Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]([F:22])([F:21])[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([CH:19]=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:1][N:2]([CH2:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6](=[O:7])[C:5]([F:22])([F:4])[F:21])[CH2:9][CH2:10][C:11]=2[CH:18]=1)[CH3:3]
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL (23.4 mmol) of a 2 M dimethylamine solution in THF were added to a solution of 4.5 g (16.59 mmol) 3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde in 150 mL THF and the solution was adjusted to pH 5 with 1 mL glacial acetic acid. After 30 min 4.62 g (21.79 mmol) sodium triacetoxyborohydride were added and the reaction mixture was stirred overnight at RT. The reaction solution was carefully combined with saturated NaHCO3 solution, stirred for 30 min, exhaustively extracted with EtOAc, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the desired product was obtained, which was further reacted without purification.
Reaction SMILES: [CH3:1][C:2]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])([O:4][N:5]1C(=O)C2=CC=CC=C2C1=O)[CH3:3].O.NN>C(Cl)Cl>[CH3:3][C:2]([O:4][NH2:5])([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])[CH3:1]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CC(C)(ON)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
In 80 ml of methylene chloride is dissolved 7.68 g of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide and under ice-cooling and stirring 0.97 ml of hydrazine hydrate is added. The mixture is stirred at room temperature for 2 hours, after which 0.97 ml of hydrazine hydrate is further added. The mixture is stirred for 3 hours and the resultant crystalline precipitate is separated by filtration and washed with methylene chloride. The filtrate and washings are combined and further washed with diluted aqueous ammonia and water in this order, and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column [silica gel: 300 g; eluent: ethyl acetate-hexane (1:1)] to give 4.58 g of O-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyl]hydroxylamine as a yellow oil. This product solidifies on cooling.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([NH:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Product: CCCCOc1ccc(CC(=O)N[C@@H](C(=O)O)[C@@H](C)O)cc1

Procedure:
4-Butoxyphenylacetic acid (288 mg, 1.38 mmol) is converted to the acid chloride and added to D-allo-Thr (150 mg, 1.26 mmol) to get 2c-9, following the procedure described in Example 6. The crude product is purified by chromatography (2.5×18 cm column, gradient 4% CH3OH and 0.3% HOAc in CH2Cl2): NMR δ 0.96 (t, J=7.4, 3 H), 1.14 (d, J=5.8, 3 H), 1.47 (m, 2 H), 1.74 (m, 2 H), 3.53 (br s, 2 H), 3.91 (t, J≃6.5, 2 H), 4.10 (br s, 1 H), 4.53 (br s, 1 H), 4.90 (br s, >2 H), 6.76 (br d, J=6.0, 1 H), 6.84 (d, J=8.4, 2 H), 7.13 (d, J=8.4, 2 H); MS (HR-EI) m/z 309.1567 (M calcd. for C16H23NO5, 309.1576) [α]D26 -26±2 (CHCl3); m.p. 90°-94° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([Br:15])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([Br:15])[C:7]=2[N:8]=1)[CH:17]=[CH2:18]
Reactant: C=CCNc1nc(Cl)nc2c(Br)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(Br)c2n1
Yield: 93.5 %

Procedure:
305 mg (1.0 mmol) of 4-allylamino-7-bromo-2-chlorothieno[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 304 mg (yield: 93.3%) of the title compound.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=3[CH2:12][N:11]([S:21]([CH3:24])(=[O:23])=[O:22])[C@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:4]=[CH:3]1.[N:32]1[CH:37]=C[CH:35]=[C:34](S([Cl:41])(=O)=O)[CH:33]=1>>[ClH:41].[ClH:1].[ClH:41].[C:19]([C:17]1[CH:16]=[CH:15][C:14]2[N:8]([CH2:7][C:5]3[N:4]=[CH:3][NH:2][CH:6]=3)[CH2:9][C@@H:10]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:11]([S:21]([C:24]3[CH:37]=[N:32][CH:33]=[CH:34][CH:35]=3)(=[O:22])=[O:23])[CH2:12][C:13]=2[CH:18]=1)#[N:20]
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccnc1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 15 %

Procedure:
Example 387 was prepared as a yellow solid in 15% yield from Compound C of Example 248 and 3-pyridinesulfonyl chloride as described for Example 284.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:19]([C:20]([O:22]CC)=O)=[C:18](/[CH:25]=[CH:26]/[N:27](C)C)[N:17]=[C:16]([S:30][CH3:31])[N:15]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH4+].[OH-]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([NH:13][C:14]2[C:19]3[C:20](=[O:22])[NH:27][CH:26]=[CH:25][C:18]=3[N:17]=[C:16]([S:30][CH3:31])[N:15]=2)[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:32])[CH:8]=1
Reactant: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [NH4+]
Agent: [OH-]
Product: CSc1nc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1

Procedure:
The title compound was prepared as described in Example 1f by starting from (E)-ethyl 4-(3,5-bis(trifluoromethyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-(methylthio)pyrimidine-5-carboxylate and aq. NH4OH solution and continuing until the reaction yielded pale yellow solids, title compound (537 mg). MS m/z: 421.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=Cc1ccncc1
Product: O=C(O)c1cc(Br)ccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-5-bromobenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 170.4, 149.4, 149.4, 148.7, 133.9, 132.3, 123.2, 122.0, 112.2, 104.9, 44.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[N:32][CH:33]=1)#[N:27]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:35]([NH:34][C:31]2[CH:30]=[N:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=2)=[O:36])=[C:18]([O:23][CH3:24])[CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CN(Cc2ccccc2)C(=O)OC(C)(C)C)ccc1N
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Solvent: CN(C)C=O
Product: COc1cc(CN(Cc2ccccc2)C(=O)OC(C)(C)C)ccc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 80 °C
Yield: 67.3 %

Procedure:
(4-Amino-3-methoxy-benzyl)-benzyl-carbamic acid tert-butyl ester (0.25 g, 0.73 mmol) and phenyl 5-cyanopyrazin-2-ylcarbamate (0.21 g 0.87 mmol) (Example 10) were dissolved in DMF (2.5 mL) and heated at 80° C. for 2 hours. The mixture was allowed to cool to room temperature then partitioned between water (15 mL) and EtOAc (25 mL). The separated aqueous layer was extracted with EtOAC (25 ml), and then the combined organic extracts were washed with water (15 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 15-25% EtOAc in hexane to afford the title compound (0.24 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:16][CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42]>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[CH2:12]1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCN(Cc2ccccc2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-benzylpiperidine-3,3-dicarboxylic acid 3,3-dibenzyl ester (19.6 g 41.8 mmol) and sodium carbonate (5.1 g, 48.1 mmol) in chloroform cooled with a water/ice bath, is added 2,2,2-trichloroethyl chloroformate (11 g, 51.8 mmol). The mixture is stirred overnight at room temperature and concentrated under reduced pressure. The residue is dissolved in diethyl oxide, washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3,3-dibenzyl ester which cristallizes upon standing.
Reaction SMILES: [OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][C:4](N1[C@H](C(C)C)CSC1=S)=[O:5].[Li+].[OH-].Cl.CC[O:44]C(C)=O>C1COCC1.O>[OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][C:4]([OH:44])=[O:5]
Reactant: CCOC(C)=O
Reactant: CC(C)[C@@H]1CSC(=S)N1C(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
At 0° C. to a solution of (S,E)-3-hydroxy-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-(tritylthio)hept-4-en-1-one (934 mg, 1.66 mmol, prepared according to the procedure in Yurek-George, A. et al, J. Am. Chem. Soc. 2004, 126, 1030) in THF (30 mL) was added a solution of LiOH (196.1 mg, 8.19 mmol) in H2O (10 mL). The reaction mixture was allowed to warm to rt over 1 h, whereupon 1M HCl was added until the pH reached 2. EtOAc (30 mL) was then added and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL) the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluant 3:7-1:1-1:0 EtOAc/Hexane) gave the 3 as a white solid (600 mg, 1.43 mmol, 86%).
Reaction SMILES: [C:1]([CH:5]([NH:12][NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[C:29](Cl)=[O:30].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:5]([N:12]([C:29](=[O:30])[C:28]1[CH:32]=[C:33]([CH3:35])[CH:34]=[C:26]([CH3:25])[CH:27]=1)[NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CCCCCCC(NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
164 mg (0.49 mmol) of 3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-heptyl)-hydrazide and 82 mg 3,5-dimethylbenzoyl chloride were dissolved in 10 mL CH2Cl2. 7 mL of 25% K2CO3 were added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 layer was dried and solvent was removed in vacuo to provide 240 mg of crude product. This material was purified by silica gel column chromatography, eluting with a step gradient of 5-20% ethyl acetate in hexane. The desired product eluted in the 15% ethyl acetate fraction, TLC Rf=0.62 (1:1 ethyl acetate:hexane), to yield 195 mg 3,5-dimethyl-benzoic acid N-(1-tert-butyl-heptyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.2 (s, NH), 7.05 (s, 2H), 7.03 (m, 1H), 7.01 (s, 1H), 6.83 (d, 1H), 6.25 (d, 1H), 4.67 (d, 1H), 3.81 (s, 3H), 2.28 (s, 6H), 1.79 (s, 3H), 1.55 (br m, 2H), 1.3 (br, 8H), 1.34+1.07 (s+s, 9H), 0.089 (br s, 3H).
Reaction SMILES: [Li].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[Br-].[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:28][CH:27]=1>C(O)C>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:13]/[C:12]2[CH:15]=[CH:16][C:9]([O:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][O:2]3)=[CH:10][CH:11]=2)=[CH:28][CH:27]=1
Reactant: OCCCCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1
Agent: [Br-]
Agent: [Li]
Solvent: CCO
Product: OCCCCCCOc1ccc(/C=C/c2ccc(OC3CCCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
0.23 g of lithium was dissolved in 150 ml of ethanol. Then 6.2 g of 4-(tetrahydropyran-2-yloxy)benzaldehyde (H) was added. The solution was cooled in an ice-water bath and 16.5 g of 4-(6-hydroxyhexyloxy)phenylmethyltriphenylphosphonium bromide (I) was added. After stirring for 2 hours at room temperature, a white precipitate was obtained. 3.34 g of (E)-4-(6-hydroxyhexyloxy)-4′-(tetrahydropyran-2-yloxy)stilbene (J, 31%) was obtained after collection by filtration and two washings with 150 ml of ethanol.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.Cl>O1CCCC1.O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:20][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1

Procedure:
In 60 ml of tetrahydrofuran was suspended 18.7 g of 60% sodium hydride followed by addition of 39.4 of diethyl carbonate. Then, a solution of 25 g of p-methoxyacetophenone in 70 ml of THF was added dropwise with refluxing and the mixture was further refluxed for 5 hours. After cooling, the reaction mixture was poured slowly into iced water, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was distilled under reduced pressure to provide 30.1 g of the desired compound as a pale yellow oil. b.p. 161°-164° C. (3 mmHg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:16][C:11]1[C:10]([F:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
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: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3F)ccn2)cn1
Temperature: 70 °C
Yield: 55.1 %

Procedure:
Nitrogen was bubbled though a solution of 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (2 g, 7.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.6 g, 7.8 mmol) and Na2CO3 (1.65 g, 15.6 mmol) in DME (12 mL) and H2O (4 mL) for 20 min. Pd(PPh3)4 (450 mg, 0.4 mmol), was added and then resulting mixture was degassed in vacuo, blanketed with nitrogen and heated to 70° C. for 16 h. The reaction was concentrated to dryness under reduced pressure. The crude product was suspended in water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (1.3 g, 55% yield). 1H NMR (400 MHz, DMSO-d6), δ 8.40 (d, J=6.0 Hz, 1 H), 8.32 (s, 1 H), 8.02 (s, 1 H), 7.26 (s, 1 H), 6.96 (t, J=8.8 Hz, 1 H), 6.71-6.68 (m, 2 H), 5.62 (s, 2 H), 3.92 (s, 3 H); MS (ESI) m/z: 303.2[M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 63 °C
Reaction time: 8.5 h
Yield: 51 %

Procedure:
To a mixed solution of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-glucose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 8.5 hours under reflux in a warm-water bath at 63° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. The reaction solution was diluted with chloroform, washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent and cyclohexanone were distilled off under reduced pressure, and the residue was recrystallized from ligroin, thus affording 9.6 g (51%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose. m.p. 133°-136° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[C:1]1([NH:7][C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCCCC1
Reactant: O=C(Nc1ccccc1)N1CCN(Cc2ccc(O)cc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(OC3CCCCC3)cc2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
To a mixture of 4-(4-hydroxy-benzyl)-piperazine-1-carboxylic acid phenylamide (311 mg) and cyclohexanol (150 mg) in DCM (4 mL) was added polymer-supported Ph3P (500 mg) followed by di-tert-butyl azodicarboxylate (345 mg). The reaction mixture was shaken overnight, and filtered. Chromatography of the filtrate gave the title compound as a white solid (110 mg). 1H NMR (400 MHz, CDCl3): 7.36-7.19 (m, 6H), 7.05-7.00 (m, 1H), 6.88-6.84 (m, 2H), 6.30 (s, 1H), 4.25-4.20 (m, 1H), 3.50-3.47 (m, 6H), 2.48-2.46 (m, 4H), 2.01-1.97 (m, 2H), 1.82-1.80 (m, 2H), 1.60-1.29 (m, 6H).
Reaction SMILES: [C:1](OCCCl)(=[O:5])[CH:2]([CH3:4])[OH:3].[C:10]([O:14][CH:15]([CH3:17])[CH3:16])(=[O:13])[CH2:11][OH:12]>C(OCC)C>[C:1]([O:12][CH2:11][C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(C)OC(=O)CO
Reactant: CC(O)C(=O)OCCCl
Solvent: CCOCC
Product: CC(C)OC(=O)COC(=O)C(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chloroethyl lactate (1.91 g, 12.5 mmol) and various amounts of isopropyl glycolate (1.48, 2.22 and 2.95 g; 12.5, 18.8 and 25.0 mmol, respectively) in 25 mL of ethyl ether containing 0.125% tert-butylbenzene were added to 1.75 g Lipase P30 powder and the reaction mixtures were agitated on an orbital shaker (175 RPM) at room temperature for 48 hr. After 48 hr, conversion of 2-chloroethyl lactate to the title compound was estimated (by GC, Method A) to be 30, 38 and 44% with 1.0, 1.5 and 2.0 equivalents of isopropyl glycolate, respectively. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C7H10O5Tms (M--CH3) 247.1001, obsd 247.0990. A portion of one of the reactions was partially purified by flash chromatography (ethyl acetate/hexane, 20/80) to give a mixture of 2-chloroethyl lactate and the title compound. The partially purified mixture was separated by flash chromatography (CH2Cl2 /isopropanol, 99/1) to give the title compound: 1H NMR δ 1.27 (d, 6H, J=6.3 Hz), δ 1.49 (d, 3H, J=7.0 Hz), δ 3.28 (d, 1H, J=4.6 Hz), δ 4.42 (m, 1H), δ 4.60 (d, 1H, J=15.8 Hz),δ 4.71 (d, 1H, J=15.8 Hz), δ]5.09 (m, 1H, J=6.3 Hz); 13C NMR 20.3, 21.7, 61.5, 66.9, 69.6, 166.8, 174.9.
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:8])[O:6][CH3:7])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[CH:25](=[O:29])[CH:26]([CH3:28])[CH3:27].Cl>C1COCC1.CCOCC>[CH:9]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:8])[O:6][CH2:7][CH:25]([OH:29])[CH:26]([CH3:28])[CH3:27])([CH3:11])[CH3:10]
Reactant: CC(C)C=O
Reactant: COC(=O)N(C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(O)COC(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
478 mg (3 mmol) of methyl N,N-diisopropylcarbamate are lithiated with 392 mg (3.3 mmol) of TMEDA in 4 ml of THF at -78° C. using 3.3 mmol of sec-BuLi. After 1 h, the reaction mixture is treated with 144 mg (2 mmol) of isobutyraldehyde and stirred for 21 h. The reaction mixture is then treated at -78° C. with 10 ml of 2N hydrochloric acid and 10 ml of ether and the mixture is warmed to room temperature. The phases are separated, the aqueous phase is extracted twice with ether and the combined organic phases are neutralized with saturated NaHCO3 solution. After drying over magnesium sulphate, the solvent is stripped off and the crude product of 500 mg weight is purified by chromatography on silica gel using ether/petroleum ether (1:3). 299 mg (64.6% of theory) of the title compound are obtained as a colorless liquid.