Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:18]=3[C:19]=2[N:20]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:18]=3[C:19]=2[N:20]=1)=[S:35]
Reactant: O=C(Nc1ccccc1Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C(Nc1ccccc1Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 5 h
Yield: 74.2 %

Procedure:
A mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-chloro-phenyl)-amide (260 mg), Lawesson's reagent (193 mg) and toluene (10 mL) was heated to reflux. After 5 hours, the reaction mixture was cooled and the precipitate was collected by filtration to yield the corresponding thioamide, 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbothioic acid (2-chloro-phenyl)-amide (160 mg).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:12]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])#[N:13]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([C:12]#[N:13])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
Part B. To a mixture of tert-butanol (3.50 g, 47.22 mmol), pyridine (3.72 g, 46.78 mmol) and cat. DMAP in methylene chloride (15 mL) is added dropwise 3-cyanobenzoyl chloride (6.81 g, 41.07 mmol) and pyridine (3 mL) in methylene chloride (10 mL) at 0° C. The resulting mixture is stirred at room temperature for 20 h. The solvent is evaporated, and the residue is purified by flash chromatography (1:1 methylene chloride/hexanes) to afford 3-cyano-benzoic acid tert-butyl ester (6.84 g, 82.1% yield) as white solid. 1H NMR (300 MHz, CDCl3): δ 8.24 (1H, s), 8.20 (1H, dd, J=7.9, 1.2 Hz), 7.78 (1H, dd, J=6.7, 1.1 Hz), 7.52 (1H, m), 1.58 (9H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[N:19][C:20]#[N:21])SC)[CH:12]=[CH:13][CH:14]=1>O.C(O)C>[C:20]([N:19]=[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=1)[NH:1][CH2:2][C:3]([OH:5])=[O:4])#[N:21]
Reactant: NCC(=O)O
Reactant: CSC(=NC#N)Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CN=C(NCC(=O)O)Nc1cccc(Cl)c1
Yield: 89.6 %

Procedure:
Three grams (39.9 mmol) of glycine and 1.5 g (37.2 mmol) of sodium hydroxide are mixed in 10 cm3 of water and added to 6 g (26.5 mmol) of N-(3-chlorophenyl)-N'-cyano-S-methylisothiourea in solution in 40 cm3 of 95% ethanol. The mixture is reflux heated for 1 hour. After cooling, the resulting precipitate is filtered and then washed with 2×50 cm3 of ethyl ether. The resulting solid is dissolved in 50 cm3 of 1N sodium hydroxide solution. This solution is washed with 3×10 cm3 of dichloromethane and then acidified with a 3N solution until a pH close to 2 is obtained. The white solid which forms is then filtered and washed in 2×10 cm3 of water, following which it is dried in vacuo. 6 g of N-[cyanoimino(3-clorophenylamino)methyl]-2-aminoethanoic acid (yield 89%) is obtained with a melting point of 109° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][Br:23])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)CC1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Temperature: -1.7999999523162842 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of (4-phenylcyclohexyl)-acetic acid ethyl ester (10.0 g, 40.6 mmol) (patent WO2004 047755) in DCM (100 mL) at 0° C. is added AlCl3 (9.94 g, 74 mmol) portionwise. After it is stirred at −1.8° C. for 10 min, bromoacetyl bromide (3.59 mL, 40.6 mmol) is added dropwise over 2 min. The reaction mixture is allowed to stir at −1.8° C. for 2 h. It is then poured slowly to water/ice mixture (200 mL) and stirred for 30 min. The mixture is extracted with DCM (2×50 mL). The organic phase is separated and washed with NaHCO3 (3×100 mL), and brine (3×100 mL), dried with Na2SO4, concentrated and dried under high vacuum to give the title compound (12.8 g) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.17 (m, 2H) 1.20 (t, J=8.00 Hz, 3H) 1.39-1.51 (m, 2H) 1.56-1.68 (m, 1H) 1.76-1.87 (m, 4H) 2.18 (d, J=4.29 Hz, 2H) 2.48 (td, J=12.32, 2.65 Hz, 1H) 4.08 (q, J=7.24 Hz, 2H) 4.35 (s, 2H) 7.25 (d, J=8.34 Hz, 2H) 7.85 (d, J=8.59 Hz, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[O:30]1CCC[CH2:31]1.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:31][OH:30])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cccc(CCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4.24 g (25 mmol) of silver nitrate were added to a solution of 10.14 g (25.0 mmol) N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (iv) above] in a mixture of 500 ml of acetone, 100 ml of tetrahydrofuran and 200 ml of water, and the resulting mixture was stirred for 7 hours at 60° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 6.41 g (yield 66%) of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: O=C(O)c1cccc(Cl)c1

Procedure:
The compound (e1) (54 mg) and m-chloroperbenzoic acid (23.4 mg) were stirred together in water (2 ml). After 10 minutes the m-chlorobenzoic acid that had formed was filtered off, the pH was adjusted to 7 by the addition of a small amount of dilute sodium bicarbonate solution and the water was then removed by evaporation on a rotary evaporator to yield the compound (e2) as a solid (60%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][OH:24])[CH:17]=[C:16]([Cl:26])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:26])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH:21][CH2:22][CH2:23][OH:24])=[O:25]
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C(NCCO)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: O=C(NCCO)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-N-(2-hydroxyethyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide (Compound No. 75) was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-[(2-hydroxyethyl)carbamoyl]benzoic acid.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared from the coupling of 2m and benzene sulfonamide by the method described in Procedure 1, Method A. Yield (65%); ESI m/z: 490 (M−H−, 100%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=[O:20].[Br:22]C(F)(F)C(Br)(F)F.Cl>O1CCCC1>[Br:22][C:17]1[S:16][C:15]([C:19]([OH:21])=[O:20])=[C:14]([Cl:13])[CH:18]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: O=C(O)c1sccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1sc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.8 ml) in tetrahydrofuran (75 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 30.5 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of 3-chloro-2-thiophenecarboxylic acid (3.92 g) in tetrahydrofuran (40 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise 1,2-dibromo-1,1,2,2-tetrafluoroethane (6.0 ml). The mixture was stirred at the same temperature for one hour, and then, warmed to room temperature. The mixture was poured into a diluted aqueous hydrochloric acid solution, and the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixed solvent of diisopropyl ether and hexane to give 5-bromo-3-chloro-2-thiophenecarboxylic acid (3.79 g) as a yellow solid. ESI-Mass m/Z 239/241 (M−H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:2]2[CH:3]=[C:4]([CH:11]3[N:15]4[CH:16]=[N:17][CH:18]=[C:14]4[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(C2CCc3cncn32)cc1Cl
Product: O=[N+]([O-])c1ccc(C2CCc3cncn32)cc1NC1CC1
Reaction time: 30 h
Yield: 99.6 %

Procedure:
A mixture of 3.15 g of 5-(3-chloro-4-nitrophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol (preparedas described in EP-A-0,426,225) and 30 ml of cyclopropanamine was stirred for 30 hours at reflux temperature. The reaction mixture was evaporated and the residue was stirred in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was co-evaporated with methylbenzene, yielding 3.4 g (99.6%) of (±)-N-cyclopropyl-5-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-nitrobenzenamine (interm. 6).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]#[CH:4].[H][H]>[Pd].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[CH2:3][CH3:4]
Reactant: [H][H]
Reactant: C#CC(C)(O)CCC(C)CC
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Product: CCC(C)CCC(C)(O)CC
Yield: 91 %

Procedure:
0.5 g of an 0.5% strength palladium/aluminum oxide catalyst is added to 154 g (1 mole) of 3,6-dimethyl-oct-1-yn-3-ol and hydrogenation is carried out at 20°-50° C. and 0.5 bar hydrogen pressure. When hydrogen absorption has ceased (after 6-8 hours), the catalyst is filtered off and the filtrate is fractionated. 145 g of main fraction, boiling at 42°-43° C./0.01 mbar, are obtained; nD25 =1.4345. This corresponds to a yield of 91%. Scent: fresh, floral, lavender-like.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:22]([Cl:44])=[CH:21][N:20]=1>>[Cl:44][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:39])=[O:40])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CN(C)S(=O)(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4S(=O)(=O)N(C)C)n3)cc21

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-5-morpholin-4-yl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as tan foam (0.076 g, 52%). MP: 130-151° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.06 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.10 (s, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.35 (d, J=3.0 Hz, 1H), 7.29-7.26 (m, 1H), 7.18 (dd, J=8.7 Hz and 2.1 Hz, 1H), 7.04 (dd, J=9.2 Hz and 2.9 Hz, 1H), 6.94 (br s, 1H), 3.92-3.88 (m, 4H), 3.76-3.62 (m, 2H), 3.23-3.17 (m, 4H), 2.73 (s, 6H), 2.35-2.26 (m, 2H), 2.15-1.95 (m, 2H), 1.33 (s, 6H), 1.18 (t, J=7.2 Hz, 3H). MS: 628.25 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Yield: 73.6 %

Procedure:
A N,N-dimethylformamide solution (2.2 mL) of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (329 mg, 1 mmol), and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (277 mg, 1 mmol) is heated at 90° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 423 mg (74%) of the title compound as a yellow solid. MS (ESI) m/z 575.2 (M+H)+1
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Yield: 99.6 %

Procedure:
To a solution of p-toluenesulfonic acid salt of L-alanine benzyl ester (7.03 g, 0.02 mol) and triethylamine (4.55 g, 0.045 mol) in methylene chloride (80 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (3.71 g, 0.02 mol) in methylene chloride (20 ml) under ice-cooling and stirring. After the addition was completed, the mixture was stirred for 0.5 hour under the same condition and for 0.5 hour at ambient temperature. The mixture was washed with diluted hydrochloric acid and water twice successively. After drying over MgSO4, the solvent was removed in vacuo to give N-(3-nitrobenzoyl)-L-alanine benzyl ester (6.54 g, 99.6% yield) as a colorless crystal, which was used in a following reaction without further purification. 1H-NMR (CDCl3, δ): 1.56 (3H, d, J=7.2 Hz), 4.86 (1H, q, J=7.2 Hz), 5.24 (2H, dd, J=12.3 Hz, 13.6 Hz), 6.98 (1H, br, d, J=7.0 Hz), 7.37 (5H, s), 7.63 (1H, t, J=8.0 Hz), 8.14 (1H, dd, J=1.2Hz, 8.0 Hz), 8.35 (1H, d, t, J=8.0 Hz, 0.92 Hz), 8.62 (1H, t, J=0.92 Hz); APCI-MS: 329 (M+ +1)
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cc(Cl)cc(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a white solid (0.25 g, 67% yield), mp=115–117° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=+24.9° (c=1, EtOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[O:16]=[S:17]1(=[O:40])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=3)=[C:26]([CH3:39])[CH:25]=2)[CH2:19][CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:37][C:33]3[CH:32]=[C:31]([C:27]4[C:26]([CH3:39])=[CH:25][C:24]([O:23][CH:20]5[CH2:19][CH2:18][S:17](=[O:40])(=[O:16])[CH2:22][CH2:21]5)=[CH:29][C:28]=4[CH3:30])[CH:36]=[CH:35][CH:34]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCS(=O)(=O)CC5)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]=[C:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.CCOC(C)=O>C1COCC1>[C:5]([C:1]1([C:16]2([OH:15])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17]2)[CH2:4][CH2:3][CH2:2]1)#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(C2(C#N)CCC2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 15.7 %

Procedure:
To a solution of cyclobutanecarbonitrile (1.75 g, 21.5 mmol) in THF (15 mL) was added 2.0M lithium diisopropylamide (11 mL, 22.5 mmol) dropwise and the solution was stirred at −78° C. for 45 minutes. Then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (4.0 g, 21.5 mmol) in THF (2 mL) was added to the solution and the mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (25 mL×3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether:EtOAc=2:1 to obtain the title compound (0.9 g, 38.2% yield) as a white solid. 1H NMR: (400 MHz, CDCl3): δ 3.64-3.40 (m, 4H), 2.44 (t, J=7.8 Hz, 2H), 2.33-2.23 (m, 2H), 2.13-1.88 (m, 4H), 1.47 (s, 9H)
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH2:15][NH2:16])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:16][CH2:15][C:5]1([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:30]
Reactant: NCC1(CC2CC2)CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1(CC2CC2)CCC2(CC1)OCCO2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {[8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}amine (7 g; 31.0 mmol) and n-ethyldiisopropylamine (6.45 ml; 37.2 mmol) in DCM (60 ml) at 0° C. was added 2,4-dichlorobenzoyl chloride (4.781 ml; 34.17 mmol) dropwise and the solution stirred for 4 hours warming to ambient temperature. The reaction was partitioned between DCM (50 ml) and water (20 ml). The aqueous phase was extracted with DCM (20 ml) and the combined organics dried over MgSO4, filtered and evaporated to give a colourless oil which was used in the next step without further purification. (11.5 g) 1H NMR δ (ppm)(CDCl3): 7.67 (1H, d, J=8.3 Hz), 7.43 (1H, d, J=2.0 Hz), 7.32 (1H, dd, J=2.0, 8.4 Hz), 6.25 (1H, s), 3.93 (4H, s), 3.56 (2H, d, J=6.2 Hz), 1.67 (8H, m)), 1.33 (2H, d, J=6.7 Hz), 0.75-0.65 (1H, m), 0.51-0.47 (2H, m), 0.05 (2H, q, J=5.0 Hz). MS (m/e)=398
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18]CC3C=CC=CC=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[C:3]1=[O:26]>[Pd].C1COCC1.CO>[OH:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@@H:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:26])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H]2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)cc(O[C@@H]2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 98 %

Procedure:
A solution of methyl 3-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate (Intermediate 13) (1.42 g, 4.0 mmol) was added to a suspension of 10% palladium on carbon (140 mg, catalytic) in THF (40 mL) and methanol (40 mL). The mixture was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give the product (1.04 g, 98%). 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.56-2.68 (m, 1H), 2.97 (s, 3H), 3.37-3.55 (m, 2H), 3.86 (s, 3H), 4.93 (t, 1H), 6.81 (s, 1H), 7.04 (s, 1H), 7.12 (s, 1H), 7.66 (s, 1H); m/z 266 (M+H)+