Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4](/[N:6]=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:33][CH2:34][C:35]1[O:36][C:37]([CH2:40][CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:39]=1.CC(C)(O)C#N>C1COCC1>[C:44]1([CH2:43][O:42][CH2:41][CH2:40][C:37]2[O:36][C:35]([CH2:34][CH2:33][C:4]#[N:6])=[CH:39][CH:38]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: OCCc1ccc(CCOCc2ccccc2)o1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCCc1ccc(CCOCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
DEAD (1.285 mL, 8.17 mmol) was added to a stirred solution of Ph3P (2.14 g, 8.17 mmol) in 12 mL of dry THF at 0° C. The solution was stirred for 30 min at rt and compound 255E (670 mg, 2.72 mmol) was added. The reaction was stirred for 15 min and acetone cyanohydrin (0.745 mL, 8.17 mmol) was added at −15° C. The reaction was stirred for 30 min at −15° C., then at rt overnight. The mixture was then concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 100% CH2Cl2 gave 180 mg (0.705 mmol, 26%) of compound 255F as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][CH:22]=[CH2:21])[C:6]([O:8][CH3:9])=[O:7])[CH:13]=[CH2:14]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Yield: 87 %

Procedure:
A solution of 3.04 g (15.8 mmol) of methyl 4-hydroxy-3-propenylbenzoate (Example 42, Step B) was refluxed with anhydrous potassium carbonate (4.37 g, 2 equiv) and allyl bromide (3.5 mL, 2.5 equiv) in acetone overnight. The mixture was filtered through Celite and the filter cake was washed with more acetone and dichloromethane. After removing the solvents, the resulting oil was distilled under high vacuum to give 3.2 g (87%) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: CC(=O)NCCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)NCCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of N-acetylethanolamine (1.120 g, 10.86 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.199 g, 52%). Mass (m/z): 383.2 (M++1), 381.1 (M+−1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH2:16][N:7]1[CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:6]1
Reactant: COc1cccc(F)c1C=O
Reactant: COC(=O)C1CNCC(OC)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(OC)CN(Cc2c(F)cccc2OC)C1
Reaction time: 0.25 h

Procedure:
To Methyl 5-methoxypiperidine-3-carboxylate (500 mg, 2.9 mmol) in DCM (10 mL) was added 2-fluoro-6-methoxybenzaldehyde (890 mg, 5.8 mmol) and 10 drops of acetic acid. After stirring for 15 min, sodium triacetoxyborohydride (2.4 g, 11.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. After quench with saturated Na2CO3, the mixture was extracted with DCM. Dried and concentrated to give crude product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:50]=[C:49]3[N:45]([CH2:46][CH2:47][C:48]3=[O:51])[CH:44]=2)O1>O1CCOCC1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]3[CH:50]=[C:49]4[N:45]([CH2:46][CH2:47][C:48]4=[O:51])[CH:44]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc3n(c2)CCC3=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc3n(c2)CCC3=O)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (10.51 mg, 0.015 mmol), tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one (148 mg, 0.599 mmol) in dioxane (4 mL) and saturated aqueous NaHCO3 (1 mL) was heated to 100° C. in a Biotage Initiator microwave for 1 hour. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(1-oxo-2,3-dihydro-1H-pyrrolizin-6-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (7 mg, 6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.78 (m, 1H), 2.10-2.11 (m, 1H), 3.01-3.04 (m, 2H), 3.34-3.34 (m, 1H), 3.66-3.67 (m, 1H), 3.76-3.78 (m, 1H), 3.84-3.86 (m, 1H), 3.95-3.97 (m, 1H), 4.37-4.39 (m, 4H), 4.50-4.51 (m, 1H), 7.05 (d, J=6.35 Hz, 1H), 7.60 (s, 1H), 7.90-7.92 (m, 2H), 8.43 (s, 1H), 8.56 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H20FN5O3, 386. found, 386.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[C:4]([F:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:4]([F:11])=[CH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:2]=1[F:1]
Reactant: Cc1c(F)cc2sccc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc2sccc2c(F)c1CBr

Procedure:
To a solution of 0.48 g of 4,6-difluoro-5-methylbenzo[b]thiophene in 5 ml of carbon tetrachloride are added 0.92 g of N-bromosuccinimide and 0.01 g of 2,2'-azobisisobutylonitrile, and the resulting mixture is refluxed for 16 hours. After cooling, insolubles are removed from the thus cooled mixture by filtration, and the filtrate obtained is concentrated under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane], to obtain 0.18 g of colorless, solid 5-bromomethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH:19]([CH2:21][C:22](OC)=[O:23])[CH3:20]>CN(C)C=O>[CH3:20][N:19]1[C:8](=[O:10])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22](=[O:23])[CH2:21]1
Reactant: CNCC(=O)OC
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2cccnc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 5.18 g (37.5 mmol) of 3-aminopicolinic acid in 100 ml of dimethylformamide is treated with 6.20 g (38.2 mmol) of N,N'-carbonyldiimidazole and the mixture is stirred at room temperature for 1 hour. To the light brown solution obtained there are added 3.84 g (38 mmol) of triethylamine and 5.30 g (38 mmol) of methyl sarcosinate hydrochloride and the mixture is stirred at the boiling point for 6 hours. After removing the dimethylformamide in vacuo, the residue is crystallized from ethanol. There is obtained 3,4-dihydro-4-methyl-2H-pyrido[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 272°-274°.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].[Na+].[I-]>CN(C=O)C>[F:1][C:2]1[C:3]([O:10][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)COc1c(F)cccc1C=O
Temperature: 65 °C
Yield: 99.3 %

Procedure:
To a suspension of 3-fluoro-2-hydroxybenzaldehyde (4.18 g, 29.8 mmol) and K2CO3 (12.25 g, 89 mmol) in DMF (81 mL) was added (chloromethyl)trimethylsilane (4.06 g, 33.1 mmol) and NaI (4.96 g, 33.1 mmol). Upon completion of addition, the mixture was heated in 65° C. oil bath overnight. After this time, the mixture was cooled to rt, quenched with water (20 mL) and then extracted with Et2O (2×30 mL). The combined organic layers were washed with H2O (2×15 mL), dried (Na2SO4), filtered and concentrated to afford Compound 1A as a light yellow oil (6.7 g, 98% yield). 1H NMR (500 MHz, CDCl3) δ ppm 10.41 (s, 1 H), 7.60 (dd, J=9.1, 1.7 Hz, 1 H), 7.32 (ddd, J=11.8, 8.3, 1.7 Hz, 1 H), 7.01-7.12 (m, 1 H,) 4.01 (d, J=1.7 Hz, 2 H), 0.17-0.21 (m, 9 H). 19F NMR (471 MHz, CDCl3) δ ppm −129.13.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](OC=C)(=O)[CH3:9]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:8]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])=[CH2:9]
Reactant: O=C(O)CCCBr
Reactant: C=COC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C=COC(=O)CCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromobutyric acid (1.0 g, 6.0 mmol) in vinyl acetate (54 mL) add with stirring palladium(II) acetate (188 mg, 0.84 mmol) and continue stirring overnight at ambient temperature. Filter and concentrate in vacuo to provide the crude desired intermediate.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Li])CCC.IC.C(OCC)(=O)C>O>[C:1]([NH:5][S:6]([C:9]1([CH3:13])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Temperature: -69 °C
Yield: 99 %

Procedure:
To a four necked, 5 L round bottom flask was added N-(tert-butyl)-3-chloropropane-1-sulfonamide (Previously dried by azeotroping with 3×100 mL toluene) (100 g, 468 mmol) and THF (1500 mL). This was cooled to an internal temperature of −69° C. then butyl lithium (2.5M in hexanes, 412 mL, 1.02 mol) was added dropwise over a period of 55 min while keeping the internal temperature below −65° C. The ice bath was removed and the reaction mixture was warmed to rt over 1.5 h and then cooled back down to an internal temperature of −69° C. Butyl lithium (196 mL, 515 mmol) was added to the reaction mixture over a period of 25 min while keeping the internal temperature below −65° C. The reaction mixture was then warmed to rt over the course of 1.5 h. The reaction mixture was recooled to an internal temperature of −69° C. and iodomethane (58.5 mL, 936 mmol) was added dropwise over a period of 40 min while keeping the internal temperature below −65° C. The reaction mixture was then warmed to an internal temperature of −50° C. over the course of 4 h. The cold bath was removed and a solution of saturated NH4Cl (1000 mL) was added. The quenched reaction mixture was transferred to a separatory funnel along with ethyl acetate (100 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. (3×75 mL). The combined organic layers were washed with brine (700 mL), dried with MgSO4, and concentrated in vacuo to an off white solid which was dried under high vac for 30 min to yield N-(tert-butyl)-1-methylcyclopropane-1-sulfonamide as a white solid (88.5 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ 4.07 (bs, 1 H), 1.51 (s, 3 H), 1.38-1.41 (m, 2 H), 1.36 (s, 9 H), 0.77-0.80 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15].[CH3:17][OH:18]>>[CH3:17][O:18][C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:15]
Reactant: O=C(Cl)c1cnoc1-c1ccc(Cl)cc1Cl
Reactant: CO
Product: COC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 63.1 %

Procedure:
5-(2',4'-Dichlorophenyl)-4-isoxazolecarbonyl chloride (2.0 g.; 0.007 mol.) was covered with methanol and the solution was heated on a steam cone for 2 hours. The excess methanol was then removed under reduced pressure and the resulting residue was dissolved in hot pentane. The product crystallized from the pentane solution to yield methyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (1.2 g.; 63.1% yield) having a melting point of 83°-84° C. and the following analysis:
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=O.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:26][NH:27]2)=[CH:23][CH:22]=1>>[C:6]1([C:4]2[C:3](=[O:2])[NH:33][C:31](=[O:32])[C:30]=2[C:25]2[C:24]3[C:28](=[CH:29][C:21]([C:20]([F:34])([F:19])[F:35])=[CH:22][CH:23]=3)[NH:27][CH:26]=2)[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(C(F)(F)F)ccc12

Procedure:
Beginning with (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and 6-(trifluoromethyl)indole-3-acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][OH:15])=[O:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(=O)(OC)OC>[CH3:16][S:17]([O:15][CH2:14][C:13]#[C:12][CH2:11][O:10][CH:8]=[O:9])(=[O:19])=[O:18]
Reactant: O=COCC#CCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COC(=O)OC
Product: CS(=O)(=O)OCC#CCOC=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
41.5 g (0.409 mol) of triethylamine was added to 300 ml of dimethyl carbonate solution of 44.0 g (0.386 mol) of 4-formyloxy-2-butyn-1-ol, and cooled to 0° C. 46.9 g (0.409 mol) of methanesulfonyl chloride was dropwise added to the solution while the inner temperature was controlled to be not higher than 15° C. After the addition, this was stirred at 25° C. for 1.5 hours, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, the aqueous layer was separated, and the organic layer was concentrated to give 72.6 g (yield 98%) 4-formyloxy-2-butyn-1-yl methanesulfonate. For use in the battery test, this was purified through silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[O:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:16][C:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 89.2 %

Procedure:
13 g of methyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate, 50 ml of dimethylformamide and 9.6 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 11 g of methyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:32][C:33]2[CH:40]=[CH:39][CH:38]=[C:35]([CH3:36])[CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: Cc1cccc(CBr)c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccc(C)c3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, Part A, and 3-methylbenzyl bromide. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11]Br.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>C(#N)C>[Cl:29][C:27]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([NH:20][C@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]2[N:13]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:28]=1
Reactant: N#Cc1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N1CCCC1

Procedure:
Sodium carbonate and 1,4-dibromobutane were added to an acetonitrile solution of 2-{[(1S*,2S*)-2-aminocyclohexyl]amino}-4-chlorobenzonitrile, followed by heating under reflux for 2 days. By post-treating the reaction liquid, 4-chloro-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzonitrile was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#N)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(O)=[O:18]>[Ni]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCN(c2ccc(C#N)cc2)CC1
Reactant: O=CO
Agent: [Ni]
Product: CN1CCCN(c2ccc(C=O)cc2)CC1

Procedure:
4-(4-Methylhomopiperazin-1-yl)benzonitrile (15 g) was dissolved in formic acid (225 ml) and Raney nickel (15.5 g) was added. The mixture was refluxed under heating for 2.5 hr. After the reaction, the catalyst was filtered off and the mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give the objective 4-(4-methylhomopiperazin-1-yl)benzaldehyde as an oil (16.1 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:13][C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)[N:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Cc1nc(N)cs1
Product: Cc1ccc2ccnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=257.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH2:17][C@H:16]1[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)=O)(C)(C)C>C(OCC)(=O)C>[Cl:1][C:26]1[CH:27]=[CH:28][C:23]([C@H:16]2[NH:15][C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH2:17]2)=[CH:24][CH:25]=1
Reactant: C[C@H](O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1C(=O)OC(C)(C)C
Reactant: Cl
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@H]1CC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 3 h

Procedure:
4 N hydrochloric acid/ethyl acetate (7.5 mL) was added to an ethyl acetate (7.5 mL) solution of (2S,5R)-2-(4-fluorophenyl)-5-((S)-1-hydroxyethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (850 mg, high polarity compound). Stirring was continued for 3 hours at room temperature. The solvent was removed under a vacuum, and sodium bicarbonate aqueous solution was added, and the resultant was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (580 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH:12][C:25]([C:15]34[CH2:24][CH:19]5[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]5)[CH2:22]3)[CH2:16]4)=[O:26])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1

Procedure:
Commercially available 6-methanesulfonyl-benzothiazol-2-ylamine, triethylamine, and adamantane-1-carbonyl chloride were processed as described for Example 17A to afford the title compound. MS (ESI+) m/z 391 (M+H)+;
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:31][C:32]([NH:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(C#N)=NO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
To a mixture of ethyl 2-cyano-2-hydroxyiminoacetate (100 g, 0.704 mol) and water (600 ml), were added a saturated aqueous solution of sodium bicarbonate (200 ml) and sodium hydrosulfite (340 g, 1.96 mol) under ice-cooling, and then benzyloxycarbonyl chloride (144 g, 0.848 mol) was added dropwise under ice-cooling. After the addition was completed, the reaction solution was stirred at 20-30° C. for about 4 hours. Completion of the reaction was confirmed using TLC shown below, precipitated crystals were collected by filtration and washed with sprayed water (50 ml×3). The obtained crystals were recrystallized from ethanol (600 ml), filtered and washed with sprayed ethanol (50 ml×3), dried in airflow at 40° C. to give ethyl 2-benzyloxycarbonylamino-2-cyanoacetate (118.7 g, yield 64.2%).