Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:17]([CH:16]([CH2:19][CH3:20])[CH2:15][N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]1=[O:21])[CH3:18]
Reactant: NCCCC(=O)O
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.12 mmol), 4-aminobutyric acid (732 mg, 7.1 mmol) and NaOMe solution (10.7 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 19 mg of the title compound as a yellow solid. MS: (+) m/z 452.32 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(F)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(F)ccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 35.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,5-difluorophenylboronic acid (Aldrich; 529 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,5-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (305 mg, 35%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:12])=[NH:11].[CH:13](=[C:20]([C:23]#[N:24])[C:21]#[N:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:24][CH2:23][C:20]1[C:21]([NH2:22])=[N:11][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccccc1
Reactant: N=C(N)c1cc2ccccc2[nH]1
Product: NCc1c(N)nc(-c2cc3ccccc3[nH]2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=315.8 (M+H+), was prepared from 1H-indole-2-carboxamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]3[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=3[N:12]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(Cl)c(Cl)c3)nc2c1

Procedure:
3,4-Dichlorobenzoyl chloride (4.6 g, 0.022 mol) is added to 2-amino-4-nitrophenol (3.4 g, 0.022 mol) in toluene (250 ml) and the mixture is refluxed for 24 hours. para-Toluenesulfonic acid (1.0 g) is added, the mixture is refluxed for 24 hours and cooled, and the product is filtered off. It is recrystallized from isopropyl ether. Yield: 6.8 g; IR (KBr): 3100, 1531, 1350 cm−1.
Reaction SMILES: CC(S([NH:7][C:8]1([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10][CH2:9]1)=O)(C)C.[ClH:16].O1CCOCC1>CO>[ClH:16].[F:13][C:12]([F:15])([F:14])[C:8]1([NH2:7])[CH2:11][O:10][CH2:9]1
Reactant: CC(C)(C)S(=O)NC1(C(F)(F)F)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Methyl-N-(3-(trifluoromethyl)oxetan-3-yl)propane-2-sulfinamide (52 mg, 0.212 mmol) was dissolved in methanol (1 mL). The solution was cooled down at ice-water bath and added slowly 4 N HCl in dioxane (240 μL, 0.954 mmol). The mixture was warmed to room temperature, stirred for 5 h, then concentrated. The solid was washed with ether twice then dried in vacuo to give the title compound (27 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:9]=[C:10]([C:11]#[N:12])[C:3]=12
Reactant: CC(C)(C)OC(=O)CCl
Reactant: N#Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nc(C#N)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 22 h
Yield: 62.5 %

Procedure:
To a mixture of 4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (76.6 g, 0.476 mol) and potassium carbonate (197 g, 1.427 mmol) in DMF (680 mL) at 0° C. was added tert-butyl chloroacetate (68.1 mL, 0.476 mol) dropwise while maintaining the internal temperature below 20° C. The resulting mixture was stirred for 22 h, filtered and washed with EtOAc (100 mL×2). The solid obtained was suspended in ice water (1.5 L), filtered, washed with ice water (500 mL) and ether (100 mL×2), then dried in vacuo to afford tert-butyl 2-(4-amino-3-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (81.6 g, 62.3% yield). MS (ES) m/z 275.0 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][NH2:19])[CH2:3][CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1.[NH2:20][C:21]1[C:22]([C:29]([NH:31][C:32](=N)SC)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1>CC(O)C.CS(C)=O>[OH:15][C@H:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1[CH:16]=[CH:17][C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:18][NH:19]/[C:32](=[N:31]/[C:29]([C:22]3[C:21]([NH2:20])=[N:26][C:25]([NH2:27])=[C:24]([Cl:28])[N:23]=3)=[O:30])/[NH:1]2)=[CH:7][CH:8]=1
Reactant: NC[C@H](N)CCCc1ccc(OC[C@H](O)CO)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2/NC[C@@H](CCCc3ccc(OC[C@H](O)CO)cc3)N2)nc1Cl
Temperature: 90 °C

Procedure:
To a stirred solution of (R)-3-[4-((R)-4,5-Diamino-pentyl)-phenoxy]-propane-1,2-diol (Intermediate O) (32.8 mg, 0.122 mmol) in propan-2-ol (3 ml) is added 1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (45.8 mg, 0.122 mmol) and the resultant reaction mixture is heated at 90° C. for 18 hours. The reaction is allowed to cool to room temperature and diluted with DMSO (1.5 ml) and purified on a Waters 3000 preparative HPLC system (Microsorb™ C18, Water (0.1% TFA): MeCN). The fractions containing product are passed through a 1 g SCX-2 cartridge which is eluted with 1:1 Water:MeCN (20 ml), MeCN (20 ml) and 7M NH3 in MeOH (20 ml). The ammonia elutions are concentrated in vacuo to afford the title compound; [M+H]+ 464
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:27])[C:23]([CH2:25]O)=[CH2:24])[CH:16]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)Cl.CCN(S(F)(F)[F:37])CC>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:27])[C:23]([CH2:25][F:37])=[CH2:24])[CH:16]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=C(CO)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=C(CF)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C

Procedure:
To ethyl-4-(3-{[2-(hydroxymethyl)acryloyl]amino}phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (17 mg, 0.045 mmol) was added CH2Cl2 (0.90 mL) and the reaction was cooled to −78° C. before DAST (12 μL, 0.090 mmol) was added. The reaction was allowed to warm to room temperature over 2 hours. The reaction was quenched by pouring into a separatory funnel containing aqueous sodium bicarbonate (saturated) and was extracted with ethyl acetate (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford a residue that was dissolved in 2 mL of DMSO, and was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions affords a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369. 1H NMR (600 MHz, DMSO-D6) δ 13.02 (bs, 1H), 10.25 (s, 114), 8.97 (s, 1H), 8.36 (m, 1H), 8.09 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.38 (d, 1H, J=7.8 Hz), 6.19 (s, 1H), 5.94 (s, 1H), 5.26 (s, 1H), 5.18 (s, 1H), 3.90 (q, 2H, J=7.2 Hz), 0.90 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([CH2:26][CH2:27][C:28](=[O:34])[N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:36][C:22]4[NH:23][C:24]([CH3:35])=[C:25]([CH2:26][CH2:27][C:28](=[O:34])[N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(3-oxo-3-pyrrolidin-1-yl-propyl)-1H-pyrrole-2-carbaldehyde (64.6 mg, 0.26 mmol) and piperidine (3 drops) in ethanol was stirred at room temperature under nitrogen for 2 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (51%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H, NH), 11.61 (br s, 1H, NH), 9.13 (brs, 1H), 8.26 (s, 1H), 7.70 (dd, J=2.4 & 6.9 Hz, 1H), 7.31-7.42 (m, 3H), 3.25 (m, 4H, 2×CH2), 2.63 (t, J=7.5 Hz, 2H, CH2), 2.35 (m, 2H, CH2), 2.31 (s, 3H, CH3), 2.12 (s, 3H, CH3), 1.76 (m, 4H, 2×CH2). MS 509 [M++1].
Reaction SMILES: [CH2:1]([N:10]([C@@H:27]([CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.IN1C(=[O:41])CCC1=O>>[C:1]([N:10]([C@@H:27]([CH3:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@@H:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:41])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@H](c1ccccc1)N(CC=Cc1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Product: C[C@@H](c1ccccc1)N(C(=O)C=Cc1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Yield: 44.8 %

Procedure:
Compound (28) from Example 13 (0.200 g, 0.44 mmol) was treated with N-iodosuccinimide (0.197 g, 0.88 mmol) using standard iodoetherification conditions. Flash chromatography of the product on silica gel [ethyl acetate/petroleum (1:9)] afforded the title compound (54) (Rf 0.50) as a yellow oil (0.093 g, 45%). δH (200 MHz; CDCl3) 7.72 (1H, d, J=16.0, CH=CHPh), 7.57-7.22 (15H, m, Ph), 6.51 (1H, d, J=16.0, PhCH=CH), 5.45 (1H, d, J=4.9, CHCHOH), 4.25 (1H, d, J=4.9, PhCHCH), 3.81 (1H, d, J=6.5, PhCHCH3), 1.92 (1H, br s, OH), 1.34 (3H, d, J=6.5, PhCHCH3), 1.32 (9H, s, (CH3)3C). The corresponding 3-(α-methylbenzylamino) derivative (Rf 0.25) was also recovered as a colourless oil (0.045 g, 30%. δH (200 MHz; CDCl3) 7.48-7.14 (10H, m, Ph), 4.50 (1H, d, J=3.8, CHCHOH), 4.09 (1H, d, J=3.8, PhCHCH), 3.76 (1H, q, J=6.6, PhCHCH3), 1.38 (3H, d, J=6.6, PhCHCH3), 1.31 (9H, s, (CH3)3C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1.Cl>ClCCl.CO>[ClH:1].[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:14](=[O:16])[C:13]#[C:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[Cl:1])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCCN(CCOc1ccc(N)cc1OC)CC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 185 mg (0.66 mmol) of 4-[2-(cyclopropylmethylpropylamino)ethoxy]-3-methoxyphenylamine. Yield: 180 mg (59% of theory); melting point: 185° C.-188° C.; C26H28ClF3N2O3 (M=508.96)*HCl; calc.: molecular ion peak (M+H)+: 509/511 (Cl); found: molecular ion peak (M+H)+: 509/511 (Cl); Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][F:27]>[I-].[K+].O>[F:27][CH2:26][CH2:25][O:12][C:11]1[C:2]([OH:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[OH:13]
Reactant: FCCBr
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(O)c(OCCF)c(O)c1
Reaction time: 18 h
Yield: 18.1 %

Procedure:
To a 100 mL round bottom flask was added methyl 3,4,5-trihydroxybenzoate (7.00 g, 88.0 mmol) followed by 25 mL of dimethyl sulfoxide. Potassium Carbonate (7.88 g, 57.0 mmol), potassium iodide (31.6 mg, 0.19 mmol) and 1-bromo-2-fluoroethane (5.79 g, 45.6 mmol) were successively added followed by 25 mL more of dimethyl sulfoxide. The reaction mixture was stirred for 18 h after which it was diluted by adding water (100 mL). The mixture was poured into a separatory funnel and extracted with DCM (3×40 mL). The organic layer was then washed with water (4×120 mL) and brine, and dried over magnesium sulfate. The organic layer was then concentrated to obtain an oil. The crude oil was purified using silica gel flash chromatography (DCM/ether 39:1) to obtain 1.9 g (22%) of the title compound (Rf˜0.17 in 19:1 DCM/ether). 1H NMR (600 MHz, CDCl3): δ 7.25 (s, 2H), 5.96 (s, 2H), 4.7 (t of d, 2H, J=48, 1.2 Hz), 4.37 (t of d, 2H, J=24, 1.2 Hz), 3.87 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 166.8, 149, 136.8, 126.4, 109.8, 82.16 (d, J=334 Hz), 72.6 (d, J=37.5), 52.3. MS (ESI): 231.4 (M+H, 100); FIRMS: Calc'd for C10H11FO5 (M+H): 231.06633; Found: 231.0664.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18].[CH3:20]O>>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:20])=[O:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)CCc1ccc(O)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
With cooling at -30° C. or below, thionyl chloride (75 ml) was added dropwise to methanol (150 ml). At -30° C., 3-(4-hydroxy-3-nitrophenyl)propionic acid (26.20 g, 0.12 mol) was added to this solution. The reaction solution was stirred at room temperature for 1 hour and then at 40 to 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure. Then, a procedure of adding toluene (100 ml) to the residue and concentrating the mixture under reduced pressure was repeated twice. Thereafter, the resulting residue was crystallized from ether-hexane to give methyl 3-(4-hydroxy-3-nitrophenyl)propionate (26.20 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44]Cl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:42][O:43][CH3:44])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COCCl
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 g, 2.18 mmol) in dichloromethane (10 mL) was added diisopropyl ethylamine (0.6 mL, 3.3 mmol), chloromethyl methyl ether (250 μL, 3.3 mmol) and DMAP (40 mg, 0.33 mmol). The reaction mixture was refluxed for 12 h. Solvents were removed and the residue as purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (780 mg, 71%) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[CH:9]=[CH2:10].FC(F)(F)C(NC1C=CC=CC=1)=O>>[CH2:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: Nc1ccccc1
Agent: O=C(Nc1ccccc1)C(F)(F)F
Product: C=CCNc1ccccc1

Procedure:
N-Allylaniline [NMR (200 MHz, DMSO-d6): δ 3.68 (t, J=5.2 Hz, 2H); 5.10 (d, J=10.2 Hz, 1H); 5.23 (d, J=17.2 Hz, 1H); 5.78 (br s, 1H); 5.75-5.97 (m, 1H); 6.52 (t, J=7.3 Hz, 2H); 6.56 (d, J=7.8 Hz, 2H); 7.06 (t, J=7.3 Hz, 2H)] was prepared from aniline and allyl bromide via trifluoroacetanilide using the general method described by Hodge (Harland, P. A.; Hodge, P; Maughan, W.; Wildsmith, E. Synthesis, 1984, 941).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16]S(C)(=O)=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Reactant: Oc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1nc(CCOc2ccc(F)cc2)cs1
Temperature: 80 °C
Yield: 42 %

Procedure:
To a mixture of Methanesulfonic acid 2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-ethyl ester (6.0 g, 18 mmol) and 4-fluoro phenol (5.21 g, 46 mmol) in Toluene (60 ml) K2Co3 (7.7 g, 55 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was filtered to remove solid residues, washed with ethyl acetate (50 ml) and combined organic layer washed with brine (20 ml) dried over Na2SO4. Solvent was removed under reduced pressure, crude product was purified by column chromatography using 1:10 EtOAC and Hexanes to obtain {4-[2-(4-Fluoro-phenoxy)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (2.56 g, 40%). 1H NMR (400 MHz, CDCl3): 1.53 (s, 9H), 3.09 (t, J=6.4 Hz, 2H), 4.20 (t, J=6.4 Hz, 2H), 6.21 (s, 1H), 6.811-6.84 (m, 2H), 6.95 (t, J=8.8 Hz, 2H). 8.28 (brs, 1H). MS (EI) m/z: 338.89 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([OH:10])[C:6]([CH3:9])([CH3:8])[CH3:7].CN1C=CN=C1>>[C:1]([O:10][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)CO
Agent: Cn1ccnc1
Product: CC(=O)OCC(C)(C)C
Temperature: 20 °C
Yield: 86 %

Procedure:
6.47 g (82.5 mmol) of acetyl chloride were added dropwise to a solution of 6.61 g (75.0 mmol) of neopentyl alcohol (2,2-dimethyl-1-propanol) and 6.76 g (82.5 mmol) of 1-methylimidazole while stirring at 20° C. The reaction mixture was stirred for a further 30 minutes and subsequently heated to 75° C. This resulted in the suspension initially formed being converted into a liquid two-phase mixture. The upper phase was separated off to give 8.40 g (theory: 9.76 g) of neopentyl acetate as a colorless oil having a purity of 98% (GC).
Reaction SMILES: O=[C:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(NC(=O)O)C.[NH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>[C:3]([C:2]([NH:18][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH2:11])(=[O:4])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(N)=O
Reactant: CC(=O)C(=O)c1ccccc1
Agent: CCNC(=O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=C(NC(=O)OCC)C(=O)c1ccccc1
Reaction time: 2 h
Yield: 22.5 %

Procedure:
In a flame dried nitrogen purged 100 ml round bottom flask equipped with a magnetic stirring bar, Dean-Stark trap and a reflux condenser were added 3.0 g (20.3 mmol) α-keto-propiophenone, 3.6 g (40.5 mmol) urethane (ethyl carbamate),10 mg (0.1 mmol) hydroquinone, 60 mg (0.3 mmol) paratoluenesulfonic acid and 20 ml of toluene. The mixture was refluxed under nitrogen with vigorous stirring for 31/2 hours. The solvent was removed under reduced pressure and the residue distilled through a short path distillation column giving approximately 1 g of ethyl N-(1-benzoylvinyl)carbamate bp≃130°-135° C. (1mm).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([F:12])[CH:19]=[C:18]([F:20])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(F)cc(F)c1
Product: O=C(Nc1cc(F)cc(F)c1)c1cc(Br)ccc1O
Yield: 36.3 %

Procedure:
Using 5-bromosalicylic acid and 3,5-difluoroaniline as the raw materials, the same operation as the example 16 gave the title compound.