Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12]C(C)C)=[O:10].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O>[OH:31][CH2:35][C:34]1([C:9]([O:11][CH3:12])=[O:10])[CH2:32][CH2:33]1
Reactant: CC(C)COC(=O)Cl
Reactant: C1CCOC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1(CO)CC1

Procedure:
The compound (9.0 g) obtained in Referential Example 161 and triethylamine (9.7 ml) were dissolved in tetrahydrofuran (180 ml), and the solution was cooled to −10° C., to which isobutyl chloroformate (9.1 ml) was added dropwise, and the resultant mixture was stirred for 1 hour. On the other hand, sodium borohydride (7.1 g) was dissolved in tetrahydrofuran (100 ml)-water (25 ml) and cooled with ice. While removing insoluble matter by filtration, the solution prepared previously was added dropwise, and the resultant mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a cooled 10% aqueous solution of citric acid to conduct extraction with ethyl acetate. After the extract was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9-2:1) to obtain the title compound (4.25 g).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CO.[CH2:14](Br)[C:15]#[CH:16].C[O-].[Na+]>CCOCC>[CH2:16]([NH:10][S:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:15]#[CH:14]
Reactant: O=S(=O)(NO)c1ccccc1
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C#CCNS(=O)(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To 8.6 g. piloty acid dissolved in 50 ml. methanol, propargyl bromine (6.6 g.) was added. 10.8 g. sodium methoxide (25%) was added slowly dropwise. An exothermic reaction resulted, the temperature was maintained at 30° C. The reaction mixture was stirred for approximately 1 hour at room temperature. The solvent was removed in vacuo. There was obtained a yellow solid. This material was treated with ether and the solid filtered off and dried. There was obtained 3.1 g. of the title compound, a low melting solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O[CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:18]([O:17][CH2:16][CH2:15][O:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: C=C(C)C(=O)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-napthoic acid (8.0 g, 46 mmol), 2-hydroxyethylmethacrylate (18.1 g, 139 mmol), dimethylamino-pyridine p-toluenesulfonic acid salt (5.5 g, 19 mmol), and anhydrous dichloromethane (45 mL) was cooled to 0° C. under nitrogen, and 1,3-dicyclohexyl-carbodiimide (12.5 g, 60 mmol) were added. After 15 min, the reaction mixture was warmed to ambient and stirred for 3 h. The precipitated urea by-product was filtered, and the filtrate was washed successively with 10% aqueous HCl, 10% aqueous NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated to deposit a gold oil. The product was purified by column chromatography to provide 8.2 g (62% of theory) of a pale yellow oil. 1H NMR (CDCl3): δ 1.90 (s, 3H), 1.55 (m, 2H), 1.70 (m, 2H), 5.60 (s, 1H), 6.20 (s, 1H), 7.55 (m, 3H), 7.90 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.90 (d, 1H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=[C:15]([O:29][CH3:30])[CH:14]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:30][O:29][C:15]1[CH:14]=[C:13]([CH:11]=[CH2:1])[CH:18]=[CH:17][C:16]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (785 mg, 2.2 mmoL) in THF (5 mL) was treated with 1M lithium bis(trimethylsilyl) amide in THF (2.2 mL), stirred for 30 minutes, treated with a solution of Example 122I (540 mg, 2.0 mmol) in THF (2 mL), stirred for 1 hour, and filtered through a pad of silica gel (20 g). The pad was rinsed with 1:1 ether/dichlormethane and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% dichloromethane/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36](=[O:45])([O:41][CH:42]([CH3:44])[CH3:43])[O:37][CH:38](Cl)[CH3:39]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:36](=[O:45])([O:41][CH:42]([CH3:44])[CH3:43])[O:37][CH:38]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:39]
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)OC(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 11.1 %

Procedure:
The title compound was prepared according to the procedure as described in Example 26 step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol), KOH (69 mg, 1.23 mmol) in anhydrous DMF (2 mL), a solution of TBAB (396 mg, 1.23 mmol) in anhydrous DMF (0.5 mL) and a solution of 1-chloroethyl isopropyl carbonate (101 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1), and recrystallized in methanol to afford the title compound as a white solid (42 mg, 11.1%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:32][CH:31]([NH:33][C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)=[O:35])[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:30][CH:31]([NH:33][C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=3)=[O:35])[CH2:32]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: O=C(NC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
0.59 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (b) above] was suspended in 0.94 ml of anisole, and 3.32 ml of trifluoroacetic acid and 0.15 ml of trifluoromethanesulfonic acid were added dropwise to the suspension, whilst ice-cooling, after which the mixture was stirred at the same temperature for 1 hour. At the end of this time, 1,2-dichloroethane was added to the reaction mixture, and the solvent was removed by distillation under reduced pressure. The residue was then washed by repeated decantation, in turn, with hexane and with diethyl ether. The residue was diluted with ethyl acetate and made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated and washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure to give 0.44 g of the title compound, in the form of an amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:67])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]#[CH:66])=[CH:59][CH:58]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:55])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[NH:27][C:28](=[O:47])[NH:29][C@H:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].[N:68]([CH2:71][CH2:72][CH2:73][NH2:74])=[N+:69]=[N-:70]>C1COCC1.O.C(Cl)Cl.[Cu].[O-]S([O-])(=O)=O.[Cu+2]>[NH2:74][CH2:73][CH2:72][CH2:71][N:68]1[CH:66]=[C:65]([CH2:64][O:63][C:60]2[CH:61]=[CH:62][C:57]([CH2:56][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:55])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]([C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[NH:27][C:28](=[O:47])[NH:29][C@H:30]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:13][C:9]3[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:67])[CH:12]=[CH:11][N:10]=3)=[CH:58][CH:59]=2)[N:70]=[N:69]1
Reactant: [N-]=[N+]=NCCCN
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCN)nn2)cc1)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
To a solution of (14S,18S)-tri-tert-butyl 1-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (250 mg, 0.266 mmol) and 3-azidopropan-1-amine (200 mg, 2.0 mmol) in THF (5.0 mL) and water (1.0 mL) was added copper powder (17 mg) and 1 N CuSO4 (0.05 mL). The mixture was stirred at room temperature for 6 hrs under nitrogen, diluted with DCM, washed with aqueous saturated solution of EDTA. The solvent was evaporated under reduce pressure to afford a residue, which was purified by Biotage SP4 to afford (14S,18S)-tri-tert-butyl 2-(4-((1-(3-aminopropyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-1-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (158 mg, 57%) as a yellow oil. MS (ESI), 520.4 (M/2+H)+.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:14]2[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]=2[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Yield: 722.7 %

Procedure:
A mixture of 2-[(3-oxo-cyclohex-1-enylamino)-methylene]-malonic acid diethyl ester (2.8 g, 1 mmol) and diphenylether (20 mL) was refluxed for 15 min. After cooling, n-hexane (80 mL) was added. The resulting solid was isolated via filtration and recrystallized from methanol to give 4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (1.7 g 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24]S[CH:22]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC([O:42]C)=CC=2)=NC=1)C.O1C=CC(C(O)=O)=C1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24][O:42][CH:22]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccsc3)nn2)cc1
Agent: O=C(O)c1ccoc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 57, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-furoic acid (50 mg, 0.45 mmol). Except, that during the saturated sodium bicarbonate solution wash, a solid was formed which was collected by filtration and dried to give N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-furancarboxamide (110 mg) as a yellow solid. MS m/z 340 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCOCC3)cc21

Procedure:
2.18 g of 6,7-dichloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 3 cm3 of morpholine and 30 cm3 of DMSO were heated for 5 hours at 125°-130° C. About 3 hours were required for total dissolution of the dihalogeno-acid, and the reaction product then precipitated from the mixture. After returning to room temperature, the mixture was diluted with 30 cm3 of water. The precipitate was filtered off, washed with water and recrystallised from a mixture of DMF (1 volume) and methylcellosolve (1 volume). 1.68 g of 6-chloro-1-methyl-7-morpholino-4-oxo-1,4-dihydro quinoline-3-carboxylic acid were obtained; m.p. 334° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[C:15](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:23]=[O:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A solution of 6.0 g (16.3 mmol) of 4-(2,2-Dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester in 150 ml THF was treated at −78° C. with 21.4 ml (34.2 mmol) of n-BuLi (ca 1.6 M in hexane). After 2 h at this temperature 4.9 g (16.3 mmol) of paraformaldehyde were added. The reaction was warmed up to RT for 3 h and after 1 h at this temperature partitioned between water/ether (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 4:1) gave 3.34 g (86%) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 239 (M).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30](F)[CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:35]=[C:28]([Br:27])[CH:29]=[CH:30][C:31]=5[C:32]#[N:33])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1ccc(Br)cc1F
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc(Br)ccc5C#N)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-bromo-2-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12.
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.[CH2:9]([N:12]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][C:15]1C=CC=C2[C:16]=1[CH:17]=[CH:18]N2)[CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH2:24]([N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][C:15]1[C:4]2[C:3]([CH:18]=[CH:17][CH:16]=1)=[N:2][C:6](=[O:7])[CH:5]=2)[CH2:25][CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCN(CCC)CCc1cccc2[nH]ccc12
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCc1cccc2c1=CC(=O)N=2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
N-chlorosuccinimide (2.52 g, 18.9 mmol) was added to a solution of 4-[2-(dipropylamino)ethyl]indole (IV) (3 g, 12.28 mmol) in toluene (10 mL) and was stirred at room temperature for 1 h. The resultant mixture was washed with an aqueous solution of NaOH 5% and then an aqueous solution of HCl 1N (30 mL) was added to the organic layer and was heated at reflux temperature for 1 h. When the mixture reached room temperature, the organic layer was separated and the aqueous layer was basified with an aqueous solution of NaOH and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain 2.1 g (66%) of 4-[2-(dipropylamino)ethyl]indol-2-one (I), which was purified and converted into its hydrochloride salt.
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[N:28][C:29](=[O:32])[CH2:30][Cl:31])[S:26][CH:27]=1)[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[N:28][C:29](=[O:32])[CH2:30][Cl:31])[S:26][CH:27]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=NC(=O)CCl)[nH]1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)ON=C(C(=O)O)c1csc(=NC(=O)CCl)[nH]1
Yield: 79.1 %

Procedure:
In 116.5 ml of anisole there were suspended 6.10 g of benzhydryl 2-acetoxyimino-2-(2-chloroacetylimino-4-thiazolin-4-yl)acetate(syn-isomer) and under ice-cooling and stirring, 65.7 ml of trifluoroacetic acid were added dropwise. The mixture was stirred at that temperature for 15 minutes, after which the trifluoroacetic acid was distilled off under reduced pressure. To the residue was added n-hexane, whereupon an oily product separated out. The product was wahsed well with n-hexane and the n-hexane was discarded ater being removed by decantation. This procedure was carried out once again. To the oily residue was added ether, whereupon a crystalline powder separated out. Following the addition of a small amount of ether, the crystalline powder was collected by filtration, washed with a small amount of ether and dried. By the above procedure there were obtained 3.125 g of 2-acetoxyimino-2-(2-chloroacetylimino-4-thiazolin-4-yl)acetic acid (syn-isomer).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH:14]1([NH:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:20]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O-:21])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: ONC1CCCCC1
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOc1cc(C=[N+]([O-])C2CCCCC2)ccc1OC
Yield: 57 %

Procedure:
A solution of 3-ethoxy-4-methoxybenzaldehyde (1 eq.) in benzene was refluxed with N-cyclohexylhydroxylamine (1.3 eq.) in the presence of p-toluenesulfonic acid (0.1 eq.) for 72 h. The title compound was isolated in 57% yield as a solid, m.p. 113.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:22]([Si:19]([CH3:21])([CH3:20])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The procedure used was similar to that described by Corey and Venkateswarlu (Corey, E. J.; Venkateswarlu, A., J. Am. Chem. Soc., 1972, 94, 6190-6191). 6-Phenyl-1-hexanol (14.0 g) and imidazole (13.36 g) were dissolved in dry DMF (40 mL). tert-Butyldimethylsilyl chloride (14.20 g,) was then added in one portion. The resulting solution was allowed to stir for 8 hours at room temperature. Aqueous sodium bicarbonate (100 mL, 10% by wt.) was then added and the resulting solution was allowed to stir for 15 minutes. The desired product was then extracted from the mixture with petroleum ether (3×250 mL). The petroleum ether extract was then washed with distilled H2O (7×300 mL), dried over MgSO4 and roto-evaporated to give the desired product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[S:10]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:13][CH2:14][C@@H:15]1[O:17][CH2:16]1)(=[O:12])=[O:11].C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]([CH2:16][C@@H:15]([OH:17])[CH2:14][O:13][S:10]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:12])=[O:11])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Yield: 66.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (10 g, 67.79 mmol) and (R)-(−)-glycidyl tosylate (17.02 g, 74.58 mmol) were dissolved in acetonitrile (50 ml), sodium hydrogencarbonate (6.26 g, 74.15 mmol) was added to the solution, and the resulting mixture was stirred under reflux for 3.5 hours. The reaction mixture was allowed to return to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford (R)-2-chloro-1-[2-hydroxy-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole (16.9 g, yield 66%) as a light yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([OH:7])[CH3:6])C.[OH-].[Li+]>O1CCCC1.O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]([OH:7])([CH3:6])[C:4]([OH:15])=[O:3])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(C)(O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)c1ccc(Cl)cc1

Procedure:
A solution of 5.72 g of the 2-(4-chlorophenyl)-2-hydroxy propionic acid ethyl ester in 170 ml tetrahydrofurane is hydroysed at 0° C. with a solution of 30.5 ml 1N lithiumhydroxide in 19 ml water. When the reaction is complete, the reaction mixture is diluted with water, washed with diethyl ether, acidified with 1N HCl and extracted with ethyl acetate. The extracts are washed with brine, dried over sodium sulfate and evaporated to give 2-(4-chlorophenyl)-2-hydroxy propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.O.[C:15]([OH:19])(=[O:18])[CH:16]=[O:17]>CCOC(C)=O>[OH:17][CH:16]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[C:15]([OH:19])=[O:18]
Reactant: O=CC(=O)O
Reactant: COc1ccc2c(c1)CCCC2=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(C(O)C(=O)O)C2=O
Temperature: 120 °C
Yield: 29.8 %

Procedure:
A mixture of 6-methoxy-1-tetralone (20 g, 114 mmol) and glyoxylic acid monohydrate (10.5 g, 114 mmol) was heated at 120° C. in a melt for 5 min. After slight cooling, EtOAc (100 mL) was carefully added. The solid which precipitated was collected to afford 8.5 g (30%) of hydroxyl-(6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic acid; Mp 212-214° C., MS m/z 251 (M+H).