Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH3:33].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:30][CH2:31][O:32][CH3:33])[CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=c1cc(N2CCN(c3cccc(CO)c3F)CC2)cc[nH]1
Reactant: COCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc(N2CCN(c3cccc(CO)c3F)CC2)ccn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
4-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (300 mg) was suspended in DMF (7.5 ml), and potassium carbonate (273 mg), 2-bromoethylmethyl ether (275 mg), and tetrabutylammonium iodide (37 mg) were added thereto, followed by stirring at 60° C. overnight. Water and CHCl3 were added to the reaction mixture, and the organic layer was washed with saturated brine and then dried over Na2SO4. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain (2-fluoro-3-{4-[2-(2-methoxyethoxy)pyridin-4-yl]piperazin-1-yl}phenyl)methanol (104 mg).
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.O=[C:33]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:43]=[C:42]([C:50]([OH:52])=[O:51])[CH:41]=2)[CH2:35][CH2:34]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C@@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][C:40]3[N:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[N:43]=[C:42]([C:50]([OH:52])=[O:51])[CH:41]=3)[CH2:35][CH2:34]2)[CH2:26]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=C1CCC(Oc2cc(C(=O)O)nc(C(F)(F)F)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(C(=O)O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (500.0 mg, 1.036 mmol) and 6-[(4-oxocyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid in dry 1,2-dichloroethane (14.36 mL, 182.3 mmol) were stirred for 5 minutes and sodium triacetoxyborohydride (898 mg, 4.24 mmol) was added. The reaction mixture was stirred at 25° C. for 16 hours, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate and the solvent was evaporated. The residue was purified by LCMS (pH 10) and the fractions containing the second peak were combined and evaporated. 1H NMR (400 MHz, CD3OD) δ 8.90 (m, 1H), 8.83 (s, 1H), 8.55 (m, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.15 (d, 1H), 5.78 (s, 4H), 5.23 (m, 1H), 3.50-3.70 (m, 3H), 1.40-2.40 (m, 8H). 19F NMR (376 MHz, CD3OD) δ −70.52 (s), −77.53 (s). MS (ES): 698(M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([OH:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=[C:27]=[O:28])C=CC=CC=1>C(OCC)(=O)C>[OH:13][C:4]1[C:3]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:27](=[O:28])[NH:1][C:2]=2[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1
Reactant: Nc1c(-c2ccccc2)c(O)nn1-c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(c(O)nn2-c2ccccc2)c2ccccc12
Temperature: 290 °C
Yield: 81 %

Procedure:
2.51 Grams (0.01 mole) of 5-amino-3-hydroxy-1,4-diphenylpyrazole is mixed with 1.62 ml (0.015 mole) of phenylisocyanate and is gradually heated to 290° C. The obtained residue is then ground and boiled with 40 ml of ethyl acetate. 2.7 Grams of crude compound recovered by filtering the hot mixture is taken up with aqueous 4% NaOH. On acidifying the filtered solution with acetic acid, 2.24 g of the title compound precipitates. Yield 81%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O>C(COC)OC>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccccn1
Solvent: COCCOC
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.4 %

Procedure:
A mixture of 2-aminopyridine (Aldrich; 0.487 g), 1,3-dichloroacetone (Aldrich; 0.73 g), and dimethoxyethane (6 mL) is stirred at room temperature for 2.5 h and then at 60° C. for 30 min. Dimethoxyethane is then removed under reduced pressure and ethanol (10 mL) is added. The mixture is stirred at 80° C. for 20 min and then cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate and the organic layers are filtered through sodium sulfate and concentrated. Dichloromethane and ethyl acetate are added to the residue and the solids are removed by filtration. The filtrate is concentrated and the residue is chromatographed on silica gel using ethyl acetate/hexane (50/50) to give 0.495 g of 2-(chloromethyl)imidazo[1,2-a]pyridine; mp >255° C.; 1H NMR (CDCl3) δ 4.78, 6.80, 7.19, 7.58, 7.62, 8.08.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>C(O)C(C)C>[CH2:5]([O:6][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH:4]([CH3:8])[CH3:3]
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na]
Solvent: CC(C)CO
Product: CC(C)COc1ncccc1C(=O)O
Temperature: 80 °C
Yield: 168.1 %

Procedure:
Sodium metal (3 g, 0.127 mol) was added in small amounts to isobutanol (100 mL)—some warming (80° C.) was needed to facilitate dissolution. 2-Chloronicotinic acid (10 g, 0.064 mol) was added and the solution refluxed for 1 h. A thick mixture resulted and a further 100 mL isobutanol was added and the mixture refluxed for 3 h. The mixture was cooled and quenched with 2N hydrochloric acid. The product was extracted into ethyl acetate and the organics washed with dilute hydrochloric acid (pH 3), dried (MgSO4) and concentrated to give a brown solid. Purification by flash column chromatography (ethyl acetate as eluant) gave 10.5 g of product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[O:14]1[C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=[N:15]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:19]([C:18]2[O:14][N:15]=[CH:16][CH:17]=2)=[O:20])[CH:8]=1
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1ccno1
Yield: 21 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and isoxazole-5-carbonyl chloride. After precipitation the product was further purified by reverse phase C18 preparative HPLC (water/acetonitrile containing 0.1% formic acid 30%-100% gradient) to yield the desired product (61.1 mg, 21%). 1H NMR (400 MHz, d6-DMSO): δ 11.90 (s, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 8.06 (d, 1H), 7.96 (s, 1H), 7.56 (dd, 1H), 7.30 (s, 1H). MS (EI) for C11H7ClN6O2: 290.7 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][CH2:17][Cl:16])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Reactant: C#CCCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C#CCCCCCl)n[nH]c2c(=O)[nH]1
Temperature: 60 °C
Yield: 166.9 %

Procedure:
To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (4.97 g, 15.62 mmol) in N,N-dimethylformamide (100 mL) was added bis(triphenylphosphine)palladium(II)dichloride (1.228 g, 1.750 mmol) and copper(I) iodide (0.595 g, 3.12 mmol). The solution was stirred and degassed with nitrogen for 5 minutes then the reaction mixture placed under a nitrogen atmosphere. A solution of 6-chloro-1-hexyne (3.64 g, 31.2 mmol) and triethylamine (4.36 mL, 31.2 mmol) in N,N-dimethylformamide (30 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for a further 10 minutes then heated to 60° C. for 2.5 hours. The reaction mixture was concentrated in vacuo at 60° C. and the resulting residue partitioned between ethyl acetate (250 mL) and a 1:1 mixture of water:brine (500 mL). The organic layer was separated and the aqueous layer back extracted with ethyl acetate (250 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give a brown solid (8.0 g). The residue was dissolved in a 1:1 mixture of MeOH:DCM and absorbed onto Florisil. The solid was loaded and purified by chromatography on silica (330 g) using a 0-100% ethyl acetate-cyclohexane gradient over 10 column volumes followed by flushing with ethyl acetate for 9 column volumes. The appropriate fractions were combined and evaporated in vacuo to give a yellow solid (3.55 g). The solid was triturated with diisopropyl ether, filtered and dried in vacuo at 50° C. to give the title compound as a pale yellow solid (3.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][S:16][CH3:17])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][S:16][CH3:17])[C:11]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C@@H:27]3[CH2:26][O:25][C:24]([CH3:36])([CH3:23])[O:28]3)[N:31]=2)=[O:13])[C:7](=[O:18])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CSCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.4 %

Procedure:
In a round bottom flask under argon was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (171 mg, 0.50 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 118 mg, 0.60 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (250 μL, 1.5 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (331 mg, 0.75 mmol) and the mixture was stirred for 3.5 h at 25° C. After this time, the mixture was diluted with ethyl acetate (30 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL) dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 100% ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methylsulfanyl-butyramide (121 mg, 46%) as a white foam: HR-ES-MS m/z calculated for C24H29N4O5ClS [M+H]+ 521.1620, observed 521.1622.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:24])[NH2:25]
Reactant: NC(=O)CI
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC(N)=O)c([N+](=O)[O-])c1

Procedure:
is obtained analogously to Example 55) starting from 3.66 g of 4-methoxycarbonyl-2-nitrophenol, 6.91 g of potassium carbonate and 4.62 g of iodoacetamide: mp 185°-7° C.; Rf (O)=0.56.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[CH3:37][N:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[N:19]2[C:20]([CH:21]=[N:22][C:17]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][N:11]=3)=[N:18]2)=[CH:23][CH:24]=1)[S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cn1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cn3)nn12)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 5-Morpholin-4-yl-pyridin-2-ylamine (0.108 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), Cesium fluoride (0.104 g, 0.686 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and tert-Butyl alcohol (1.50 mL) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid (40 mg, 33%). LCMS (E/I+) 480.14 (M+H). NMR 1H (DMSO-d6)-10.49 (bs, 1H), 9.09 (s, 1H), 7.86-7.92 (m, 1H), 7.84 (bs, 1H), 7.70-7.80 (m, 1H), 7.66-7.73 (m, 1H), 7.50-7.64 (m, 3H), 7.13 (bs, 1H), 7.11 (bs, 1H), 3.75 (bs, 4H), 3.14 (s, 3H), 3.11 (bs, 4H), 2.83 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][C:20]#[CH:21])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][C:20]#[C:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C#CCCc1nc2c(Br)cccc2o1
Reactant: Brc1ccccn1
Product: Brc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (63 mg, 0.40 mmol) and 4-bromo-2-(but-3-ynyl)-benzo[d]oxazole (100 mg, 0.40 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 60 mg (0.18 mmol, 46%) of 4-bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid with a purity of 85%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:40][C:41]([F:44])=[CH:42][N:43]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1F)#[N:27].[Cl-].[NH4+]>CN(C)C=O>[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:40][C:41]([F:44])=[CH:42][N:43]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:27]
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(F)s2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Nc2ncc(F)s2)cc1C#N
Temperature: 80 °C
Yield: 47.8 %

Procedure:
To a stirred solution of 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 28, 188 mg, 0.75 mmol) and potassium carbonate (173 mg, 1.25 mmol) in N,N-dimethylformamide (2.5 mL) was added 3-cyano-4-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide (Preparation 34, 151 mg, 0.5 mmol) and the reaction mixture was stirred at 80° C. After stirring for 16 hours, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (3×10 mL). The collected organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography (40% ethyl acetate in dichloromethane elution) to afford the title compound as a white solid (127 mg, 48%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[C:10]([OH:13])(=[O:12])[CH3:11]>>[C:10]([O:13][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Agent: O=O
Product: CC(=O)OCc1ccccc1

Procedure:
A process for producing benzyl acetate by oxyacetoxylation of toluene with acetic acid and oxygen in a liquid phase in the presence of oxyacetoxylation-active catalyst, comprising steps of feeding toluene, acetic acid, and oxygen to an oxyacetoxylation reactor to cause reaction and to obtain an effluent from the reactor; introducing the effluent from the reactor to a gas-liquid separator to separate a gas phase mainly composed of oxygen and nitrogen and a liquid phase mainly composed of toluene, acetic acid, and benzyl acetate; introducing the liquid phase discharged from the gas-liquid separator to a starting material recovery column to separate the liquid phase by distillation into a column top distillate mainly composed of toluene and acetic acid and a column bottom liquid mainly composed of benzyl acetate; recycling the column top distillate from the starting material recovery column to the oxyacetoxylation reactor; introducing the column bottom liquid of the starting material recovery column to a low-boiler removal column to separate the column bottom liquid by distillation into a column top fraction mainly composed of benzaldehyde and a column bottom fraction mainly composed of benzyl acetate; introducing the column bottom fraction of the low-boiler removal column to a high-boiler removal column for distillation to obtain benzyl acetate from the column top thereof.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:28]=[C:27]([F:29])[C:19]([NH:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22])=[N:18][C:16]1=[O:17])(=O)C.[OH-].[Na+].CO.Cl>C(Cl)Cl>[F:29][C:27]1[C:19]([NH:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22])=[N:18][C:16](=[O:17])[N:15]([CH:28]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)cc1F

Procedure:
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4 -(propoxycarbonyl)cytidine (2.5 g) in CH2Cl2 (17 ml) was added dropwise 1N NaOH (17 ml) with stirring and cooling with ice bath. After stirring for 1 hr at 0° C., MeOH (0.9 ml) was added to the mixture. And pH of the reaction mixture was adjusted to 6 by the addition of concentrated HCl and partitioned. The aqueous layer was extracted with a mixed solvent of CH2Cl2 /MeOH(95/5) successively (40 ml×10). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solution was evaporated, and the residue was crystallized from ethyl acetate to give 5'-deoxy-5-fluoro-N4 -(propoxycarbonyl)cytidine as colorless crystals (1.6 g, y. 79.8%): mp. 125°-126.5° C.; EI-MS m/z 331 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of Example 89B (6.3 g, 27.4 mmol) in dichloromethane (100 mL) were added commercially available 3,4-dihydro-2H-pyran (Aldrich) (21 g, 250 mmol) and pyridinium-p-toluenesulfonic acid (Aldrich) (3.5 g, 14.0 mmol). The reaction mixture was stirred for overnight at room temperature and then diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford 7.4 g (82%) of the title compound. MS (ESI+) m/z 329 (M+H)+
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][NH:11][C@H:12]1[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:29][Si:30]([CH2:33][CH2:34][O:35][C:36](ON1C(=O)CCC1=O)=[O:37])([CH3:32])[CH3:31].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1>[CH2:3]([O:10][NH:11][C@H:12]1[CH2:17][N:16]([C:36]([O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[O:37])[C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)O
Yield: 86.4 %

Procedure:
To (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid, dihydrochloride (3.23 g, 10 mmol) described in Example 11 were added 1,4-dioxane (10 mL), water (15 mL) and 5M sodium hydroxide (6 mL), and stirred under ice cooling. Potassium carbonate (1.38 g), N-(trimethylsilylethyloxycarbonyloxy)succinimide (2.85 g) were added further to the mixture, and the temperature was elevated to room temperature, followed by stirring overnight. The mixture was adjusted to pH 4 with citric acid.monohydrate, and extracted with ethyl acetate (50 mL) twice. The organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1:1→1:0) to afford 3.41 g of the title compound (yield 86%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1>CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:30]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Yield: 15.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (3 g), dimethylaluminium chloride in heptane (1.0 molar, 34.62 ml) and 4-aminobenzoic acid (1.58 g) to give the desired 4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-benzoic acid (0.522 g) as a white solid. MS (ESI): 449.1 (MH+).