Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[CH3:6][S:7]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.5 %

Procedure:
To 3-chloro-1-propanol (5.02 mL, 60 mmole) in CH3CN (200 mL) was added methanesulfonyl chloride (10.4 g, 90 mmole) and triethyl amine (13 mL, 90 mmole). The reaction mixture was stirred at room temperature for 12 hours under an argon atmosphere. 200 mL of saturated NaHCO3 (aq) was added and the stirring was continued for 15 minutes. The mixture was extracted several times with ether. The combined ether layers were dried over Na2SO4, the Na2SO4 was filtered and the filtrate was evaporated to give 10 g (96.6%) of the title compound: TLC (Rf: 0.3; 20% EtOAc/Hexane), 1H NMR (CDCl3) δ 2.2 (m, 2 H, CH2), 3.0 (s, 3 H, CH3), 3.6 (t, 2 H, CH2), 4.4 (t, 2 H, CH2). 13C NMR (CDCl3): δ 31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C:7](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>CO>[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:41])=[O:2])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
There was added 2 ml of N-sodium hydroxide to a solution of 0.556 g (0.001 mole) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine methyl ester in 10 ml of methanol. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residual aqueous solution was washed with ethyl acetate and after acidification with 4 N-hydrochloric acid, the resulting separated oil was extracted into ethyl acetate and the extracts were dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residual oil was purified on a column of silica gel (60-200 mesh) by elution with ether. The oily product was crystallized from ether to yield 0.357 g (66%) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine, mp 171°-173°, RfA 0.68, [α]D26 =-30.2° (c, 1% in THF); ir (CHCl3) 1730 (Sh, C=O9, 1670 (C=O), 1630 cm-1 (Sh, C=C); NMR (CDCl3) δ1.5-2.3 (m, 4 H, Pro ring), 3.0-3.5 (m, 2H, >CH--CH2Ph), 3.2-3.7 (m, 2H, Pro ring), 4.2-4.5 (m, 1H>CHCH2Ph), 4.6-5.0 (m, 1H, Pro ring), 5.0 (s, 2H,>N-OCOCH2Ph), 7.0-7.6 (m, 16H, ArH and PhCH=C--), 8.0-8.27 (br, 1H, -NH exchanged by D2O); 9.03-9.5 (br, 2H, -NH or -COOH, exchanged by D2O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:12][S:11][CH:10]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CNN>C(Cl)Cl.CO>[NH2:16][CH:13]1[CH2:12][S:11][CH:10]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:9][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:37])[C:14]1=[O:15]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N)C1=O
Reaction time: 48 h
Yield: 102.7 %

Procedure:
To a solution of 2.5 g of t-butyl[2-(1-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] in a mixture of 20 ml of methylene chloride and 2 ml of methanol was added 0.77 ml of methylhydrazine, and the reaction mixture was allowed to stand for 2 days at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure, 15 ml of methylene chloride were added to the residue and the mixture was stirred. The resulting precipitate was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 1:20 by volume mixture of methanol and ethyl acetate as eluent, to give 1.92 g of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH3:32][NH:33][CH3:34]>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:33]([CH3:34])[CH3:32]
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(N(C)C)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C23H24N6O2, 416.20.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[O:37][C:33]=2[CH:32]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:26][C:27]1[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]2[CH:45]=[CH:44][C:34]3[N:35]=[C:36]([NH:38][C:39]([CH:41]4[CH2:42][CH2:43]4)=[O:40])[O:37][C:33]=3[CH:32]=2)[CH:28]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)oc4c3)c2)c1
Yield: 74.1 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (222 mg, 1.72 mmol), thionyl chloride (1 mL, 13.7 mmol), toluene (5 mL), N-[6-(3-aminophenoxy)-1,3-benzooxazol-2-yl]cyclopropanecarboxamide (126 mg, 407 μmol) produced in Example B1(vii), pyridine (5 mL), and N,N-dimethylpyridine-4-amine (68.5 mg, 561 μmol) as starting materials, and in the same manner as in Example B1(viii), the title compound (145 mg, 74%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>O>[CH2:12]=[C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccc(CC(C(=O)O)C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=C(Cc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzylmalonic acid, (20.2 g., 0.09 mol) was suspended in N,N,N1, N1 -tetramethylmethanediamine (45 ml). Acetic anhydride (45 ml) was added dropwise, keeping the temperature below 45° C. by cooling in an ice-bath as necessary. The resulting clear solution was stirred for 11/2 hour at ambient temperature and then was poured into ice and water. The white solid product was collected, combined with comparable product from a second 0.083 mol run, and dried at 0.1 mm at room temperature to give 22.4 g. (68%) of product, m.p. 88°-91° C. A sample recrystallized from ether-petroleum ether melted at 90°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][N:27]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:23]([NH:40][C:41]([C:43]3[N:44]=[C:45]([CH2:48][N:49]4[CH2:54][C@H:53]([CH3:55])[O:52][C@H:51]([CH3:56])[CH2:50]4)[S:46][CH:47]=3)=[O:42])[CH:22]=2)[CH:16]=[N:17][C:18]=1[O:19][CH3:20])(=[O:11])=[O:10].[OH-].[Na+]>CC(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[C:23]([NH:40][C:41]([C:43]3[N:44]=[C:45]([CH2:48][N:49]4[CH2:50][C@H:51]([CH3:56])[O:52][C@H:53]([CH3:55])[CH2:54]4)[S:46][CH:47]=3)=[O:42])[CH:22]=2)[CH:16]=[N:17][C:18]=1[O:19][CH3:20])(=[O:10])=[O:11]
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 62.1 %

Procedure:
N-{6-[5-{[(2,4-Difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (105 mg) was dissolved in IPA (1 mL) and 2M NaOH (aq) (1 mL) and stirred at room temperature overnight. The IPA was evaporated and the remaining aqueous phase was diluted with water (2 ml), then acidified to ca. pH 4 using 2M HCl (aq) to give a precipitate that was extracted into DCM, passed through a hydrophobic frit, then evaporated to dryness. The residue was purified by ISCO companion 12 g silica cartridge using a 0-6% methanol in DCM gradient over 16 mins at 30 ml/min. Product containing fractions were combined, evaporated to dryness then further dried on a vacuum line to give title compound, (53 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](B(O)O)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[NH4+]>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]=[C:25]([C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[CH:4][N:3]=[C:2]3[Cl:1])=[CH:7][CH:8]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc2ccnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3ccnc(Cl)c3c2)CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
1-Chloroisoquinolin-7-yl boronic acid (0.55 g, 2.67 mmol), 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.68 g, 2.05 mmol), lithium chloride (0.26 g, 6.16 mmol), 2M aqueous sodium carbonate (2.9 ml, 5.8 mmol) and acetonitrile (15 mL) were combined under nitrogen, and palladium tetrakistriphenylphosphine (0.12 g, 0.103 mmol) added. The reaction mixture was refluxed for 90 minutes, cooled to room temperature, and concentrated in vacuo to give a wet solid. Ammonium hydroxide (3 mL of 30% aqueous solution) was added, and the material partitioned between methylene chloride (150 mL) and 2M aqueous sodium carbonate (25 mL). The organic phase was separated, and the aqueous extracted successively with methylene chloride. The combined organic extracts were dried over magnesium sulfate, and purified by flash column chromatography on silica gel to give the product as a white solid (0.43 g, 1.25 mmol). 1H NMR (CDCl3) δ 8.26-8.20 (m, 2H), 7.88-7.75 (m, 2H), 7.57 (d, 1H), 6.28 (br s, 1H), 4.20-4.12 (m, 2H), 3.76-3.66 (m, 2H), 2.75-2.62 (m, 2H), 1.56 (s, 9H). ESI MS (M+1)+: 259, 261 (Cl).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:13][C:14]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[Cl:27].[BH4-].[Na+].Cl>C1COCC1.O>[NH2:13][C:14]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:17]([CH2:18][OH:19])=[CH:16][C:15]=1[Cl:27]
Reactant: Nc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(CO)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
69.56 g (0.43 mol) CDI were added to a solution of 93.4 g (0.39 mol) 4-amino-3-chloro-5-trifluoromethyl-benzoic acid (described in Arzneim.-Forsch. 1984, 34(11A), 1612-1624) in 1 L THF and the mixture was stirred for 1 h at 40° C. The reaction mixture was then carefully added to a solution of 51.4 g (1.36 mol) NaBH4 in 450 mL of water at RT under a nitrogen atmosphere and with cooling. The mixture was stirred for 2 h at RT, combined with 500 mL water and 300 mL semiconc. HCl, stirred for another hour and then exhaustively extracted with EtOAc. The combined org. phases were dried over Na2SO4 and evaporated down i. vac. The oil remaining was combined with 500 mL PE and stirred while cooling with ice. The precipitate was suction filtered, washed with PE and dried. 29.7 g of the desired product were obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:19])[C:4]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[O:20]=[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:31][CH:32]=O>>[CH3:2][N:3]([CH3:19])[C:4]([C:6]1([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:32][CH2:31][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:29][CH2:30][C:21]2=[O:20])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=CCN1C(=O)CCc2ccccc21
Reactant: CN(C)C(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Product: CN(C)C(=O)C1(c2ccc(Cl)cc2)CCN(CCN2C(=O)CCc3ccccc32)CC1

Procedure:
Compound 115 was prepared by the same method as Compound 86 with the exception that Compound 2-3 was used instead of Compound 1-9 and that Compound 1-8 was used instead of Compound 1-4. Compound 115 was isolated as a white solid (53%, mp 243-245° C.). 1H (300 MHz, CDCl3,) δ 7.44-7.01 (m, 8H), 4.55 (m, 2H), 3.62 (m, 2H), 3.31-2.40 (m, 18H); MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[S:13])([F:4])[F:3].[CH2:14]([C:21]1[N:25]2[C:26]3[S:40][C:39]4[CH2:41][NH:42][CH2:43][CH2:44][C:38]=4[C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl>[CH2:14]([C:21]1[N:25]2[C:26]3[S:40][C:39]4[CH2:41][N:42]([C:12](=[S:13])[NH:11][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[C:2]([F:4])([F:3])[F:1])[CH2:43][CH2:44][C:38]=4[C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: Clc1ccccc1C1=NCc2nnc(Cc3ccccc3)n2-c2sc3c(c21)CCNC3
Solvent: ClCCCl
Product: FC(F)(F)c1ccccc1NC(=S)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCc2nnc(Cc4ccccc4)n2-3)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
Trifluoromethylphenylisothiocyanate (0.56 g, 0.0027 mol) is added to a mixture containing 1-benzyl-6-(2-chlorophenyl)-7,8,9,10-tetrahydro-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.8 g, 0.0018 mol) in anhydrous 1,2-dichloroethane (13 ml). The reaction medium is agitated at ambient temperature for 12 hours. The precipitate is filtered on frit then washed with isopropyl ether, with ethyl acetate then with isopentane and finally dried under vacuum. 0.28 g (24%) of final product is obtained in the form of a pale yellow coloured solid. Melting point: 239–240° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:23]OC)[CH2:18][Si](C)(C)C)=[CH:11][CH:10]=1.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]2[C:38](=[O:39])[CH2:37][CH2:36][C:35]2=[O:40])[CH:30]=[C:31]([Cl:33])[CH:32]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]2[CH2:18][CH:37]3[C:38](=[O:39])[N:34]([C:29]4[CH:28]=[C:27]([Cl:26])[CH:32]=[C:31]([Cl:33])[CH:30]=4)[C:35](=[O:40])[CH:36]3[CH2:23]2)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: COCN(CCc1ccc(Cl)cc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(CCc3ccc(Cl)cc3)CC2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
To prepare the compound of formula (Im), wherein R11 is chloro and m is 2, TFA (32 μl, 0.41 mmol) was added to an ice-cooled mixture of 4-chloro-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzeneethanamine (1.5 g, 5.25 mmol) (Preparation 14) and N-(3,5-dichlorophenyl)succinimide (1 g, 4.13 mmol, prepared according to Fujinami et al., Agr. Biol. Chem. [1972], p. 318, incorporated herein by reference) in methylene chloride (10 mL). The reaction mixture was allowed to warm to RT over 3 h. The solution was washed with ammonium hydroxide. The organic layer was dried over MgSO4 and concentrated in vacuo to afford after chromatography over silica gel (CH2Cl2) the above-referenced compound as a white solid (1.56 g). Mp=115° C. 1H NMR (CDCl3): 7.40 (1H, br s), 7.15-7.35 (4H, m), 7.07 (2H, d, J=8.3 Hz), 3.4-3.5 (2H, m), 3.3-3.4 (2H, m), 2.55-2.8 (4H, m), 2.35-2.5 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=1)[C:5]2=[O:29].C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>C1(C)C=CC=CC=1>[CH3:12][C:7]1[N:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)[C:5](=[O:29])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH:3]=2)[N:8]=1
Reactant: Cc1nc2ccc(Br)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(-c3ccccn3)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
6-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone synthesized in Example 34 (100 mg, 0.25 mmol) and 2-(tributylstannyl)pyridine (90 mg, 0.25 mmol) were dissolved in toluene (1 mL), and the atmosphere in the system was replaced by nitrogen. Palladium tetrakis(triphenylphosphine) complex (30 mg, 0.025 mmol) was added, and stirred at 120° C. for 12 hours. Insoluble matter was filtered off through cerite, chloroform was added to the filtrate, the organic phase was washed with distilled water, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=9/1), and the target substance (20 mg, 20%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COCCNCCOc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCNCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 38 %

Procedure:
A mixture of 6-methoxy-7-(2-(2-methoxyethylamino)ethoxy)-3,4-dihydroquinazolin-4-one (300 mg, 1 mmol), thionyl chloride (5 ml) and DMF (0.1 ml) was heated at reflux for 45 minutes. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The resulting gum was partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic layer was separated and the aqueous layer extracted with methylene chloride (4×40 ml). The combined extracts were passed through phase separating paper and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(2-methoxyethylamino)ethoxy)quinazoline (120 mg, 38%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1([CH2:27][OH:28])[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[C:21]1([CH2:20][N:17]2[CH2:18][CH2:19][C:14]3([NH:13][C:10](=[O:11])[CH2:9][O:28][CH2:27]3)[CH2:15][CH2:16]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1COCC2(CCN(Cc3ccccc3)CC2)N1
Temperature: 23 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Triethylamine (2 mL 14 mmol) was added to a DCM (50 mL) solution containing chloroacetyl chloride (1 mL, 14 mmol) and compound 391 (3 g, 14 mmol). The resulting mixture was stirred 2 h at 23° C. The solvent was stripped and THF was added followed by potassium tert-butoxide (5 g, 41 mmol). The resulting solution was stirred overnight at room temperature. The reaction was then concentrated to dryness and the resulting residue was washed with 200 mL of absolute ethanol. The ethanolic solution was then concentrated to give 3.16 g of 9-(phenylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecan-2-one. The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 261, Calculated 261.
Reaction SMILES: [F-:1].[Cs+].Cl[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>C(#N)C>[F:1][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: Cc1ccc(SCCl)cc1
Reactant: [F-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(SCF)cc1
Yield: 67.7 %

Procedure:
Cesium fluoride (149.55 g, 2 eq) was added to a mixture of PEG400 (90 mL) and acetonitrile (540 mL). The mixture was stirred a few minute under an argon atmosphere and then acetonitrile (90 mL) was removed by distillation. (Chloromethyl)(p-tolyl)sulfane (102.68 g, 492.25 mmol) was added. The reaction mixture was stirred at a temperature between 80° C. and 85° C. until the reaction was complete. The suspension formed, was filtered and the filtrate was concentrated. The crude product was purified by distillation to give 52.09 g (68%) of the desired product as slightly yellow oil (bp: 57° C. at 40 Pa).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].O>O1CCCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
Thionyl chloride (0.66 ml, 9.0 mmol) was added dropwise to a solution of (2S)-2-hydroxy-3-phenylpropionic acid (500 mg, 3.0 mmol, optical purity 100% ee (S)) in 5 ml of tetrahydrofuran at room temperature, and the mixture was stirred for 15 hours. To the reaction mixture was added 170 mg (0.60 mmol) of tetra-n-butylammonium chloride, and the mixture was heated at 40° C. for 4 hours. Water (5 ml) was added to the reaction mixture and, after 30 minutes of stirring, the mixture was extracted with 90 ml of ethyl acetate. The organic phase was washed with 10 ml of a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 499 mg (yield 90%) of the desired (2R)-chloro-3-phenylpropionic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](Cl)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:12]>O1CCCC1>[F:1][C:2]1[C:3]([C:9]([NH2:12])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: O=C(Cl)c1ncc(Cl)cc1F
Solvent: C1CCOC1
Product: NC(=O)c1ncc(Cl)cc1F
Reaction time: 4 h

Procedure:
4.0 g of 3-fluoro-5chloro-2-pyridinecarbonyl chloride (Example H6) are added in portions to a stirred mixture of 26 ml of 30% aqueous ammonia solution and 4 ml of tetrahydrofuran. The yellowish suspension is subsequently stirred for 4 hours and filtered and the material on the filter is washed with water and n-hexane. After drying in vacuo at 40° C., 1.34 g of the desired compound are obtained as a white solid of melting point 162-164° C.