Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1)=O.[CH3:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:25][NH:26][CH2:1][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1
Reactant: CN
Reactant: O=Cc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (340 mg, 1.03 mmol) in DCE (10 mL) was added MeNH2 (1032 μl, 2.065 mmol). After stirring for 1 h at rt, sodium triacetoxyborohydride (438 mg, 2.07 mmol) was added and the mixture was stirred overnight, whereupon it was quenched with saturtaed NaHCO3 (aq) at 0° C. and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material (assumed quantitative) was used as such in step 4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][NH2:24]>>[CH3:22][O:23][NH:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CON
Product: CONCc1ccc(-c2nc3cccc(C(=O)OC)c3o2)cc1
Yield: 65 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxyamine, methyl 2-(4-((methoxyamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 65%. LC-MS (ESI) m/z: 313 (M+1)+) was made.
Reaction SMILES: [CH3:1][C:2](O)([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>C(Cl)Cl>[N:20]([C:2]([CH3:14])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[N+:21]=[N-:22]
Reactant: CC(C)(O)Cc1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Product: CC(C)(Cc1ccc(C(F)(F)F)cc1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
26.3 g of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol was dissolved in 400 mL of methylene chloride, and 25 mL (0.19 mol) of trimethylsilyl azide and 24 mL (0.19 mol) of boron trifluoride diethyl etherate complex were added dropwise under cooling with ice. The reaction mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 25.4 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:13]=[CH:12]3)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:38]=[CH:39][CH:40]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:38]=[CH:39][CH:40]=4)[N:3]=3)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccn3)c2)n1
Reactant: C=CC(=O)Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-amine (Step 3) (90.0 mg, 0.266 mmol) in IpOH (3.0 ml) was added DIEA (0.07 mL, 0.40 mmol) and N-(3-aminophenyl)acrylamide (47.5 mg, 0.293 mmol). The mix was heated at 100° C. for 18 h. The solution was cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{3-[4-(1-pyridin-2-ylmethyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=464[M+H]+. Calc'd for C25H21N9O: 463.19.
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].C(Cl)Cl.CCN(CC)CC.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH2:24]>CN(C1C=CN=CC=1)C>[C:15]([O:22][CH2:3][C:2]#[CH:1])(=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCO
Reactant: O=C(Cl)c1ccccc1
Reactant: O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of prop-2-yn-1-ol (3.63 ml, 62.4 mmol), DCM (180 ml), and Et3N (17.40 ml, 125 mmol) at 0° C. were added benzoyl chloride (7.25 ml, 62.4 mmol) and DMAP (0.381 g, 3.12 mmol). The reaction was stirred while warming to room temperature overnight. The reaction was diluted with water and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated to afford prop-2-yn-1-yl benzoate which was used in subsequent reactions without further purification. m/z (ESI) 161 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CN(C=O)C.[H-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[N:7]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: BrCc1cccnc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Benzyl 3-oxopiperazine-1-carboxylate (400 mg) and 3-(bromomethyl)pyridine hydrobromide (647 mg) were mixed with DMF (8 ml), and sodium hydride (55% suspended in oil) (194 mg) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. Water and CHCl3 were added to the reaction mixture at 0° C., and the organic layer was washed with water and saturated brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:32][CH3:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=O)=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])[CH3:13]>>[CH2:32]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])[CH3:33]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)c2c1CCCC2
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c2c1CCCC2
Yield: 67.3 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (20 mg, 0.1 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (3-diethylaminopropyl)amide (30 mg) to give 33 mg (46%) of the title compound as an orange solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C(#N)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:3]=[C:2]=[S:1])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)N=C=S
Temperature: 60 °C
Reaction time: 2 h

Procedure:
After adding potassium thiocyanate (65.3 mg) and acetonitrile (4 ml) to 2-(4-fluorophenyl)acetyl chloride (58 mg) under a nitrogen atmosphere, the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to room temperature, and then ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture and stirring was continued for 30 minutes. After partitioning the reaction mixture, the separated organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to provide a crude product of 2-(4-fluorophenyl)acetyl isothiocyanate as a yellow oil. After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (70 mg) in ethanol (2 ml), D-10-camphorsulfonic acid (43 mg) was added and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Then, 2-(4-fluorophenyl)acetyl isothiocyanate-acetonitrile (0.5 ml×3) was added and the mixture was stirred for 2 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (0.5 ml) and hexane (4 ml) were added to the resultant residue to produce a suspension of the solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (36.9 mg, 37.8%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[O:30])=[CH:19][N:20](COCC[Si](C)(C)C)[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH:32]([CH2:33][OH:34])[CH2:35][OH:36])=[O:30])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(CO)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(CO)CO)c3n2)c2ccc(Cl)cc21
Reaction time: 18 h
Yield: 33.3 %

Procedure:
To a stirred solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.035 g, 0.066 mmol) in dichloromethane (3 mL) was added TFA (0.38 g, 0.25 mL, 3.3 mmol) at 20° C. After 18 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (3 mL) and ethylenediamine (0.2 g, 0.22 mL, 3.3 mmol) added. The mixture was stirred for 3 h, then concentrated in vacuo. The residue was collected by filtration and purified by HPLC eluting with MeCN/water (20-95%) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.009 g, 0.022 mmol, 34%) as a white powder. MS (M+H)+=401; 1H NMR (DMSO-d6) δ: 12.86 (br. s., 1H), 9.15 (s, 1H), 8.73 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.93-5.02 (m, 2H), 4.17 (s, 4H), 3.56-3.77 (m, 4H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][C:41](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:42].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:41](=[O:42])[CH3:40])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic arthydride, pyridine and dimethylaminopyridine in methylene chloride to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:17][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([CH3:17])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCCc2c1[nH]c1ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
1-Oxo-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (0.12 g, 0.57 mmol) was dissolved in anhydrous THF (5 mL), cooled to 0° C., and methyl magnesium chloride (0.12 g, 1.71 mmol, 3M in THF) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 h at room temperature then cooled to 0° C., saturated NH4Cl (10 mL) was added and then extracted with EtOAc (4×25 mL). The combined organic extracts were dried over Na2SO4 concentrated under reduced pressure to give the crude material which was purified by column chromatography [EtOAc-hexane (3:7) as eluant] to obtain the title compound (0.03 g, 23%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.4 (s, 1H), 7.9 (s, 1H), 7.42 (d, J=12.0 Hz, 1H), 7.39 (d, J=12.0 Hz, 1H), 5.0 (s, 1H), 2.64-2.61 (m, 2H), 2.0-1.7 (m, 4H), 1.4 (s, 3H). IR cm−1 2216 (CN).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:10]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][Cl:28])[CH2:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[ClH:28].[C:3]([CH:2]([CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:22]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: ClCCN1CCN(c2cccc3ccccc23)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(CCN1CCN(c2cccc3ccccc23)CC1)C(C)=O
Product: Cl

Procedure:
This compound was prepared according to the process described in Example 10, Stage C, from ethyl acetoacetate and 1-(1-naphthyl)-4-(2-chloroethyl)piperazine.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCCNCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were added N-hexyl-benzylamine (0.079 g, 0.41 mmol) and DMAP (0.045 g, 0.37 mmol) followed by 1-ethyl-3-(3dimethylaminopropyl) carbodiimide hydrochloride (0.071 g, 0.37 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.139 g (80%) of a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15](C(C)(C)C)[C:16]([NH2:18])=[O:17])=[CH:11][N:10]=[C:9]2[CH3:23])=[CH:5][C:4]=1[F:26])#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[O:17])=[CH:11][N:10]=[C:9]2[CH3:23])=[CH:5][C:4]=1[F:26])#[N:2]
Reactant: Cc1ncc(CCN(C(N)=O)C(C)(C)C)n1Cc1ccc(C#N)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc(CCNC(N)=O)n1Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
{2-[3-(4-cyano-3-fluoro-benzyl)-2-methyl-3H-imidazol-4-yl]-ethyl}-tert-butyl urea (as described above in Step A) (0.41 g) was dissolved in TFA/CH2Cl2 3:1 (5.0 mL) and stirred at ambient temperature for 72 hr. The solvents were removed in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccc(C)cc1)c1ccc(C)cc1
Yield: 97.6 %

Procedure:
Substantially the same procedure as in Reference Example 4 was repeated using 4,4'-dimethylbenzhydrol (11.8 g, 55.5 mmol) and ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) to give 19.8 g (yield: 97%) of the title compound.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:13]1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])[C:14]=1C#N)#N.C(O)CCC.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:1]([O:16][CH2:15][CH2:14][CH2:13][CH3:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)C=Cc1ccccc1
Yield: 94 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), BuOH (10 mL) and toluene (15 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Butyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C4H9) is isolated in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ7.48 (1H, d), 7.25 (2H, m), 7.11 (3H, m), 6.23 (1H, m), 3.98 (2H, t), 1.45 (2H, m), 1.19 (2H, m), 0.74 (3H, t); 13C-NMR (CDCl3, 75.4 MHz) δ166.5, 144.2, 134.4, 129.9, 127.9, 118.2, 64.0, 30.7, 19.1, 13.6.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=C[CH:8]=1)[NH2:4].[F:12][C:13]([F:23])([F:22])[C:14]1[N:15]=[C:16]([C:19](Cl)=[O:20])[S:17][CH:18]=1.O1[CH2:29][CH2:28][O:27][CH2:26]C1>>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:29][C:28]([O:27][CH3:26])=[C:5]([CH3:6])[C:3]=1[NH:4][C:19]([C:16]1[S:17][CH:18]=[C:14]([C:13]([F:23])([F:22])[F:12])[N:15]=1)=[O:20]
Reactant: O=C(Cl)c1nc(C(F)(F)F)cs1
Reactant: COC(=O)c1ccccc1N
Reactant: C1COCCO1
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Under nitrogen atmosphere, a solution of methyl anthranilate (2 g, 1 eq.) in 1,4-dioxane (30 mL) was added at 0° C. to a solution of 4-trifluoromethyl-thiazole-2-carbonyl chloride (4.36 g, 2 eq.) in 1,4-dioxane (65 mL). The reaction mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (DCM/MeOH) to yield compound 204 as a white solid in 81% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.51 (s, 3H), 3.80 (s, 3H), 3.85 (s, 3H), 6.75 (d, J=8.75 Hz, 1H), 7.87 (d, J=8.75 Hz, 1H), 7.95 (s, 1H), 10.48 (s, 1H).
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])[CH3:7].Cl[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34].Cl>O1CCOCC1.O>[CH2:6]([O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH:20][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[C:17]([O:19][CH:11]([CH2:12][CH3:13])[CH3:9])=[O:18])=[O:10])[CH3:7]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)N[C@@]1(C(=O)OC(C)CC)[C@H](OCc2ccc(Cl)c(Cl)c2)C[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 mL of saturated sodium hydrogen carbonate was added to 200 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-ethyl ester suspended in 1 mL of dioxane, and the mixture was stirred for 10 minutes at room temperature. 0.18 mL of allyl chloroformate was added thereto, and the solution was stirred for 8 hours at room temperature. After the reaction solution was acidified with 1 mL of 1N hydrochloric acid, 10 mL of water was added thereto, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was dissolved in 20 mL of N,N-dimethylformamide. 141 mg of 1-iodobutane and 106 mg of potassium carbonate were added to the solution, and the mixture was stirred for 16 hours at room temperature. Water was added thereto, and the reaction solution was extracted twice with ethyl acetate. After the ethyl acetate layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled under reduced pressure and purified by column chromatography (silica gel: Kanto Chemical silica gel 60 (spherical), eluent: hexane-ethyl acetate=5:1), thereby yielding 159 mg of (1R,2R,3R,5R,6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester.