutes. Thin layer chromatography showed that starting material was consumed completely. The solution was concentrated to give 4-isopropyl-3-phenoxybenzoic acid (100 mg, 81.3%) as a white solid which was used in the next step directly. LRMS (M+H+) m/z: calcd 257.11. found 257. 1H NMR (300 MHz, DMSO) δ 12.94 (s, 1H), 7.71 (m, 1H), 7.68 (m, 1H), 7.40 (m, 2H), 7.38 (s, 1H), 7.36 (m, 1H), 7.11 (m, 2H), 1.22 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12]>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([CH3:12])[N:6]2[N:5]=[C:4]([OH:7])[N:3]=[C:2]2[N:1]=1
Reactant: Nc1n[nH]c(=O)[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(O)nc2n1
Yield: 88.2 %

Procedure:
To a solution of 5-amino-2,4-dihydro-3H-1,2,4-triazol-3-one (29 g, 0.29 mol) in glacial acetic acid (140 mL) was added pentane2,4-dione (29 g, 0.29 mol) and the solution was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. The solid was filtered and washed with ethanol (200 mL) to give the product (42 g, 80%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH:42][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1nc2ccccc2[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H-benzo[d]imidazol-2-yl)methanamine (10.24 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12.8 mg, 0.023 mmol, 49.3% yield): LCMS=561.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.58 Hz), 7.51-7.79 (10 H, m), 7.34 (2 H, dd, J=6.05, 3.19 Hz), 5.27 (1 H, s), 4.76-4.94 (2 H, m); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:20][CH2:19][CH2:18][O:17]1>O>[OH:17][CH2:16][CH2:20][CH2:19][CH:18]1[CH:19]2[CH2:20][CH2:16][O:17][CH:18]2[C:13]2[CH:14]=[C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[CH:10][C:11]=2[NH:12]1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: OC1CCCO1
Solvent: O
Product: OCCCC1Nc2ccc(Nc3ccccc3)cc2C2OCCC12
Temperature: 25 °C
Yield: 86 %

Procedure:
The mixture of 4-(N-phenylamino)-aniline (2 mmol), 2-hydroxy-tetrahydrofuran (6 mmol) and InCl3 (0.2-0.4 mmol) in water (5 mL) was stirred at room temperature. The reaction was monitored by TLC. After 24 h stirring at room temperature, the reaction mixture was extracted with ethyl ether (3×20 mL). Removal of solvent and flash column chromatography gave 1,2,3,4-tetrahydroquinoline derivatives in 86% yield (cis:trans=46:54).
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=O)=O.[ClH:18]>CO.O1CCOCC1>[ClH:18].[CH3:1][S:2][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CSC1CCNCC1

Procedure:
A solution tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (100 mg, 0.38 mmol) in methanol (1 mL) and 4 N hydrogen chloride in dioxane (4 mL) was refluxed for 2 min and then concentrated to provide 4-(methylthio)piperidine hydrochloride salt as a colorless solid. MS (EI) for C6H13NO2S: 163 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1>>[C:8]1([C:6]2[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=[C:2]([C:19]3[CH:20]=[CH:21][S:17][CH:18]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: OB(O)c1ccsc1
Product: O=C(O)c1cc(-c2ccsc2)nc(-c2ccccc2)n1

Procedure:
This compound was prepared using a method analogous to that of Example 32, step 32.1, 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid replacing intermediate 14.1 and thiophene-3-boronic acid replacing phenylboronic acid. The crude was however crystallized (EtOH/H20 2/1). LC-MS (A): tR=1.03 min; [M+H]+: 283.03.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:8])(=O)=O.CC(C)([O-])C.[K+].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[N:45]=[CH:44][C:43](O)=[CH:42][CH:41]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1.Cl>O.CS(C)=O>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[CH:41]=[CH:42][C:43]([O:5][CH2:6][C@H:7]([O:9][CH:10]5[CH2:15][CH2:14][CH2:13][CH2:12][O:11]5)[CH3:8])=[CH:44][N:45]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: C[C@@H](COS(C)(=O)=O)OC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OC1CCCCO1
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (214 mg, 0.90 mmol) and potassium tert-butoxide (200 mg, 1.8 mmol) were added to a dimethyl sulfoxide solution (5 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (300 mg, 0.90 mmol) obtained in Example 6-3), and the reaction solution was stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, then water and aqueous 1 N hydrochloric acid solution (0.9 ml, 0.9 mmol) were added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-[(5-{[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxy}pyridin-2-yl)oxy]quinazoline-4-amine (322 mg, yield: 75%) as a pale brown solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]1([CH2:12][CH2:13][N:14]2[C:20](=[O:21])[C@H:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[NH:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][C:3]([N:17]1[C@@H:18]2[CH2:24][CH2:23][CH2:22][C@@H:19]2[C:20](=[O:21])[N:14]([CH2:13][CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]1=2)=[O:4]
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1CCc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of bromoacetyl bromide (0.29 mL, 3.3 mmol) in dichloromethane (5 mL) was added dropwise a solution of (3aR*,10aS*)-9-(2-phenylethyl)-2,3,3a,4,9,10a- hexahydrobenzo [b]cyclopenta[e][1,4]diazepin-10(1H)-one (0.92 g, 3.0 mmol) in dichloromethane (5 mL). The solution was stirred for 3 hours at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica-gel column chromatography (hexane - ethyl acetate 5:1,then 1:1) to afford the desired product (924 mg, 72%). Oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C@@H:11]3[C@@H:6]([N:7]([C:15]([C:17]4[CH:25]=[CH:24][C:20]5[NH:21][CH:22]=[N:23][C:19]=5[CH:18]=4)=[O:16])[CH2:8][CH2:9][CH2:10]3)[CH2:5][C:4]=2[C:3]=1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:39](OCC)(OCC)[O:40]CC>CO>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:7]3[C@H:6]4[C@H:11]([C:12]5[CH:13]=[C:14]6[O:40][CH:39]=[N:1][C:2]6=[CH:3][C:4]=5[CH2:5]4)[CH2:10][CH2:9][CH2:8]3)=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: Nc1ccc2c(c1O)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3cc4ocnc4cc3C[C@H]21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of (cis-7-amino-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-(1H-benzoimidazol-5-yl)-methanone (100 mg), 4-toluenesulfonic acid hydrate (5 mg), triethyl orthoformate (40 μL), and methanol (1 mL) is stirred at 60° C. for 2 h. After cooling to room temperature, the mixture is concentrated and the residue is dissolved in ethyl acetate. The resulting solution is washed with 1 M NaOH solution, dried (Na2SO4), and concentrated to give the title compound. Yield: 50 mg (49% of theory); LC (method 1): tR=2.24 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[H][H].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2)cc1OC

Procedure:
The 1-(4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane prepared in (2) above in an amount of 5.5 g (0.015 mol) was dissolved in methanol (200 ml) and ethyl acetate (200 ml) and, thereafter, 10% Pd/C (2 g) was added to the resulting reaction solution and the reaction mixture was stirred in hydrogen gas for 8 h, followed by filtration and concentration under vacuum to yield the end compound 1-(4-aminophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (5 g).