Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])=[C:6]2[C:10]=1[CH2:9][N:8]([CH:11]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:12][C:13](=[O:16])[NH:14][OH:15])[C:7]2=[O:28].[C:35](OC(=O)C)(=[O:37])[CH3:36]>CC#N>[C:35]([O:15][NH:14][C:13]([CH2:12][C@@H:11]([N:8]1[C:7](=[O:28])[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:29][C:30]([CH:32]2[CH2:33][CH2:34]2)=[O:31])[CH2:9]1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)=[O:16])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc(C(CC(=O)NO)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(C)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To the solution of cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 92 mmol) in CH3CN (50 ml) was added acetic anhydride (0.1 ml, 92 mmol) at room temperature. The mixture was stirred overnight. The solvent was removed in vacuo and the resulted solid was stirred with ether (10 ml) for 2 hrs. The suspension was filtered and the solid was dried in oven to give (1R)-cyclopropanecarboxylic acid {2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.4 g, 80%): mp 139-141° C.; 1HNMR (CDCl3): δ 0.85-0.92 (m, 2H, c-CH2), 1.05-1.11 (m, 2H, c-CH2), 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 1.62-1.68 (m, 1H, c-CH), 2.12 (s, 3H, CH3), 3.02 (dd, J=5, 16 Hz, 1H, CHH), 3.50 (dd, J=5, 16 Hz, 1H, CHH), 3.85 (s, 3H, OCH3), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.12 (d, J=17 Hz, 1H, CHH), 4.38 (d, J=17 Hz, 1H, CHH), 5.61-5.65 (m, 1H, CHN), 6.81-6.94 (m, 3H, Ar), 7.31 (d, J=10 Hz, 1H, Ar), 8.38 (d, J=10 Hz, 1H, Ar), 10.41 (s, 1H); 13C NMR (CDCl3): δ 9.0, 9.1, 15.3, 16.7, 18.7, 36.8, 48.2, 54.4, 56.5, 65.2, 112.2, 112.8, 119.7, 119.8, 120.2, 122.4, 131.1, 133.5, 137.2, 139.8, 149.3, 150.1, 167.0, 169.0, 170.0, 173.5; Anal. Calcd. for C26H28ClN3O7: C, 58.92; H, 5.33; N, 7.93; Found: C, 58.58; H, 5.00; N, 7.76.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CCCl)CC1
Reactant: CNCc1ccccc1
Product: CN(CCC1CCN(C(=O)c2ccccc2)CC1)Cc1ccccc1

Procedure:
A mixture of 1-benzoyl-4-(2-chloroethyl)piperidine (11.61 g), N-methylbenzylamine (16.75 g) and IMS (100 ml) was boiled under reflux for 16 hours. The mixture was evaporated to dryness and then 4M hydrochloric acid (50 ml) was added to the residue. The mixture was washed with ether and the acidic layer was then basified with 4M sodium hydroxide solution and extracted with dichloromethane to give an oil. Excess amine was distilled off at 13 mbar and the residue was triturated with petroleum ether b.p. 40°-60° C. The supernatant petroleum ether was decanted off and the residual oil was dried under vacuum to give 1-benzoyl-4-[2-(N-benzyl-N-methylamino)ethyl]piperidine. A small portion of the oil was dissolved in ether and acidified with ethereal oxalic acid. The supernatant liquid was decanted off and the solid residue was triturated with acetone and filtered to give the oxalate salt, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO.[Br:17]Br>Br.O>[Br:17][CH2:13][C:12]([C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])=[O:14]
Reactant: CC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Reactant: BrBr
Agent: Br
Solvent: CO
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(2,5-dimethyl-4-nitrophenyl)ethanone (300 mg, 1.55 mmol) in HBr (48%) (5 mL)/methanol (2.4 mL) was added bromine (250 mg, 1.55 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine and concentrated. The residue was purified with silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2-bromo-1-(2,5-dimethyl-4-nitrophenyl)ethanone as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](O)=[O:27])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:25])([CH3:24])[C:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:27])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCOCC3)c1)N2
Yield: 90.7 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), morpholine (0.53 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 36 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.87 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C, 28; H, 37; N, 3; O, 4; (M+H)+: 480.62, observed: 480.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>CO.O>[Cl:14][C:8]1[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])c(Cl)s1

Procedure:
The product from Example 351A (1 equiv) was dissolved in a methanol/water 3/1 mixture followed by the addition of lithium hydroxide (5 equiv). The resultant solution was stirred at room temperature for 24 hours followed by the addition of 1N aqueous hydrochloric acid until the solution was a pH of 2. The mixture was then extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].[C:7]([NH:10][C@@H:11]1[C@H:16]([OH:17])[CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C@H:12]1[O:22][CH:23]([CH3:25])[CH3:24])(=[O:9])[CH3:8]>C1COCC1>[C:7]([NH:10][C@@H:11]1[C@H:16]([O:17][CH2:5][CH:4]=[CH2:3])[CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C@H:12]1[O:22][CH:23]([CH3:25])[CH3:24])(=[O:9])[CH3:8]
Reactant: C=CCBr
Reactant: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1CC(C(=O)OC)=C[C@@H](OC(C)C)[C@@H]1NC(C)=O
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Sodium hydride (60%, 35 mg, 0.875 mmol) and allyl bromide (0.051 mL, 0.589 mmol) were added to a 0° C. solution of Example 13L (80 mg, 0.295 mmol) in THF (15 mL). After stirring for 5 hours, the reaction mixture was quenched with saturated NH4Cl, and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography using ethyl acetate to afford 83 mg (90%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[C:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:36](Cl)(=[O:38])[CH3:37].CCN(CC)CC.Cl>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:36](=[O:38])[CH3:37])[C:11]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2c(N)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(NC(C)=O)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
A mixture of 4-amino-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (160 mg, 0.34 mmol; see Example 5(a)), acetyl chloride (50 mg, 0.63 mmol), Et3N (63 mg, 0.63 mmol) and MeCN (10 mL) was stirred at room temperature for 30 minutes, then poured into HCl (1M) and extracted with EtOAc. The combined extracts were washed with water and brine, and dried over Na2SO4. Concentration and purification by chromatography gave the sub-title compound (182 mg, 84%).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([O-])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[N:26]1(OC(N(C)C)=[N+](C)C)[C:30]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN>CN(C)C=O>[CH3:30][NH:26][C:16]([C:14]1[CH:13]=[CH:12][C:10]2[O:11][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:9]=2[CH:15]=1)=[O:17]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C([O-])c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a suspension of 23.0 g of lithium 2,2-diphenyl-1,3-benzodioxole-5-carboxylate in 200 ml of dimethylformamide were added 27.0 g of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium-hexafluorophosphate. The mixture was stirred at 20° C. for 2 hours, then 25 ml of methylamine were added, and stirring was continued for another 2 hours. The mixture was partitioned between ethyl acetate and water, the organic layer was washed successively with 2N potassium hydrogensulfate solution, saturated sodium carbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the solid residue was crystallized from ethanol to give 15.6 g of N-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]([F:16])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[OH2:17].[OH2:18].O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=O.[Mg]>ClCCl.O>[F:16][C:2]([F:1])=[CH:3][CH2:4][CH2:5][S:6]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:18])=[O:17]
Reactant: FC(F)=CCCSc1nc2ccccc2s1
Reactant: O
Agent: O=C(O)c1ccccc1C(=O)OO
Agent: [Mg]
Solvent: ClCCl
Product: O=S(=O)(CCC=C(F)F)c1nc2ccccc2s1
Reaction time: 48 h

Procedure:
2-(4,4-difluorobut-3-enylthio)benzthiazole (prepared by the method described in United Kingdom Patent Application GB2270689A, 8.25 g) in dichloromethane ( 15 cm3) was added to a rapidly stirred mixture of monomagnesium peroxyphthalic acid hexahydrate (25.7 g, 70-80% technical grade) in water (25 cm3). The mixture was stirred for 2 days, diluted with dichloromethane and water, the organic phase separated, washed with aqueous sodium carbonate, water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure to give 2-(4,4-difluorobut-3-enylsulfonyl )benzthiazole as a colourless oil, 4.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:7])=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)C(=O)c1ccc(N)nc1
Reaction time: 6 h

Procedure:
6-Aminonicotinic acid (86 mg, 0.6 mmol) was taken up in 0.65 mL pyridine and 10 mL CH2Cl2. Chlorotrimethylsilane (0.65 mL, 7 mmol) was added and the mixture stirred for 6 h. Solvent was evaporated and the product was used without purification.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:22])(=O)=O>C(OCC)C>[Cl:22][CH:3]([C:2](=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:16])([F:17])[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1C(F)(F)F
Yield: 64.3 %

Procedure:
Using ethyl 3-oxo-3-[2-(trifluoromethyl)phenyl]propanoate (1.0 g, 3.8 mmol), sulfuryl chloride (620 mg, 4.9 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20-B(i), the title compound (720 mg, 64%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1ccccc1CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2ccccc2)cc1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.2 %

Procedure:
To a stirred ice bath cooled solution of diethylbenzene (1.7 mL, 10 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting reaction mixture was added benzoyl chloride (1.2 mL, 10 mmol). The reaction mixture was allowed to warm to room temperature and was then stirred at room temperature for 1.5 hours. The reaction mixture was poured into 60 mL of iced water and stirred for 20 minutes. The resulting mixture was extracted with methylene chloride (2×40 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to afford the crude product as an orange oil. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/hexane) to afford 1.22 g (51%) of the product as a yellow oil: 1H NMR (CDCl3) δ 7.85-7.41 (m, 7 H), 7.30-7.20 (m, 1 H) 2.83-2.61 (m, 4 H), 1.35-1.17 (m, 6 H); 13C NMR (CDCl3) δ 196.8, 147.0, 141.9, 138.1, 135.3, 132.1, 132.1, 130.1,130.0, 128.1, 128.1, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C17H18O. Theoretical: C, 85.67; H, 7.61. Found: C, 85.38; H, 7.42.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][OH:10])=[S:6].[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:16])([Cl:15])[CH:12]([N:4]([CH2:3][CH2:2][OH:1])[C:5]([N:7]([CH:12]([OH:11])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:8][CH2:9][OH:10])=[S:6])[OH:11]
Reactant: OCCNC(=S)NCCO
Reactant: O=CC(Cl)(Cl)Cl
Product: OCCN(C(=S)N(CCO)C(O)C(Cl)(Cl)Cl)C(O)C(Cl)(Cl)Cl
Temperature: 80 °C

Procedure:
To 98.4 g (0.6 mole) of 1,3-bis(2-hydroxyethyl)-thiourea at 65° C. was slowly added 182 g (1.24 moles) of chloral while the temperature was maintained below 75° C. by means of external cooling. The reaction mixture was vigorously stirred and heated at 80° C. for 1 hour. On cooling 275 g of a viscous syrupy product was isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1.CC(=O)OCC>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]([OH:8])[CH2:9][N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: Brc1cccc(OCC2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1
Yield: 75.9 %

Procedure:
To a solution of 2-((3-bromophenoxy)methyl)oxirane (1.5 g, 6.55 mmol) in MeOH (15 mL) were added 1,2,3,4-tetrahydroisoquinoline (1.0 g, 7.86 mmol) at 8° C. The mixture was refluxed for 16 h. TLC (PE: EA=2:1) showed that the reaction was completed and the mixture was concentrated to yield crude material which was purified using column chromatography on silica gel to give the desired compound (1.8 g, 78.3%) as colorless oil. LCMS (m/z): 362.1/363.1 [M+H]+/[M+2H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11](=[O:27])[CH:10]([N:28]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1.O.NN>O1CCCC1>[NH2:28][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]1=[O:27]
Reactant: Cc1cccnc1CN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc21
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A solution of (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methylpyridin-2-yl)methyl-3-phtalimido-1H-1,4-benzodiazepin-2-one (1.24 g) in tetrahydrofuran (30 ml) was treated with a solution of hydrazine monohydrate (0.129 g) in tetrahydrofuran (5 ml) under stirring for 3 hours at room temperature and followed at 70° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. The resultant precipitates were filtered off by suction and the filtrate was concentrated in vacuo. The residue was taken up with ethyl acetate and extracted with 1N aqueous hydrochloric acid. The aqueous layer was alkalined with sodium bicarbonate and extracted with chloroform twice. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methylpyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.87 g), which was used in a following reaction step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][N:9]1[N:13]=[N:12][C:11]([C@@H:14]2[CH2:20][C@:19]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:21]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]2[CH2:16][CH2:17][C@H:18]3[O:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)=[N:10]1.C(N(CC)CC)C>ClCCl>[CH2:22]([N:21]1[C@@H:15]2[C@H:14]([C:11]3[N:12]=[N:13][N:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=3)[CH2:20][C@@:19]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:18]([O:35][CH2:36][C:37]1[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[C:39]([C:47]([F:49])([F:50])[F:48])[CH:38]=1)[CH2:17][CH2:16]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
Methanesulphonyl chloride (90 mg, 0.78 mmol) was added to a solution of (1R*,2R*,5S*6R*)-6-[2-(2-aminoethyl)-2H-tetrazol-5-yl]-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 141; 0.45 g, 0.71 mmol) and triethylamine (101 mg, 1 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 3 hours then washed with water (×2). The organic layer was separated, dried (MgSO4), filtered and concentrated to yield the title compound (0.47 g, 94%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: CCCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 8.2 %

Procedure:
1-(trimethylsilylethynyl)-4-(4-n-butylphenylethynyl)benzene (192 g, 11.86 mmol) was dissolved in CH2Cl2 (100 nit) diluted with MeOH (40 mL) and then treated with powdered K2CO3 (2.1 g, 15 mmol) and allowed to stir at ambient temperature for 19 h under N2. The reaction mixture was filtered to remove solids, concentrated, redissolved in CHCl3, washed with water (2×), brine, dried over MgSO4, filtered and concentrated to dryness to give a brown solid. The solid was chromatographed on silica gel, eluting with 15:1 hexanes/EtOAc to give several fractions rich in product. These fractions were combined and chromatographed again with 95:5 hexanes/EtOAc to give 0.25 g (7%) product as a waxy solid. 1H NMR (CDCl3) δ: 7.50 (s, 4H), 7.47 (d, 8.2 Hz, 2H); 7.21 (d, J=8.2 Hz, 2H); 3.20 (s, 1H); 2.63 (t, J=7.8 Hz, 2H); 1.64 (m, 2H); 1.41 (m, 2H); 0.97 (t, J=7.5 Hz, 3H). 13C{1H} NMR (CDCl3): 143.8, 132.1, 11.6, 131.4, 1128.6, 124.1, 121.6, 120.0, 911.7, 88.2, 83.4, 78.8, 35.6, 33.4, 22.2, 14.0 ppm.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[N:6]=1.C(OCC)C.C(=O)(O)[O-].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(OCC)(=O)C>[Cl:22][CH2:23][C:24]([NH:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)=[O:25]
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1nc2cc(NC(=O)CCl)ccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylbenzothiazole-5-ylamine (1.0 g, 4.2 mm) was suspended in a mixture of 1:1 ethyl ether: saturated aqueous sodium bicarbonate. To the suspension was added chloracetyl chloride (0.7 g, 6.5 mm) over a period of 10 minutes. The mixture was allowed to stir at room temperature for 24 hours, and then diluted with 50 ml of ethyl acetate. The organic layer was separated, dried over magnesium sulgate, and filtered. The solvent was evaporated from the filtrate, and the white solid residue obtained was triturated in ether and filtered, to afford 2-chloro-N-(2-methylbenzothiazol-5-yl)acetamide, a compound of formula (1).
Reaction SMILES: CC(N(C)C)=O.[CH3:7][C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[C:10]([OH:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:7][C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[C:10]([O:20][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
A dimethylacetamide solution (2 mL) of 3-methyl-6-(methyloxy)-2-[3-(methyloxy)phenyl]-1-naphthalenol (247) (0.072 g, 0.25 mmol, 1 equiv) was treated with 4-fluorobenzaldehyde (0.030 mL, 0.27 mmol, 1.1 equiv) followed by cesium carbonate (0.096 g, 0.29 mmol, 1.2 equiv). After 10 min at gentle reflux, the mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The pooled organic portions were dried (Na2SO4) and concentrated. Radial chromatography (SiO2, 1 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (248) as a pale yellow oil (0.060 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 9.80 (s, 1H), 7.68-7.59 (m, 4H), 7.19-7.14 (m, 2H), 7.05 (dd, J=9.2, 2.4 Hz, 1H), 6.78-6.65 (m, 5H), 3.93 (s, 3H), 3.64 (s, 3H), 2.26 (s, 3H). TLC (75:25; hexanes/EtOAc): Rf=0.55.