Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3C(CON)=NN=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:24]=1.[H-].[Na+].CI>CN(C)C=O>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C1=CNc2ccccc2C=N1
Reaction time: 18 h

Procedure:
A stirred solution of 8-chloro-1-[(aminooxy)methyl]6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.02 mole) in dry dimethylformamide (50 ml.) is cooled in an ice bath under nitrogen and treated successively with a 57% mineral oil suspension of sodium hydride (0.84 g,. 0.02 mole) and methyliodide (0.02 mole). The mixture is allowed to come slowly to ambient temperature and stand for 18 hours. It is then concentrated in vacuo. The residue is chromatographed on silica gel with methanol to give 8-chloro-1-[[(methylamino)oxy]methyl]6-phenyl-4H-s-triazolo]4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:25][CH2:24]1)=[O:19])([O:3]CC)=O.CC(C)([O-])C.[K+].C1COCC1.CS(O)(=O)=O>C(O)C>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][N:20]2[C:1](=[O:3])[C:6]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:8][C:7]=3[NH:17][C:18]2=[O:19])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCN1CCN(c2ccccc2OC)CC1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3sc(-c4ccccc4)cc3c2=O)CC1
Yield: 51.1 %

Procedure:
A solution of Example 5B (387 mg, 0.762 mmol) in ethanol (5 mL) was treated with 1M potassium t-butoxide/THF (0.84 mL), heated to reflux for 90 minutes, cooled, quenched with 1N HCl (0.84 mL), and partitioned between water and ethyl acetate. The insoluble solid was collected, washed with ethyl acetate, slurried in methanol, treated with methanesulfonic acid (2 equiv), and concentrated. The product was crystallized from ethanol to provide 180 mg the title compound as the bis methanesulfonate salt.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:10])[NH:6][CH:7]=[N:8][CH:9]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>C1COCC1.CN(C=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5](=[O:10])[C:4]([Br:3])=[CH:9][N:8]=[CH:7]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1[nH]cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1c(Br)cncn1Cc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
Sodium hydride (0.343 g, 8.57 mmol) was added to a solution of 5-bromopyrimidin-4(3H)-one (1.5 g, 8.57 mmol) in THF (10 mL) and DMF (6 mL) and the reaction mixture was stirred for 10 minutes. 4-Chlorobenzyl bromide (1.76 g, 8.57 mmol) was added and the reaction mixture was stirred for an additional 1 hour. The reaction was quenched by pouring the reaction mixture into ice and diluting with ethyl acetate. The organic layer washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 40S) to afford the title compound as white solid (0.388 g, 15.1%). LRMS (APCI pos) m/e 300.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.10 (s, 1H), 7.29-7.37 (m, 4H), 5.15 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:32])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:44]([O:46][CH3:47])=[O:45]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:30])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]([N:23]([CH2:24][CH3:25])[C:44]([O:46][CH3:47])=[O:45])=[O:22])=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: CCNC(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCN(C(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C(=O)OC
Temperature: 25 °C
Yield: 51.8 %

Procedure:
In a solution of 0.50 g of N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoyl]-N′-ethyl urea synthesized similarly to Synthetic Example 26 in 4 mL of tetrahydrofuran, 4 mL of 1M tetrahydrofuran solution of lithium hexamethyl disilazane was added at −78° C. with stirring, and stirred at the same temperature for 30 minutes. Then, 0.12 g of methyl chloroformate was added in the reaction mixture at −78° C. with stirring. After the completion of the addition dropwise, it was continued to stir further for 18 hours while the temperature was slowly raised to room temperature. After the completion of the reaction, 30 mL of ice water was added, and extracted with ethyl acetate (30 mL×2). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 0:1 to 1:2) to obtain 0.29 g of the aimed product as colorless resinous substance.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:49])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[C:41](Br)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:49])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH2:31][CH3:32])[C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OCC)c(Br)c1
Product: CCOC(=O)Cc1ccc(OCC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-4-ethoxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-3-pyrrolidinol to give the title compound in 17% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.91-1.96 (m, 1H), 2.40 (dd, 1H), 2.55 (dd, 1H), 2.66 (dd, 1H), 2.80-2.89 (m, 3H), 4.16 (br s, 1H), 4.40 (t, 2H), 4.69 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.87 (t, 1H), 7.92 (d, 1H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]=[C:10]2[NH:20][CH3:21])=[CH:6][CH:5]=1.[CH3:24]I>CC(N(C)C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]=[C:10]2[N:20]([CH3:24])[CH3:21])=[CH:22][CH:23]=1
Reactant: CNc1nc(=O)c2ccccc2n1Cc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1nc(=O)c2ccccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.4 g. of sodium hydride in 25 ml. of dimethylacetamide is added 2.0 g. of 1-(4'-fluorobenzyl)-2-methylamino-quinazolin-4(1H)-one. The resulting mixture is stirred for 30 minutes at room temperature and there is then added 1.5 g. of methyliodide. The resulting mixture is stirred at room temperature for 3 days, poured over ice/water, extracted twice with methylene chloride, washed twice with water, dried and evaporated in vacuo. The residue is dissolved in methylene chloride and the methylene chloride exchanged for ether on a steam bath to obtain 1-(4'-fluorobenzyl)-2-dimethylamino-quinazolin-4(1H)-one, m.p. 160°-169°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH2:13][Br:18])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nc(N)nc(-c2ccc(CBr)o2)c1C#N
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a stirred suspension of 500 mg (2.03 mmol) 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 20 ml carbon tetrachloride under argon were added 397 mg (2.23 mmol) N-bromosuccinimide and a small spatula end of benzoyl peroxide. Stirring was continued for 8 hours while the reaction mixture was irradiated with a 500 W halogen lamp. The reaction mixture was then concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 250 mg (38%) 2-amino-4-(5-bromomethyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. EI-MS m/e (%): 326 (M{81Br}+, 5), 325 ([M{81Br}-H]+, 6), 324 (M{79Br}+, 5), 324 ([M{79Br}-H]+, 6), 245 ([M—Br]+, 100).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13](O)[CH3:14])[CH:8]=1.C1(C)C=CC=CC=1>ClCCl>[ClH:3].[Cl:3][CH:13]([C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[CH:11][N:10]=1)[CH3:14]
Reactant: COc1ccnc(C(C)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccnc(C(C)Cl)c1
Product: Cl

Procedure:
36 ml of thionyl chloride are added dropwise to a cooled suspension of 57 g of (±)-1-[4-methoxy-2-pyridyl]ethanol in 400 ml of dichloromethane, in such a way that the internal temperature does not exceed 15° C. The mixture is then heated under reflux for 2.5 h, treated with 300 ml of toluene and concentrated to 150 ml. The reaction product which has precipitated is filtered off with suction and rinsed with cold toluene and petroleum ether. This gives 76.4 g (98.2%) of the title compound of m.p. 113°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([O:14]C2CCCCO2)[CH3:13])[CH2:11][O:10]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
2-(2,4-Difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane (82 g) (synthesized by the method disclosed in Japanese Unexamined Patent Publication No. Hei 4(1992)-74168) and pyridinium p-toluenesulfonate (6.3 g) were dissolved in ethanol (600 ml), and the resultant was stirred at 55° C for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 lit.) and washed with water (200 ml×2). The aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=10/1 to 8/1 to 3/1) to give (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (31.5 g) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH:20][S:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]([CH3:30])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:38](I)[CH:39]([CH3:41])[CH3:40].C(OCC)(=O)C.O>CN(C)C(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[S:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]([CH3:30])[CH:5]=1
Reactant: CC(C)CI
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccc(C)o2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)C)S(=O)(=O)c2ccc(C)o2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-[2-[N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid methyl ester prepared in reference example 3 (870 mg) in N,N-dimethylacetamide (2 ml), cesium carbonate (1.37 g) and isobutyl iodide (0.36 ml) were added and the mixture was stirred for 1 hour at 100° C. The reaction mixture was allowed to cool and poured into ethyl acetate-water (40 ml-40 ml). The organic layer was washed, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (toluene-ethyl acetate) to give the title compound (855 mg) having the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C1C=C(C(O)=O)C=CN=1.C(OC([N:37]1[CH2:42][CH2:41][O:40][C@@H:39]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([Cl:50])[CH:44]=2)[CH2:38]1)=O)(C)(C)C>>[ClH:50].[Cl:50][C:45]1[CH:44]=[C:43]([C@@H:39]2[O:40][CH2:41][CH2:42][NH:37][CH2:38]2)[CH:48]=[CH:47][C:46]=1[NH:49][C:14]([C:12]1[CH:11]=[N:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:13]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Reactant: N#Cc1ccc(-n2cc(C(=O)O)cn2)cc1
Agent: O=C(O)c1ccnc(C(F)(F)F)c1
Product: Cl
Product: N#Cc1ccc(-n2cc(C(=O)Nc3ccc([C@H]4CNCCO4)cc3Cl)cn2)cc1

Procedure:
In analogy to example 83, step a) using 1-(4-cyanophenyl)-1H-Pyrazole-4-carboxylic acid (CAS 1152945-21-5)) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 408.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.CO.[CH:24]1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1>[CH3:24][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 8 h

Procedure:
800 gm (2.61 mol) of the difficulty soluble diastereoisomer of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C, were suspended in 4 liters of benzene and 125.5 gm (3.92 mol) of methanol, and a solution of 648 gm (3.14 mol) of dicyclohexyl-carbodiimide in 650 ml of benzene was added while stirring and cooling at 20°-25° C. The acid dissolved, and dicyclohexylurea precipitated out. The mixture was allowed to stand overnight at room temperature, then the excess of carbodiimide was decomposed by addition of glacial acetic acid, and then 2 liters of water were added, the dicyclohexylurea was suction-filtered off, the organic phase was separated from the filtrate and evaporated in vacuo after drying. The obtained oil (969 gm) was recrystallized from 2.9 liters of isopropanol. Yield: 736 gm (88% of theory); m.p. 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32].O.[OH-].[Na+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:32][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)s2)cc1
Temperature: 25 °C
Yield: 128.9 %

Procedure:
To a solution of 4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoic acid methyl ester (100 mg) in dimethoxyethane (3 ml) was added phosphorus pentasulfide (82 mg). The mixture was refluxed for 5 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water and the mixture was adjusted to pH 11 with 1N-sodium hydroxide aqueous solution. The resulting precipitates were filtered, washed with water and dried to give 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester (97.4 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]2[O:5][C:4]([CH3:16])([CH3:3])[C:8](=[O:9])[C:7]=2[CH:10]=1
Reactant: Cc1ccc2c(c1C)OC(C)(C)C2=O
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Br)cc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Bromine (10.0 mL, 195 mmol) was added to a solution of acetic acid (150 mL) containing 2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (26.4 g, 139 mmol) synthesized in Reference Example 17, and the mixture was stirred at room temperature for 3 hours. After that, the reaction solution was poured into 5% aqueous solution of sodium sulfite. The generated crystals were collected by filtration, and recrystallized from methanol to give 32.8 g of the title compound (yield: 88%).
Reaction SMILES: C([C:3]1C2CCNC[C:6]=2[S:5][C:4]=1NC(=O)C=CC1C=CC=CC=1)#N.[C:23]([C:25]1[C:33]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=2[S:27][C:26]=1[NH:34][C:35](=[O:44])[CH:36]=[CH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)#[N:24].[N-]=C=[O:47]>>[CH2:4]([S:5][C:6]([N:30]1[CH2:31][CH2:32][C:33]2[C:25]([C:23]#[N:24])=[C:26]([NH:34][C:35](=[O:44])/[CH:36]=[CH:37]/[C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[S:27][C:28]=2[CH2:29]1)=[O:47])[CH3:3]
Reactant: [N-]=C=O
Reactant: N#Cc1c(NC(=O)C=Cc2cccnc2)sc2c1CCNC2
Reactant: N#Cc1c(NC(=O)C=Cc2ccccc2)sc2c1CCNC2
Product: CCSC(=O)N1CCc2c(sc(NC(=O)/C=C/c3cccnc3)c2C#N)C1

Procedure:
The following compounds 37 and 38 can be prepared according to the general procedure G described below starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-acrylamide (compound B1) or N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-3-yl)-acrylamide (compound B2) and the appropriate isocyanate or amine/carbonyldiimidazole.
Reaction SMILES: BrCC1C=CC=C(C([Cl:11])=O)C=1.C(O)(C)C.[N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>CCOCC>[ClH:11].[N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]
Reactant: O=C(Cl)c1cccc(CBr)c1
Solvent: CCOCC
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: Cl
Reaction time: 3 h

Procedure:
To a vessel containing 20 g (about 0.093 mol) of crude α-bromo-m-toluoyl chloride and 6 g (0.10 mol) of isopropyl alcohol in 50 ml of ether is added, with cooling, about 10 g (0.093 mol) of 2,6-lutidine. After about 3 hours, 4.3 g of solid 2,6-lutidine hydrochloride is filtered off. After an additional 21 hours, 100 ml of ether is added and the mixture is filtered to give an additional 5.4 g of 2,6-lutidine hydrochloride. The filtrate is washed with 2 × 100 ml of ice water, two 100 ml portions of cold dilute hydrogen bromide, 100 ml of ice water and two 100 ml portions of ice cold sodium bicarbonate solution and the ether layer is dried over calcium sulfate and concentrated under vacuum to yield 17.6 g oil. To this oil is added 16.0 g (0.079 mol) of tributylphosphine in 100 ml of acetonitrile and is heated at reflux under N2 for about 70 minutes then concentrated under vacuum to a black oil. The oil is triturated twice with 200 ml of ether and chromatographed on 150 g acid Woelm Act. I alumina with benzene. The first liter of eluate provides 15.3 g of solid which is crystallized twice from ethylacetate containing a small portion of acetonitrile to yield 6.4 g of m-isopropoxycarbonylbenzyltributylphosphonium bromide, a white solid having a melting point of 151°-153°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(=O)([O-])O.[Na+]>>[CH2:22]([NH:25][C:2]1[N:3]=[C:4]([NH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: Cc1csc2c(NC/C=C/c3ccccc3)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC/C=C/c2ccccc2)c2scc(C)c2n1
Yield: 81.4 %

Procedure:
316 mg (1.0 mmol) of 2-chloro-4-(trans-cinnamylamino)-7-methylthieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 274 mg (yield: 81.5%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([CH3:11])[N:3]=1.O.[NH2:13][NH2:14]>O>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[N:5][C:4]([CH3:11])=[N:3][C:2]=1[NH:13][NH2:14]
Reactant: COc1nc(C)nc(Cl)c1Cl
Reactant: NN
Solvent: O
Product: COc1nc(C)nc(NN)c1Cl

Procedure:
4,5-Dichloro-6-methoxy-2-methylpyrimidine (21 g, 0.11 mol), 25 ml of hydrazine hydrate, and 25 ml of water were combined and heated to reflux for 25 min. The mixture was then cooled and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The solid residue was extracted with hexane and dried to obtain 12.8 g (62 percent of theory) of the title compound as a fluffy white solid melting at 158° C.-159° C.