Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:1]1([CH2:7][C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccccc1)Nc1ccccc1
Temperature: 0 °C
Yield: 65.6 %

Procedure:
A mixture of 5.84 g (37.81 mmol) phenylacetyl chloride and 50 mL benzene was stirred at 0° C. A solution of 3.52 g (2.0 equivs.) aniline and 50 mL benzene was added dropwise. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 3 hrs. The mixture was poured into 100 mL water and was extracted with 3×100 mL ethyl acetate. The organic layers were combined and washed sequentially with 100 mL portions of 5% aqueous hydrochloric acid, water, saturated sodium carbonate and water. The organic layer was dried, filtered and solvent was removed from the filtrate to provide 5.24 g (24.80 mmol, 65%) phenylacetanilide as a tan solid, mp=114°-116° C. NMR (CDCl3 /TMS): 3.73 (s, 2H), 7.08 (t, 1H), 7.18 (bs, 1H), 7.25-7.43 (m, 9H). Mass spectrum
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)(O)[O-].[Na+]>>[CH3:5][C:6]1[C:10]([N+:1]([O-:4])=[O:2])=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1[nH]c(C)c([N+](=O)[O-])c1C
Temperature: 0 °C
Yield: 14 %

Procedure:
Nitric acid (70 w/w %, 5 mL) was added to ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (1.0 g, 6.0 mmol) cooled to 0° C. The reaction mixture was stirred and allowed to warm to RT over 1 h. The reaction mixture was poured into an ice bath with sat. sodium bicarbonate (25 mL) and extracted with EtOAc (3×50 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated. Purification by column chromatography afforded ethyl 3,5-dimethyl-4-nitro-1H-pyrrole-2-carboxylate (0.185 g, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d5): δ ppm 12.49 (br. s., 1H) 4.26 (q, 2H) 2.51 (s, 3H) 2.50 (s, 3H) 1.28 (t, 3H). MS: m/z 213.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH2:20]3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 25.8 mg, 0.22 mmol, 1.5 equiv), DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) and HATU (87 mg, 0.22 mmol, 1.5 equiv) were added to anhydrous acetonitrile (2 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 11-2 as a white solid. MS m/z (M+H): calculated=424.2345; observed=424.2353.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=2)[CH2:41]Cl)[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([C:30]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH:39]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(OC(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)NCc2ccccn2)c1
Reaction time: 18 h
Yield: 89 %

Procedure:
To a pre-cooled (ice bath) solution of 2-(aminomethyl)-pyridine (1.05 g, 9.7 mmol) in anhydrous CH2Cl2 (15 ml) was added 3-(Chlorosulfonyl) benzoic acid (714 mg, 3.23 mmol) under N2 and the ice bath was removed after addition. Stirring was continued for 18 hours at room temperature, and the reaction mixture was diluted with 300 ml CH2Cl2, and filtered through celite. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 3:6:91 CH3COOH—MeOH—CH2Cl2, gave the title compound (840 mg, 89%) as a pure white solid.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.O=S(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a mixture of 151a (1.50 g, 6.55 mmol) in CHCl3 (60 mL) cooled at 0° C. was slowly added SOCl2 (2.34 g, 19.6 mmol) while maintaining the internal temperature below 5° C. This reaction mixture was warmed to 50° C. and stirred at this temperature for 3 h. It was then cooled to 0° C. and quenched with water. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 151b (1.1 g, 68%) as a yellow solid. MS-ESI: [M+H]+ 247.9
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:8][C@@H:6]([OH:7])[C@H:5]([OH:9])[C@H:4]([OH:10])[C@H:3]1[O:11][CH3:12].[CH3:14][CH:15]([CH3:41])[CH2:16][O:17][C:18]([C:20]1[C:21](=[O:40])[O:22][C:23]2[C:37]([CH3:38])=[C:36](O)[CH:35]=[CH:34][C:24]=2[C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19]>C(OCC)C.CCCCCC>[CH3:14][CH:15]([CH3:41])[CH2:16][O:17][C:18]([C:20]1[C:21](=[O:40])[O:22][C:23]2[C:37]([CH3:38])=[C:36]([O:7][C@@H:6]3[O:8][C:2]([CH3:13])([CH3:1])[C@H:3]([O:11][CH3:12])[C@@H:4]([OH:10])[C@H:5]3[OH:9])[CH:35]=[CH:34][C:24]=2[C:25]=1[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:19]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)OC1(C)C
Reactant: Cc1c(O)ccc2c(OCc3ccccc3)c(C(=O)OCC(C)C)c(=O)oc12
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3c(OCc4ccccc4)c(C(=O)OCC(C)C)c(=O)oc3c2C)OC1(C)C

Procedure:
The operation is carried out as in Example 1 Stage A, starting from 6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranose and 2-methylpropyl-7-hydroxy-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyran-3-carboxylate, the sought product is obtained. rf=0.22 hexane-ethyl acetate (1-2).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14].O>C(O)C.Cl>[ClH:1].[NH2:12][CH:13]1[N:15]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[CH:2][S:14]1
Reactant: O=C(CCCl)c1ccccc1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1N=C(c2ccccc2)C=CS1

Procedure:
20.3 g (0.1 mol) of β-chloroethyl-phenyl ketone together with 7.6 g (0.1 mol) of thiourea in 100 ml of ethanol in which 0.5% by weight of hydrogen chloride is dissolved, are heated to the boil (for about 3 to 4 hours) until the starting compounds can no longer be detected in a sample by thin-layer chromatography. Thereafter ethanol is azeotropically distilled off whilst toluene is continuously added in the same amount as ethanol distils off and the resulting toluene reaction mixture is boiled for a further 1/2 hour on the water separator. 23 g (about 88% of the theory) of crude 2-amino-4-phenyl-1,3-thiazine hydrochloride (m.p. 204° C.) separate out as faintly yellow-coloured crystals and are filtered off. By recrystallizing from ethanol, pure 2-amino-4-phenyl-1,3-thiazine-hydrochloride is obtained with a melting point of 210° C.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1>>[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1Nc1ccc2sccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)O)c(Nc3ccc4sccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((benzothiophen-5-yl)amino)-4-(4-(methanesulfonamido)phenyl)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((benzothiophen-5-yl)amino)-4-(4-(methanesulfonamido)phenyl)benzoic acid 52 mg of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[CH2:23]([CH:22]([NH:21][C:16]1[C:15]([N+:27]([O-:29])=[O:28])=[C:14]([O:1][C:2]2[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=2[CH3:8])[N:19]=[C:18]([CH3:20])[N:17]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: Cc1cc(C)c(O)c(C)n1
Reactant: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Oc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 3-hydroxy-2,4,6-trimethylpyridine (41 mg, 0.3 mmol) in 1 ml of dry THF was treated with 60% sodium hydride in oil (13 mg, 0.3 mmol) at rt. The reaction mixture was cooled to −78° C. and a solution of (6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (78 mg, 0.3 mmol) in 1 ml of dry THF was added. The reaction was stirred at −78° C. for 1 hour, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 91 mg (84%) of white solid of the title compound, mp 134-135° C. 1H NMR (CDCl3) δ 8.30 (d, 1H), 6.89 (s, 2H), 4.30 (m, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.97 (t, 6H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[OH:22][C:24]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[O:5][CH2:6][CH2:7][N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCC2(CCC1)CO2
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCC2(O)CCCCCCC2)c1
Temperature: 120 °C

Procedure:
The suspension of phenol 24 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane (0.5 g, 3.2 mmol) and Cs2CO3 (1.14 g, 3.5 mmol) in DMSO (4 mL) was heated at 120° C. for 16 h. After completion of reaction, the mixture was quenched by the addition of 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% 7N NH3/methanol—CH2Cl2) afforded 2-(2-(3-(1-hydroxy-cyclooctylmethoxy)-phenoxy)-ethyl)-isoindole-1,3-dione as yellow oil. Yield (0.53 g, 35%): 1H NMR (400 MHz, CDCl3) δ 7.92-7.98 (m, 1H), 7.40-7.51 (m, 3H), 7.08-7.14 (m, 1H), 6.45-6.54 (m, 3H), 4.03 (s, 2H), 3.68-3.76 (m, 2H), 1.35-1.92 (m, 16H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:12][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]#[CH:15]>CN(C=O)C.CCN(CC)CC.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.[Cu]I>[C:19]([O:18][C:17]([NH:16][CH:13]([CH3:12])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC(C)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#CC(C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 51.2 %

Procedure:
Pd(Ph3P)4 (683 mg, 0.591 mmol), CuI (938 mg, 49.2 mmol), methyl 2-iodobenzoate (25.8 g, 98.49 mmol), tert-butyl but-3-yn-2-ylcarbamate (intermediate 3.2, 25 g, 147.75 mmol) in DMF (30 ml) and Et3N (27 ml) were mixed in DMF (125 ml) and the mixture was heated to 60° C. under nitrogen atmosphere for 12 hrs. The mixture was quenched with water and the product extracted with EtOAc. The collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residual was purified by column chromatography over silica gel (Hex/EtOAc 9:1) to give the title compound (15.3 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([N:16]([CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH:20]([NH2:22])[CH3:21])[CH3:15]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:16]([CH2:23][CH3:24])[CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CCN(CC)CCCC(C)N
Product: CCN(CC)CCCC(C)Nc1nc(Cl)nc2cc(Cl)ccc12

Procedure:
Analogously to example 17, 2,4,7-trichloro-quinazoline is reacted with N1,N1-diethyl-pentane-1,4-diamine to give N4-(2,7-dichloro-quinazolin-4-yl)-N1,N1-diethyl-pentane-1,4-diamine and is further reacted
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[CH:27][S:28][C:22]=2[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]1=[O:33]>ClCCCl>[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:12])[S:28][C:22]=2[N:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:20]1=[O:33]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(=O)c3cccc4ccccc34)sc21
Temperature: 25 °C

Procedure:
1-Naphthoyl chloride (1.25 ml) was added under nitrogen to a stirred slurry of aluminum chloride (1.1 g) in 1,2-dichloroethane (10 ml). A solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (2.0 g) in 1,2-dichloroethane (10 ml) was added dropwise and the resultant mixture was heated under reflux for 24 h and then allowed to cool to ambient temperature. The reaction mixture was quenched by the careful addition of water (2 ml) and was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed thrice with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution, and once with brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with toluene:ethyl acetate (9:1) gave the title compound (0.78 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([C:27](OCC)=[O:28])[N:26]=2)[CH:23]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([C:27]([NH:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:8][CH:9]=3)=[O:28])[N:26]=2)[CH:23]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc(Oc2ccc(F)cc2)cc1
Product: O=C(NCc1ccc(Oc2ccc(F)cc2)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-(4-fluorophenoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[C:14]([CH3:22])=[C:15]([N:19]=[C:20]=[S:21])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:22])=[C:15]([N:19]=[C:20]2[N:8]([CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10][S:21]2)[CH:16]=[CH:17][CH:18]=1
Reactant: ClCC[NH2+]CC1CCCC1
Reactant: Cc1c(Cl)cccc1N=C=S
Agent: [Cl-]
Product: Cc1c(Cl)cccc1N=C1SCCN1CC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[O:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[O:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H](C)c1noc(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)c1noc(-c2cccc(Cl)c2)n1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
7.13 g (26.7 mmol) (+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate and 2.33 g (56.7 mmol) lithium hydroxide monohydrate were mixed with 1:1 THF/Water (100 mL) and stirred for 18 h. Reducing the volume of the mixture in vacuo to about ½, followed by dilution with brine and extraction with ethyl acetate. 5.8 g (97%) of the title compound was obtained after evaporation and drying. 1H NMR: 8.14 (s, 1 H), 8.02 (d, 1 H), 7.57 (d, 1 H), 7.47 (t, 1 H), 5.04-5.14 (m, 1 H), 2.42 (br s, 1 H), 1.67 (d, 3 H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12][Si](C)(C)C>C(#N)CC>[Br:12][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: CCC#N
Product: FC(F)(F)c1ccnc(Br)c1

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (2.70 g, 14.9 mmol) and bromotrimethylsilane (3.90 mL, 29.6 mmol) in propanenitrile (15.0 mL) was heated under reflux for 22 h. The product (very volatile) was carefully rotary evaporated to give 4.07 g (propanenitrile contained) of thick light brown suspension w/o further purification. LC-MS calculated for C6H3BrF3N (M+H) 226.9; found 225.9/227.8.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH2:15][Cl:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]C1C=CC(CNCCCO)=CC=1>>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH2:15][Cl:16])[CH2:9]2)=[CH:7][CH:6]=1
Reactant: OCCCNCc1ccc(Cl)cc1
Reactant: ClCC1CN(Cc2ccccc2)CCCO1
Product: ClCC1CN(Cc2ccc(Cl)cc2)CCCO1
Yield: 29 %

Procedure:
(±)-4-(4-Chlorobenzyl)-2-(chloromethyl)perhydro-1,4-oxazepin was prepared analogously to the method for the preparation of (±)-4-benzyl-2-(chloro-methyl)perhydro-1,4-oxazepin described in K. Araki et al. J. Med. Chem. 36, 1356 (1993), using N-(4-Chlorobenzyl)-N-(3-hydroxypropyl)amine as starting material. Yield 29%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11]Br.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[F-].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1cccc(OC)c1CBr
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(Cc2c(OC)cccc2OC)CC1
Yield: 16.3 %

Procedure:
A stirred solution of 4.7 grams (0.020 mole) of 2,6-dimethoxyphenylmethyl bromide, 3.2 grams (0.020 mole) of ethyl piperidin-4-ylcarboxylate, and 23.5 grams (0.200 mole) of 50% potassium fluoride on Celite® filter aid in 100 mL of acetonitrile was heated at reflux for about 18 hours, after which the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of ethyl acetate in hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure to a residue. The residue was analyzed using thin layer chromatography, which indicated that the residue was impure. The residue was again subjected to column chromatography on silica gel, with mixtures of ethyl acetate in hexane and methanol in ethyl acetate as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about one gram of ethyl N-(2,6-dimethoxyphenylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: NS(=O)(=O)Cl
Product: N#Cc1cc(C(F)(F)F)ccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-5-(trifluoromethyl)benzonitrile (Example 86b) and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 2H), 7.74-7.76 (d, J=8.4 Hz, 1H), 8.01-8.03 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.23-8.233 (d, J=1.2 Hz, 1H), 10.16 (b, 1H).
Reaction SMILES: C([O:8][C:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH2:12][C:13]1[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15](=[O:21])[CH:14]=1)[C:10]#[CH:11])(=O)C(OCC)=O.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH:22]1([C:9]([OH:8])([C:10]#[CH:11])[CH2:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15](=[O:21])[CH:14]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CC(CC1=CC(=O)OC(C)(C)O1)(OC(=O)C(=O)OCC)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To the optically pure (+)-1-cyclopentyl-1-[(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)methyl]prop-2-ynyl ethyl oxalate (2.5 g, 15.1 mmol) in 50 ml of MeOH was added K2CO3 (2.0 g). The mixture was stirred at 23° C. for 8 h. After complete conversion, the mixture was neutralized with 1N HCl at cold temperature. The aqueous solution was extracted with MTBE (×3) and the organic layer was washed with brine and dry over MgSO4. After removal of MTBE, 1.75 g of the desired product (+enantiomer) was produced with 95.5% ee and 96% yield.