Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CN2CCCC2)c(Cl)c1
Yield: 56.1 %

Procedure:
Pyrrolidine (22.0 mL, 0.255 mol) was added to a suspension of intermediate 14, 2-chloro-4-hydroxybenzaldehyde (30.8 g, 0.196 mol) in dichloromethane (620 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (65.8 g, 0.295 mol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (600 mL) and dichloromethane (600 mL) were added. The reaction mixture was acidified with concentrated HCl to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with EtOAc (2×500 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CHCl3 (3×500 mL). The organic layer was dried with anhydrous Na2SO4 (50 g). The solvent was evaporated in vacuo. The obtained oil was refluxed in Et2O (400 mL) for 1 h. Then hexane (200 mL) was added, and the mixture was cooled. The formed residue was separated by filtration and dried. 1H NMR spectrum showed the presence of acetic acid (2.3% w/w). The residue was dissolved in a mixture of Et2O (100 mL) and CH2Cl2 (100 mL), and a solution of NaOH (0.4 g) in water (4 mL) was added. The product was extracted form the organic layer. The extract was dried with anhydrous Na2SO4 (50 g), evaporated, and coevaporated with dioxane. The title compound (23.5 g, 0.11 mol, 56%) was obtained as a pale-yellow powder. LC/MS data: 212.0 and 214.0 (M+H)+ (calculated for C22H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.73 (br.s., 1H, OH); 7.24 (d, 1H, J=8.3 Hz, Ar—H); 6.78 (d, 1H, J=2.4 Hz, Ar—H); 6.70 (d.d., 1H, J1=8.3 Hz, J2=2.4 Hz, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.70 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1csc(Nc2ncc(/C=C/c3ccccc3)cc2OCc2ccccc2)n1
Temperature: 80 °C
Yield: 98.6 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.300 g, 0.797 mmol), (E)-styrylboronic acid (0.142 g, 0.957 mmol), Pd(PPh3)4 (0.0461 g, 0.0399 mmol), and sodium carbonate (0.254 g, 2.39 mmol) were added to DME (10 mL) and water (5 mL) and heated at 80° C. for 18 hours. An additional 0.5 eq of (E)-styrylboronic acid, Pd(PPh3)4, and 2M sodium carbonate were added and the reaction was heated at 80° C. for an additional 6 hrs. The reaction mixture was cooled and partitioned between water and dichloromethane. The layers were separated, dried, filtered, and concentrated to provide the title compound (0.314 g, 98.6% yield). 1H NMR (CDCl3) δ 8.03 (d, 1H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 5H), 7.32 (m, 2H), 6.98 (s, 2H), 6.39 (s, 1H), 5.42 (s, 2H), 2.46 (s, 3H). Mass spectrum (apci) m/z=400.0 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]3[NH:14][C:15](=[O:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.[CH3:26]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]3[N:14]([CH3:26])[C:15](=[O:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 35 mg) in dry N,N-dimethylformamide (5 ml) was added a solution of 2-(4-fluorophenyl)-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (250 mg) in dry N,N-dimethylformamide (3 ml) dropwise under ice cooling. The mixture was stirred for 30 minutes and to the mixture was added a solution of methyl iodide (125 mg) in dry N,N-dimethylformamide (2 ml). The mixture was stirred at ambient temperature for 2 hours and poured into water. The separated oil was extracted with dichloromethane and the solution was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of dichloromethane and diisopropyl ether to give 2-(4-fluorophenyl)-4-methyl-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (180 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([C:30]([F:32])([F:33])[F:31])=[CH:27][C:28]=2[CH3:29])=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)n(C)c(=O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Temperature: 47.5 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (243 mg, 0.45 mmol) in ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.8 mL) at room temperature. The mixture was heated to 45-50° C. and was stirred for 2 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (20 mL). The aqueous solution was washed with ethyl acetate (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 186 mg (79% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C24H19Cl2F3N2O4 (M+Na) 549.0567. found 549.0573.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1COCC1.[N:24]#[C:25][NH2:26].[Na].Cl>O>[C:1]([NH:26][C:25]#[N:24])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: N#CN
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NC#N
Reaction time: 43 h
Yield: 96.3 %

Procedure:
A solution of palmitoyl chloride (5.5 g, 0.020 mol) in 50 ml of freshly distilled dry THF was added drop-wise to a suspension of sodium cyanamide (3.84 g. 0.060 mol) in 150 ml of freshly distilled dry THF at ice bath temperature. After the addition, the ice bath was removed and the reaction was allowed to proceed at 25° C for 43 hours. The solids that formed were filtered to yield 8.48 g of waxy solid residue. The residue was ground to a fine powder and stirred in 150 ml of distilled water at ice bath temperature. The resulting soapy suspension (pH 11) was acidified to pH 2 with 10% HCl, then filtered and air-dried to give 5.4 g (96.3% yield) of crude 6 as a white solid. This was dissolved in warm THF and the mixture filtered. The filtrate was concentrated in vacuo until the solution became slightly turbid. This material was crystallized from THF/petroleum ether to yield 3.6 g (crop 1) of white powder. The filtrate was concentrated and crystallized in the same fashion to yield additional 0.6 g (crop 2) of white powder (74.8% total yield), mp 62°-65° C. TLC: Rf =0.68 in ethyl acetate/petroleum ether/glacial acetic acid (10:20:1); IR (Nujol, cm-1) 3230 (NH), 2250 (C≡N), 1740 (C=O); NMR (Silanor C, δ from TMS) 1.3-1.6 (t, --CH2 --CH2 --C=O), 1-1.8 (m, --(CH2)13 --), 0.8-1 (t, CH3 --CH2 --); Anal. Calcd for C17H32N2O: C, 72.81; H, 11.50; N, 9.99. Found: C, 72.69; H, 11.65; N, 9.68.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][C:4]2[CH:20]=[CH:21][S:22][C:3]1=2.Cl>C(O)(=O)C>[CH3:12][O:11][C:9]([C@@H:8]([N:6]1[CH2:5][C:4]2[CH:20]=[CH:21][S:22][C:3]=2[CH2:2][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:10]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1

Procedure:
Methyl(S)-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (1 g, 2.95 mmol) was dissolved in acetic acid (18.8 mL) and treated sequentially with conc. HCl and SnCl2 dihydrate (1.4 g, 6.2 mmol). The reaction was allowed to stir under nitrogen and the solvent was evaporated under vacuum after its completion. The residue was basified with aqueous sodium bicarbonate and extracted repeatedly with ethyl acetate. The combined organic layer was dried, filtered and concentrated to provide clopidogrel free base as an oily product (0.75 g). 1H-NMR (CDCl3, ppm) 7.7 (1H, dd), 7.35 (1H, m), 7.2-7-35 (2H, m), 7.2 (1H, d), 6.68 (1H, dd), 4.95 (1H, s), 4.68 (1H, bs), 3.5-4.0 (2H, m), 3.75 (3H, s), 2.9 (4H, s); chiral HPLC 98:2 enantiomeric ratio.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)C.Cl[C:11]1[C:16]([I:17])=[CH:15][N:14]=[C:13]([S:18][CH3:19])[N:12]=1.[CH3:20][NH:21][NH2:22]>O>[I:17][C:16]1[C:11]([N:21]([CH3:20])[NH2:22])=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=1
Reactant: CNN
Reactant: CSc1ncc(I)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CSc1ncc(I)c(N(C)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
603 mg of potassium carbonate was added to ethanol (15 mL) solution of 1.25 g of 4-chloro-5-iodo-2-(methylthio)pyrimidine, and with cooling with ice, 0.28 mL of methylhydrazine was dropwise added thereto. This was stirred overnight at room temperature, then water was added thereto, and the precipitated crystal was taken out through filtration and dried to obtain 851 mg of the entitled compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C>[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(I)cc1

Procedure:
According to the method of V. P. Chernetskii, A. I. Kiprianov, Zh. Obsch. Khim, 1956, 26, 3465, a mixture of 2-fluoronitrobenzene (14.0 g, 100 mmol), p-iodo aniline (10.95 g, 50 mmol) and triethylamine (13.9 ml, 100 mmol) was heated under reflux for 42 hours. The mixture was cooled, diluted with ethyl acetate (300 ml) washed consecutively with water (100 ml), 2N sodium hydroxide (100 ml) and brine (100 ml). The organic layer was dried (MgSO4), concentrated under reduced pressure and the residue was recrystallised from ethyl acetate to give N-(4-iodophenyl)-2-nitroaniline, 10.03 g, as bright orange needles, m.p. 171°-2° C.
Reaction SMILES: BrC(Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.ClCCl.[CH3:29][O:30][CH2:31][O:32][CH3:33]>FC(F)(F)S([O-])(=O)=O.[Ag+].C(O)CO>[O:30]1[CH2:29][CH2:33][O:32][CH:31]1[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Reactant: COCOC
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: OCCO
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCCO4)c3c2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.5 %

Procedure:
A mixture of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.500 g, 10.0 mmol), silver trifluoromethanesulfonate (0.500 g, 19.5 mmol), ethylene glycol (5.00 ml), dichloromethane and dimethoxymethane is stirred three days at room temperature and treated with additional silver trifluoromethanesulfonate (0.300 g, 11.7 mmol). The resultant mixture is stirred one day at room temperature and treated with additional silver trifluoromethanesulfonate (0.400 g, 15.6 mmol) and ethylene glycol (1.00 ml), stirred another day at room temperature and treated again with silver trifluoromethanesulfonate (0.300 g, 11.7 mmol) and ethylene glycol (1.0 ml). After stirring an additional day the mixture is filtered. The filtrate is diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is triturated with hexanes-ethyl acetate to afford the title compound as a white solid (0.070 g, 17.5%, mp 213-216° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 3-methoxypropan-1-ol (15.9 mL, 166 mmol) in CH2Cl2 (75 mL) and pyridine (50 mL) was added 4-(dimethylamino)pyridine (1.0 g, 8.3 mmol) followed by p-toluenesulfonyl chloride (31.7 g, 166 mmol). The mixture was allowed to stir at ambient temperature for 72 hours then was quenched with 5% aqueous HCl (20 mL), extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (31 g, 127 mmol, 76% yield). MS (DCI/NH3) m/z 262 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][CH:7](C(OCC)=O)[C:8]([O:10]CC)=[O:9])([O-:3])=[O:2]>Cl.C(O)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][CH2:7][C:8]([OH:10])=[O:9])([O-:3])=[O:2]
Reactant: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of crude diethyl (2-nitrobenzyl)malonate in 6N aqueous HCl (15 ml) and acetic acid (15 ml) was stirred at refluxing temperature for 48 hours. After cooled to ambient temperature, the mixture was concentrated under reduced pressure. To the residue was added 10% aqueous NaOH solution and washed with ethyl acetate. The aqueous layer was acidified with aqueous HCl solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 3-(2-nitrophenyl)propanoic acid.
Reaction SMILES: [Cl:1]C1C=CC(C(C(Cl)=C(Cl)Cl)O)=CC=1.Cl.[CH3:16][O:17][C:18](=[O:30])/[C:19](/[Cl:29])=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=1>>[CH3:16][O:17][C:18](=[O:30])/[C:19](/[Cl:29])=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([Cl:1])=[CH:23][CH:22]=1
Reactant: OC(C(Cl)=C(Cl)Cl)c1ccc(Cl)cc1
Reactant: COC(=O)/C(Cl)=C/c1ccc(OC)cc1
Agent: Cl
Product: COC(=O)/C(Cl)=C/c1ccc(Cl)cc1
Yield: 93 %

Procedure:
p-Chlorophenyltrichlorovinyl carbinol (6.0 g, 22.0 millimoles) is added to a refluxing solution of methanolic sulfuric acid (30 ml as noted in Example 4). Hydrogen chloride evolution is noted during the stirring procedure for 45 minutes. The mixture is cooled and has a workup as in Example 4, which affords z-methyl-2-chloro-3-(4'-chlorophenyl)propenoate (4.7 g, 20.4 millimoles) in 93 percent yield (M.P.=78° C.-80° C.): 'H NMR (CDCl3) δ 7.77 (1H, s), 7.45 (4H, ab quartet), 3.81 (3H, s); 13C NMR (CDCl3) δ 163.5, 136.1, 135.8, 131.6, 131.3, 128.8, 122.3, 53.4. Analysis calculated for: C, 52.01; H, 3.50. Found: C, 51.85; H, 3.42.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].C(N(CC)CC)C.CS([Cl:34])(=O)=O>ClCCl>[Cl:34][CH2:10][C:8]1[N:9]=[C:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (4.00 g) and triethylamine (4.00 g) in dichloromethane (20 mL) was added dropwise methanesulfonyl chloride (3.00 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. Dichloromethane (150 ml) was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH:12]=[CH:11][NH:10][C:9]1=[S:13])=[O:7])[CH2:2][CH2:3][CH3:4].BrBr.C(N(CC)CC)C>ClCCl>[CH2:1]([N:5]1[C:6](=[O:7])[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1cc[nH]c1=S
Agent: BrBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1sc2nccn2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To solution containing 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione (4.73 g, 23.7 mmole) suspended in 15 mL of dichloromethane cooled to 0° C. under a nitrogen atmosphere, was added bromine (3.79 g, 23.7 mmole) dissolved in 15 mL of dichloromethane, in a dropwise manner. After the addition was complete, triethylamine (4.81 g, 47.5 mmole) dissolved in 15 mL dichloromethane was added such that the temperature of the reaction mixture never exceeded 0° C. The reaction mixture was maintained at 0° C. for an additional 2 h and then stirred for 16 h at room temperature. It was then diluted with 150 mL of dichloromethane and washed twice with water and once with a saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate and evaporated to dryness to yield 4.30 g (92%) of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one as an off-white powder: mp 142-143° C.; 1H NMR (CDCl3)δ 7.40 (d, 1H), 7.20 (d, 1H), 3.79 (t, 2H), 1.73 (m, 2H), 1.40 (m, 2H), 0.957 (t, 3H) ppm; IR (KBr)ν 1702 cm-1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=O.O.[NH2:20][NH2:21].Cl>C(O)C>[OH:18][N:16]1[C:3]2[CH:4]=[C:5]([CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])[CH:6]=[CH:7][C:2]=2[N:21]=[N:20]1
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1F
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: OC(c1ccccc1)c1ccc2nnn(O)c2c1
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A mixture of 25 parts of 4-fluoro-3-nitro-α-phenylbenzenemethanol, 20 parts of hydrazine monohydrate and 80 parts of ethanol was stirred for 1.5 hours at reflux temperature. After cooling, 20 parts of a hydrochloric acid solution 10N were added. After concentration, the residue was washed twice with 50 parts of water and dissolved in a solution of 300 parts methanol (10%) in trichloromethane. The organic layer was dried, filtered and concentrated, yielding 23.8 parts (98.6%) of 1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol as a residue (int. 64).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]([CH3:56])[CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:53]6[CH2:54][CH2:55][CH:50]([N:49]([CH3:56])[CH3:48])[CH2:51][CH2:52]6)=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CN(C)C1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCC(N(C)C)CC4)nc3)cn2)cc1
Yield: 85.5 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A in Example 1-D-48 and 4-dimethylaminopiperidine (59 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of [5′-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-dimethyl-amine as a yellow solid (197 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-73) as a yellow powder (32 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([F:16])=[CH:8][C:9]=2[CH3:15])[N:4]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:15][C:9]1[CH:8]=[C:7]([F:16])[CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2
Reactant: COc1nc2cc(F)cc(C)c2nc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc2cc(F)cc(CBr)c2nc1OC

Procedure:
8.4 g (37.8 mmol) of 2,3-dimethoxy-7-fluoro-5-methylquinoxaline, 7.4 g (41.6 mmol) of N-bromosuccinimide and 0.63 g (0.38 mmol) of azoisobutyronitrile are introduced into 140 ml of carbon tetrachloride and stirred at reflux for 6 hours. The reaction mixture is cooled and concentrated, and the residue is taken up in diethyl ether. The suspension is filtered off and the mother liquor is concentrated again. The remaining crude product is recrystallized from hexane. The title compound is obtained as white crystals of m.p. 122-125° C.