Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].S(=O)(=O)(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]([CH3:21])=O>>[CH3:18][C:19]1([CH3:21])[O:6][CH:3]([CH2:2][Br:1])[CH2:4][O:5]1
Reactant: OCC(O)CBr
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)OCC(CBr)O1
Reaction time: 24 h
Yield: 53.5 %

Procedure:
Into a 500 milliliter round bottom flask equipped with a magnetic stir bar and drying tube, a solution of 28.0 grams (0.181 mole) of 3-bromo-1,2-propanediol in 200 milliliters of acetone was added. Then, 0.5 milliliter of concentrated sulfuric acid was added and the reaction allowed to proceed at room temperature for 24 hours with continuous stirring. The reaction mixture was neutralized with 13.0 grams of K2CO3 for 30 minutes, the solution was filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in 150 milliliter of ether, extracted three times with 150 milliliter portions of water and the organic layer dried over anhydrous sodium sulfate. The filtered ether was evaporated in vacuo and 100 milliliters of hexanes was added, resulting in two layers. The upper layer was decanted and evaporated in vacuo to provide 19.1 grams (53.5%) of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl bromide. The desired analog was then prepared in an analogous manner to that of (±)-3-hexadecylthio-2-methoxy-N,N-dimethyl-N-β-hydroxyethyl-1-propyl ammonium bromide from 2.5 grams (0.013 mole) of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl bromide, 1.3 grams (0.014 mole) of N,N-dimethylaminoethanol, and 15 milliliters of CH3CN. Chromatography with Florisil® (CHCl3 :MeOH 3:1 as eluent) provided 0.860 milligrams (23%) of product as a thick oil. 1H-NMR (CDCl3): delta, 1.25 (s, 3H, CH3), 1.35(s, 3H, CH3), 3.4-3.48[s, 6H, CH2 --N(CH3)2 ], 3.75-4.25(m, 9H, CH, CH2 --O, CH2 --N--CH2 --CH2 --OH). Anal. (C10H22NO3Br) C,H,N.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19]>O1CCOCC1.CO>[ClH:19].[ClH:19].[CH:15]1([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C1CC(N2CCCNCC2)C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 1-L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and a reflux condenser. The flask was charged with a slurry of crude 4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (92.4 g, 363.8 mmol) in a mixture of dioxane/MeOH (100 mL/50 mL). HCl (4 M in dioxane, 250 mL) was added with vigorous mechanical agitation following which the reaction mixture was heated to ca. 55° C. in an oil bath. A pale orange-yellow solution resulted. The reaction mixture was maintained at ca. 55° C. for 16 h. After cooling to rt, the reaction mixture, a thick slurry, was transferred to a 2-L recovery flask and concentrated to a pasty solid. Methyl tert-butyl ether (200 mL) was added, and the slurry agitated at ca. 55° C. in an oil bath for 1 h. The solvent was removed by rotary evaporation under reduced pressure to afford the product as an off-white solid (81.2 g, 98%). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 11.92 (s, 1H), 9.87 (s, 1H), 9.46 (s, 1H), 3.76-3.03 (m, 9H), 2.43-2.33 (m, 2H), 2.17-2.15 (m, 4H), 1.75-1.60 (m, 2H). MS m/z (ESI+): 155.1 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][OH:10])[CH:2]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH:9]=[O:10])[CH:2]=1
Reactant: OCC#Cc1cccnc1
Solvent: ClCCl
Product: O=CC#Cc1cccnc1
Reaction time: 12 h
Yield: 20.3 %

Procedure:
A solution of 3-(3-pyridinyl)-2-propynol (500 mg, 3.75 mmol) in CH2Cl2 (5 mL) was treated with activated manganous dioxide (3.3 g, 34.5 mmol) at 25° C. After 12 h, the reaction mixture was filtered through celite, washed with CH2Cl2 (2×50 mL), concentrated in vacuo. Purification by flash chromatography afforded the title compound (100 mg, 20%) as yellow brown oil. MS 133 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2>C(O)(=O)C.[Zn]>[NH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([Br:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cc(Br)c2[nH]ccc2c1

Procedure:
A mixture of 7-bromo-5-nitro-1H-indole (prepared according to the procedure set forth in L. L. Melhado et al., Phytochemistry, 21, 2879 (1982)) (550 mg, 2.28 mmol) in glacial acetic acid (16 mL) was treated with zinc dust (700 mg, 10.7 mmol) for 2 hours at room temperature. The mixture was then filtered through a pad of Celite, the filtrate evaporated, and coevaporated several times with toluene. The residue was taken up in methylene chloride (with a small amount of methanol), washed with saturated NaHCO3 solution, dried (Na2SO4), and evaporated. Flash chromatography eluting with 20% ethyl acetate in hexane afforded 153 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[H][H].Cl>CO.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Yield: 48.7 %

Procedure:
2-(4-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (550 mg, 1.66 mmol) and platinum (IV) oxide (110 mg) in methanol (100 ml) was hydrogenated under 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichlormethane:methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid and wash with ethyl acetate. The solvent was removed in vacuum. 260 mg of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 47%. LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+].[N+](=[CH2:15])=[N-].[F:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[C:21]([F:24])[C:22]=1[OH:23]>CCOCC.O.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:15][CH:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[C:21]([F:24])[C:22]=1[OH:23]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)/C=C/c1cc(F)c(O)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reaction time: 0.03 h

Procedure:
To a mixture of N-methyl-N′-nitro-N-nitrosoguanidine (TCI-America catalogue #M0527, 10 g on a dry weight basis, 0.068 mol) in ether (150 mL) at 0° C. was added a cold solution of potassium hydroxide (12.60 g) in water (21 mL). After stirring for 2 minutes, a portion of the yellow ethereal solution of the resulting diazomethane was added to a solution of ethyl 3-(3,5-difluoro-4-hydroxyphenyl)acrylate (10) (2.28 g, 0.010 mol) in ether (100 mL) at 0° C. A portion of palladium (II) acetate (0.372 g, 1.66 mmol) was added followed by an additional portion of diazomethane solution. This process was continued until all the diazomethane solution and palladium (II) acetate was added. The resulting dark mixture was stirred at 0-5° C. for 4 hours and acetic acid (6 drops) was added to quench any excess reagent. After removal of solvent in vacuo, the residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to afford the desired product (12) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 6.67 (d, J=8.4 Hz, 2H), 5.05 (br, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.45-2.40 (m, 1H), 1.87-1.74 (m, 1H), 1.39-1.14 (m, 5H).
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[CH:47]([O:50][C:51](=[O:55])[O:52][CH2:53]Cl)([CH3:49])[CH3:48].C(=O)([O-])[O-].[Rb+].[Rb+].CC(N(C)C)=O>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:53][O:52][C:51]([O:50][CH:47]([CH3:49])[CH3:48])=[O:55])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Reactant: CC(C)OC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Rb+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester (Example 45, 250 mg), carbonic acid chloromethyl ester isopropyl ester [CAS No. 35180-01-9] (121 mg), rubidium carbonate (73.2 mg) and DMA (10 mL) was stirred at 85° C. for 90 minutes. After cooling the mixture to room temperature, ethyl acetate and water were added thereto. The organic layer was collected, the aqueous layer was reextracted with ethyl acetate, and all the organic layers were combined. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate-methanol) to obtain the acetic acid 2-{3-[(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxyl}ethyl ester as a solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7](O)[CH2:6][C@H:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].CS(Cl)(=O)=O.O>ClCCl.C(N(CC)CC)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)C[C@H]1c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C=CC1c1ccccc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
6.0 g (17.9 mmol) of rel-(7S,9S)-10-acetyl-7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (racemic) are dissolved in 100 ml of dichloromethane and 20 ml of triethylamine. A solution of 2.9 g (25 mmol) of methanesulfonyl chloride in 5 ml of dichloromethane is then added dropwise with ice cooling in the course of 30 min. After 2 h, the mixture is hydrolyzed with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated. The residue is crystallized using diethyl ether. 4.8 g (85%) of the title compound are isolated as a slightly brown solid (m.p. 170° C.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[BH4-].[Na+].FC(F)(F)C(O)=O.O>C1COCC1>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CCN)c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in 31 mL of THF stirred at −10° C. was slowly added 710 mg (18.7 mmol) of sodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroacetic acid. The mixture was warmed to 22° C. and stirred for about 16 h. About 100 mL of water was carefully added to the mixture (gas evolution). The mixture was extracted with ethyl acetate (5×50 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give methyl 3-(2-aminoethyl)benzoate which was used in the next step without purification.
Reaction SMILES: O1CCCC1.B.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=O)[NH:13][C:12]=2[CH:19]=1.BrC1C=C2C(CCCC2=O)=CC=1.CO>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:19]=1
Reactant: O=C1CCCc2ccc(Br)cc2N1
Agent: B
Agent: O=C1CCCc2ccc(Br)cc21
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)NCCCC2
Yield: 92 %

Procedure:
Borane tetrahydrofuran complex (1 M solution in tetrahydrofuran, 21 mL, 21 mmol) was added to a solution of 8-bromo-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared from 7-bromo-3,4-dihydro-2H-naphthalen-1-one in analogy with the general procedure described in J Chem. Soc. (C) 1969, 183; 1.00 g, 4.17 mmol) in tetrahydrofuran, and the solution was heated at reflux for 2 h. After cooling, methanol (21 mL) was added, and volatile material was removed by distillation. The residue was taken up in 5% ethanolic sulfuric acid solution (12 mL) and heated at reflux for 2 h, then basified to pH 10 by addition of 2 M aq. sodium hydroxide solution and partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Chromatography (SiO2, heptane-ethyl acetate 2:1) yielded 8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (865 mg, 92%). White solid, MS (ISP) m/e 226.1 (M+H).
Reaction SMILES: NC1C=CN=CC=1.C(O[C:13]([NH:15][C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:14])(C)(C)C>>[NH:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[C:22](=[O:23])[O:24][C:13]1=[O:14]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Agent: Nc1ccncc1
Product: O=c1[nH]c2ccncc2c(=O)o1

Procedure:
The starting materials for this synthesis was 4-aminopyridine which was protected by boc group and converted to 4-tert-butoxycarbonylamino-nicotinic acid, depicted as formula 35 in Scheme 15, by ortholithiation followed by quenching with dry ice. This intermediate was reacted with trichloromethyl chloroformate to yield 1H-pyrido[4,3-d][1,3]oxazine-2,4-dione, depicted by formula 36 in Scheme 15, which was then converted to 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula 37 in Scheme 15. The reaction of 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester with piperazine-1-yl-thiophene-2-yl-methanone gave 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester, depicted by formula 38 in Scheme 15, which was reacted with corresponding alkyl halides (R—X) to yield 1-N-substituted-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl esters as shown in Scheme 15.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1>>[Br:18][CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C)c(C)nc1C
Product: Cc1nc(C)c(CBr)nc1C

Procedure:
Dehydrated tetramethylpyrazine is dissolved into an organic solvent and then NBS is added at a mole ratio of tetramethylpyrazine to NBS=1:(0.5-0.7). The reaction liquid is then refluxed to react for 10-12 h. 2-bromomethyl-3,5,6-trimethyl pyrazine is obtained as a pale-red half-oily substance after post-treatment purification.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[F:13][C:8]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Fc1ncccc1C1=CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ncccc1C1CCOCC1

Procedure:
To a round bottomed flask was added 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine (3.5962 g, 20.07 mmol) and palladium hydroxide on carbon (1.409 g, 2.007 mmol) in EtOAc (66.9 mL). The round bottomed flask was flushed with argon and then placed under vacuum three times. A hydrogen balloon was then attached to the reaction. Upon completion, the reaction was filtered through celite to produce 2-Fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine. MS (ESI, pos. ion) m/z: 182.1 (M+1).
Reaction SMILES: C1O[C:4]2([CH:8](OS(C)(=O)=O)[CH2:7][C:6]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[N:5]2[CH3:20])[O:3]C1.[I-].[Na+]>CC(C)=O>[CH3:20][N:5]1[C:6]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH2:7][CH2:8][C:4]1=[O:3]
Reactant: CN1C2(CCC(=O)CC2)CC(OS(C)(=O)=O)C12OCCO2
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN1C(=O)CCC12CCC(=O)CC2
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal (1.28 g), sodium iodide (1.8 g) and acetone (20 mL) was refluxed with stirring for 90 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with water. After drying over magnesium sulfate the solvent was removed in vacuo. The residue was dissolved in toluene (20 mL) and treated with tri-n-butyltin hydride (1.75 g) and AIBN (20 mg) and the resulting mixture was heated at 110° C. for 1 h. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. The resulting product was stirred with a mixture of water (5 mL), 3N HCl (1.5 mL) and acetic acid (2 mL) for 16 h. The resulting product was extracted 3 times with methylene chloride, washed with sodium bicarbonate solution, dried over magnesium sulfate and the solvent was removed in vacuo to afford 1 -methyl-1-azaspiro[4.5]decane-2,8-dione as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20]COC)=[CH:15][CH:14]=2)=[N:3]1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COCOCc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
2.62 g (8.05 mmol) of 4,4-dimethyl-2-(4'-methoxymethoxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (20 ml). 6N hydrochloric acid (10 ml) was added thereto, followed by stirring at 40° C. for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogen-carbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.20 g of the title compound as a crystal (yield 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
4-(4-Benzyloxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (9.51 g, 24.9 mmol) was dissolved in CH2Cl2 (150 mL) and treated with isovaleraldehyde (2.7 mL, 24.9 mmol). The reaction was stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3, allowed to warm to room temperature as the ice melted, and stir overnight. The reaction was diluted with CH2Cl2 (300 mL), washed twice with saturated sodium bicarbonate solution and once with brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 9.59 g (85%) of the desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)(=[O:4])=[O:3].P(Br)(Br)[Br:18]>C(Cl)Cl>[Br:18][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[C:13]([F:16])([F:15])[F:14]
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Yield: 80 %

Procedure:
(4-Methanesulfonyl-2-trifluoromethyl-phenyl)-methanol (4.87 mmol) was dissolved in 40 mL of CH2Cl2 and the resulting solution was treated with PBr3 (1 N, 4.87 mL) at 0° C. for 4 h. The mixture was partitioned between CH2Cl2 and water. The combined CH2Cl2 extracts were washed with brine, dried and evaporated. The residue was purified by flash column chromatography on silica gel (heptane/EtOAc 3:1 v/v) to afford white crystals (1.24 g, 80%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[ClH:14].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([Cl:1])=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A well stirred suspension 4-dimethylaminocrotonic acid hydrochloride (5.0 g, 30 mmol) in cold (0° C.) THF (40 mL) and DMF (2 pipet drops) was treated with oxalyl chloride (3.15 mL, 36 mmol). The mixture was stirred at 20-25° C. for 3 h then cooled to 0° C. and held for 30 min. The solids were collected on Buchner funnel (under a blanket of nitrogen) and washed with cold (0° C.) THF (3×5 mL). The product was dried under vacuum (˜1 torr) at 40-50 2° C. for 3 h to give 4.0 g of 4-dimethylaminocrotonoyl chloride hydrochloride. This material is characterized as its methyl ester by treatment of the solid with methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)C1CC1
Product: CC(C)(Cc1c(C(=O)C2CC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using cyclopropanecarbonyl chloride in place of trimethylacetyl chloride in Step B.