Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)(=[O:24])=[O:23])([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:29][CH:28]=1)(=[O:23])=[O:24])([O-:15])=[O:14]
Reactant: O=C1CCc2cccc(F)c2C1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccc(F)c3C2)cc1)Cc1ccccn1
Yield: 91.9 %

Procedure:
Following General Procedure B: Reaction of 8-fluoro-2-tetralone (159 mg, 0.97 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (400 mg, 0.97 mmol) and NaBH(OAc)3 (411 mg, 1.9 mmol) in a mixture of CH2Cl2 (10 mL) and acetic acid (0.2 mL) for 18 hours followed by purification of the crude material by column chromatography on silica gel (CHCl3/MeOH/NH4OH 20:2:1) afforded the title compound (500 mg, 92%) as a yellow foam.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].Cl.[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]>ClC1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:18])[C:16]([N:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:20]([CH2:22][CH3:23])[CH3:21])=[CH:25][CH:26]=2)[CH3:31])=[NH:17])=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6].[ClH:1]
Reactant: CCC(C)c1ccc(N(C)C#N)cc1
Reactant: [Cl-]
Reactant: CCC(C)c1ccc(NC)cc1
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CCC(C)c1ccc(N(C)C(=N)N(C)c2ccc(C(C)CC)cc2)cc1
Reaction time: 5 h
Yield: 37.4 %

Procedure:
Aluminum chloride (0.39 g, 2.93 mmol) was added to a stirred solution of 4-sec-butylphenyl-N-methyl cyanamide (0.5 g, 2.66 mmol) in chlorobenzene (14 mL) at 145° C. After 10 minutes 4-sec-butylphenyl-N-methyl amine hydrochloride (0.466 g, 2.34 mmol; prepared from 4-sec-butylphenyl-N-methyl amine and 1.0 M HCl-ether) was added and continued reflux. After 5 hours, the reaction mixture was evaporated on rotavapor and the product was purified by flash chromatography using chloroform/methanol (10:1) to afford the title compound (0.34 g, 38%) as an extremely hygroscopic solid, mp: 65-66° C.; TLC: Rf=0.13 (CHCl3:CH3OH; 10:1); 1H NMR (CD3OD): δ 6.99 (d, 4H, J=8.46 Hz, ArH), 6.80 (d, 4H, J=8.34 Hz, ArH), 3.36 (s, 6H, 2×-NCH3), 2.50 (m, 2H, 2×—CH), 1.58-1.53 (m, 4H, 2×-CH2), 1.16 (d, 6H, 2×-CH3), 0.79 (t, 6H, J=7.35 Hz, 2×-CH3); HRMS: 351.2660 (351.2674 Calcd. for C23HH33N3); Anal.: C23H33N3·HCl; 1.75H2O (418.74); Calcd. (%): C, 66.19, H, 8.64; N, 10.07; Found (%): C, 66.56, H, 8.55; N, 11.27; HPLC: (CH3CN:H2O 50:50 with 0.1% TFA): 99% pure.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCCCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.17 ml of butyl iodide were used. As a result, 280 mg of 3-butyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[S:11][C:7]=2[CH:6]=1.[CH3:23][NH2:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:10]2[S:11][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:24][CH3:23])[CH:22]=[CH:21][C:8]=3[N:9]=2)=[CH:15][CH:16]=1
Reactant: CN
Reactant: Clc1ccc(CSc2nc3ccc(OCCBr)cc3s2)cc1
Product: CNCCOc1ccc2nc(SCc3ccc(Cl)cc3)sc2c1
Yield: 97.5 %

Procedure:
Prepared from 6-(2-bromoethoxy)-2-(4-chlorobenzyl-mercapto)-benzothiazole and methylamine analogously to Example 3. Yield: 97.5% of theory, Melting point: 56-58° C., 1H-NMR spectrum (200 MHz, CDCl3, signals at ppm): 1.56 (s, 1H); 2.52 (s, 3H); 3.0 (t, 2H); 4.22 (t, 2H); 4.51 (s, 2H); 7.03 (dd, 1H); 7.23 (d, 1H); 7.33 (AB, 4H); 7.77 (d, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]4=[O:35])[CH:22]=3)[CH:13]=2)[C:9]([CH3:38])=[N:8][CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][C:46](=[O:48])[CH3:47])=[CH:7][N:8]=[C:9]2[CH3:38])=[CH:13][C:14]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]2=[O:35])[CH:22]=1)#[N:17]
Reactant: CC(=O)Cl
Reactant: CCC1(c2cccc(Oc3cc(Cn4c(CCN)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(c2cccc(Oc3cc(Cn4c(CCNC(C)=O)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile dihydrochloride (as described in Example 11) (0.06 g, 0.108 mmol) in CH2Cl2 (3.0 mL) was added triethylamine (0.06 mL, 0.43 mmol) and acetyl chloride (0.010 mL, 0.14 mmol). After stirring for 2 hr, the solvents were removed in vacuo and the residue was partitioned with EtOAc and saturated NaHCO3. The EtOAc was dried with brine and MgSO4 and evaporated in vacuo to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[C:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:4]1[CH:5]=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)[CH:18]=[CH:19][C:3]=1[C:1]#[N:2])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.6 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (200 mg, 0.75 mmol) in THF (50 mL) was added NaH (43 mg, 95%, 1.81 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of t-butyl bromoacetate (0.25 mL, 1.65 mmol). The reaction was heated at 70° C. for 24 hours. After the cooling of the reaction solution to room temperature, the mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified using reverse phase chromatography, eluting from 5% MeOH/H2O to 90% MeOH/H2O, afforded 36 mg of the title compound in 12.6% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.26 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 7.09 (dd, J=2.3, 8.2 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.68 (dd, J=2.0, 8.6 Hz, 1H), 4.96 (s, 2H), 4.86 (s, 2H), 1.37 (s, 9H); MS (ES) m/z: 380 (M−H)−; HPLC purity: 99.11% (220 nm), 98.48% (254 nm).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[C:27]#[C:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.O>C(Cl)Cl>[Br:5][CH2:1][C:27]#[C:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(C#CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#CCBr)cc1
Reaction time: 13 h
Yield: 109.2 %

Procedure:
1.7 g of carbon tetrabromide and 1.15 g of triphenylphosphine were added to 10 ml of a solution of 0.70 g of ethyl 4-(3-hydroxy-1-propynyl)benzoate in methylene chloride at room temperature. The obtained mixture was stirred at that temperature for 13 hours, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 5% diethyl ether/n-hexane) to give 1.0 g of the title compound as a pale-yellow oil. 1H-NMR (400 MHz, CDCl3) δ(ppm); 1.38(t, J=7.2 Hz, 3H), 4.17(s, 2H), 4.36(q, J=7.2 Hz, 2H), 7.50(d, J=8.4 Hz, 2H), 7.99(d, J=8.4 Hz, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][C:31](=[O:37])[N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]=[C:25]([CH3:38])[C:22]=1[CH:23]=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:23]([C:22]4[C:25]([CH3:38])=[CH:26][C:27]([O:29][CH2:30][C:31](=[O:37])[N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:28][C:21]=4[CH3:20])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1cc(OCC(=O)N2CCCC2)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCC(=O)N5CCCC5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (0.8 mL in 0.2 M DMSO solution), 2,6-dimethyl-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.8 mL in 0.2 M toluene solution) and FeCl3 (0.4 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge. United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-[2,6-dimethyl-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 497 (M+1).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[CH3:33][O:32][C:9]1[CH:10]=[C:11]([N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)[CH2:3][CH2:2]1
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Reactant: O=C1CCOCC1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(C2CCOCC2)CC1

Procedure:
Reaction of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one with Tetrahydro-pyran-4-one by method J resulted in the desired product with the molecular weight 533.67 (C31H39N3O5); MS (ESI): 534 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:10]([NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[O:11])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1CCCCC1N
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1CCCCC1NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 2-methylcyclohexylamine (170 mg, 1.5 mmol), 4-nitrophenyl chloroformate (302 mg, 1.5 mmol), diisopropyl(ethyl)amine (469 mg, 3.7 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (248 mg, 1.0 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH2:36]([C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46](Br)=[CH:45][C:43]=2[CH:44]=1)[CH2:37][CH2:38][CH3:39].C(OCC)(=O)C.CC1CCCCC1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:36]([C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:45][C:43]=2[CH:44]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CS(N)(=O)=O
Reactant: CCCCc1cc2cc(Br)ccc2o1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Temperature: 100 °C

Procedure:
The following are placed in a 20 ml tube predried in an oven: 2 equivalents of base and 1.5 equivalents of methanesulfonamide, 2 mol % of Pd(dba)2 and 5 mol % of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (ligand L1). The tube is stoppered with a septum and placed under an inert atmosphere of argon, and 1 equivalent of 2-n-butyl-5-bromobenzofuran (compound IX or II) dissolved in 10 volumes of solvent is then added by syringe. The reaction medium is then stirred and heated to the reflux point of the solvent or at 100° C. for 24 hours, while monitoring the reaction progress by TLC (eluent: 20/80 ethyl acetate/methylcyclohexane) or by HPLC. At the end of the reaction, the reaction medium is diluted with ethyl acetate and then filtered while hot. The filtrate is then concentrated to give, when cold, crystallization of the desired compound I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2C=CC(F)=C[CH:19]=2)[O:9]CCN2CCNCC2)=[CH:4][CH:3]=1.[Cl:25]CCC(C1C=CC(F)=CC=1)=O>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:18][CH3:19])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(CCCl)c1ccc(F)cc1
Product: CCC(=O)c1ccc(F)cc1
Product: Cl

Procedure:
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazine and 3-chloro-1-(4-fluorophenyl)-1-propanone were reacted with each other as decribed in Example VI. After evaporation of the solvent, water and chloroform were added. The working up was further as in Example VI, except that the residue of the column fraction was taken up in ethanol. 3-[4-[2-bis(4-fluorophenyl)methoxy]ethyl]-1-piperazinyl)-1-(4-fluorophenyl)-1-propanone dihydrochloride was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:14]2[C:5](=[N:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:4][C:3]1=[CH:15][C:16]([OH:18])=[O:17].O=C1N(N(N2CCOC2=O)P(Cl)(N)=O)CCO1.[C:36]1(O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:36]1([O:17][C:16](=[O:18])[CH:15]=[C:3]2[S:4][C:5]3=[N:6][C:7]4[C:12]([CH2:13][N:14]3[C:2]2=[O:1])=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Reactant: Oc1ccccc1
Agent: NP(=O)(Cl)N(N1CCOC1=O)N1CCOC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=c1sc2n(c1=O)Cc1ccccc1N=2)Oc1ccccc1

Procedure:
A solution of 1.30 g (5 mmols) (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid, 1.27 g (5 mmols) N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride, 0.49 g (5.2 mmols) phenol, and 1.10 g (10 mmols) triethylamine, in 10 ml dichloromethane was stirred at room temperature, under nitrogen atmosphere for 18 hours. Then, 10 ml of water (made slightly basic with sodium bicarbonate) were added. The precipitate was filtered of and the filtrate was dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residual orange-yellow solid was recrystallized from anhydrous ethanol. Yield--0.62 g. Mp 194°-195° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:25])=[C:19]([CH:24]=1)[CH:20]=[N+:21]([CH3:23])[CH3:22].BrC1C=CC(F)=C(C=1)C=O.CNC>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:25])=[C:19]([CH:20]([N:21]([CH3:22])[CH3:23])[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=2)[CH:24]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1cc(Br)ccc1F
Agent: CNC
Agent: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Product: CN(C)C(c1cc(Br)ccc1F)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (5-bromo-2-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 5-bromo-2-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[OH-:11].[NH4+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:11])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1ccnc(Cl)c1C(N)=O
Temperature: 0 °C
Yield: 69 %

Procedure:
A solution of 6.33 g of 2-chloro-4-methyl-3-pyridine carbonitrile (9) in 6 mL concentrated H2SO4 was stirred at 100° C. for one hour, added ice water, made alkaline with ammonium hydroxide and extracted with ethyl acetate. The extract was dried and the solvent removed to leave a crystalline residue. Recrystallization from ethyl acetate gave 4.9 g (69%) of (10).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:3][CH:2]=[CH2:1])=[CH:10][C:8]=2[O:9]1
Reactant: C=CCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)OCO2
Yield: 96.2 %

Procedure:
Allyl bromide (1.75 g., 14 mmol) was added to a solution of sesamol (2.0 g, 14 mmol) that had been dissolved in 50 ml of dry acetone, followed by addition of powdered potassium carbonate (2.4 g, 17 mmol) and the resulting cloudy solution was refluxed for 18 h. The solution was cooled and the solvent removed in vacuo. The remaining suspension was extracted into ether and the organic layer was washed with water (1×25 ml), brine solution (1×25 ml), and dried over MgSO4. Concentration of solvent yielded 2.4 g (94%) of a pale yellow oil which was used in the next step with no further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][C:16]([CH3:38])([CH3:37])[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:21][CH2:20]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.O>[CH2:7]([O:14][CH2:15][C:16]([CH3:38])([CH3:37])[CH2:17][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:32][C:33]([F:34])([F:36])[F:35])[CH2:23][CH2:24]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(COCc1ccccc1)C(=O)N1CCN(c2ccccc2OCC(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COCc1ccccc1)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Temperature: 0 °C
Yield: 96.9 %

Procedure:
A suspension of lithium aluminum hydride (0.49 g, 12.8 mmol) and THF (5 mL) was cooled to 0° C. and added to a solution of 3-benzyloxy-2,2-dimethyl-1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-1-propanone (2.8 g, 6.4 mol) in 12 mL of THF. The mixture was heated 2 hours at reflux, slowly diluted with water, filtered and concentrated. The residue was dissolved in water and the solution was extracted with methylene chloride (4×30 mL). The combined extracts were washed with water (1×25 mL), dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (8:2) to give 3-benzyloxy-2,2-dimethyl-1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (2.6 g, 6.2 mol).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:12][CH2:13][C@@H:14]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]#[N:24])=[O:17])[NH2:15])([CH3:11])([CH3:10])[CH3:9].[CH2:25]([O:27][C:28](Cl)=[O:29])[CH3:26].C(N(CC)CC)C>ClCCl>[C:8]([S:12][CH2:13][C@@H:14]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]#[N:24])=[O:17])[NH:15][C:28]([O:27][CH2:25][CH3:26])=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)SC[C@H](N)C(=O)N1CCC[C@H]1C#N
Reactant: CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N[C@@H](CSC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Yield: 34.1 %

Procedure:
A solution of (2S)-1-(S′-tert-butylcysteinyl)pyrrolidine-2-carbonitrile trifluoroacetate (1000 mg, 0.27 mmol; prepared according to Jenkins et al., WO95/15309), ethylchloroformate (35 mg, 0.32 mmol) and triethylamine (50 mg, 0.50 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60–80° C.; 8:2) yielding a white solid identified as the title compound (30 mg, 0.092 mmol, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][CH2:16][C:17](OCC)=[O:18].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:17](=[O:18])[CH2:16][O:15][CH3:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)COC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCC(=O)C(C#N)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl (methyloxy)acetate (1.65 g, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) to remove all non-basic organic impurities, and then it was acidified to pH of 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-4-(methyloxy)-3-oxobutanenitrile as a brown oil (1.8 g, 7.2 mmol, 66% yield), MS (EI) for C13H15NO4: 250 (MH+).