Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH3:33][O:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:38]2[CH2:39][CH2:40][CH:35]([O:34][CH3:33])[CH2:36][CH2:37]2)=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: COC1CCNCC1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cc(OCC(=O)N2CCC(OC)CC2)c2ccc(C)cc2n1

Procedure:
To a solution of 1000 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 956 mg pentafluorophenol and 994 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. 4-methoxypiperidine (379 mg) was mixed with 1.3 ml N-ethylmorpholine and 10 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 980 mg.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[O:30])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]>C(O)C.O.C(OCC)C>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C@@H:4]([C:3]([OH:39])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[S:7])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CS(=O)(=O)CCCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 22 h
Yield: 70.2 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl] cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (25.86 mmol, 15.87 g) in ethanol (75 mL) was added aqueous 1. ON sodium hydroxide (60 mL) at 50° C. The mixture was heated to 50-55° C. and the resulting clear light brown solution was stirred for 22 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water and allowed to cool to room temperature and was filtered to remove a small amount of solids. The filtrate was concentrated and the residual aqueous solution was washed with diethyl ether (2×75 mL). The basic aqueous layer was acidified with 3.ON HCl to form a cloudy suspension and was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (200 mL) then the dried (MgSO4) solution was filtered and evaporated to dryness. The residue was taken up in dichloromethane and diluted with diethyl ether:hexane (1:1) to obtain a solid which was collected by filtration. Trituration of the solid with hot ethyl acetate (˜100 mL) resulted in a suspension that was then diluted with diethyl ether (˜50 mL) and the solid was collected by filtration. The above Trituration was repeated to afford 10.89 g (70%) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine as a colorless solid. HR MS: Obs. mass, 599.1193. Calcd. mass, 599.1208 (M+H).
Reaction SMILES: CCN(CC)CC.[NH:8]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:36])([F:35])[F:34])=[CH:16][N:15]=2)[CH:10]=[N:9]1>CN(C=O)C.CCOC(C)=O.[Pd]>[NH:8]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:35])([F:34])[F:36])=[CH:16][N:15]=2)[CH:10]=[N:9]1
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cn[nH]c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cn[nH]c2)ncc1C(F)(F)F
Reaction time: 16 h
Yield: 26 %

Procedure:
Et3N (0.5 mL) was added to 2-(2-((2-((1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)propanamide A63 (0.211 g, 0.527 mmol) and 10% Pd/C (0.155 g) in DMF (4 mL) and EtOAc (16 mL) and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered through Celite, concentrated under reduced pressure and purified using silica gel column chromatography (80-100% EtOAc in petroleum benzine 40-60° C. then 0-10% MeOH in EtOAc). The resulting product was further triturated with a mixture of Et2O and acetone and the precipitate was collected by vacuum filtration to give the title compound 54 (0.055 g, 26%). LCMS-D: rt 3.178 min; m/z 405.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[N:5]([CH3:15])[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][C:9]([CH3:14])=[CH:8][CH:7]=2)=[O:3].[Na].[C:17](OCC)(=O)[C:18]([O:20]CC)=[O:19].[Na][Na]>C(O)C>[CH3:15][N:5]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][C:11]=2[C:12]2[O:13][C:17]([C:18]([OH:20])=[O:19])=[CH:1][C:2](=[O:3])[C:4]1=2
Reactant: CC(=O)c1c(O)c2cc(C)ccc2n1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Agent: [Na][Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1oc(C(=O)O)cc(=O)c1n2C

Procedure:
In a manner analogous to that of Example 14, 8.2 g (0.040 mole) of 1,5-dimethyl-3-hydroxy-1H-indol-2-yl methyl ketone (Example 12) was reacted with sodium metal (3.7 g, 0.16 mole) and diethyl oxalate (21.5 g, 0.20 mole) in 200 ml absolute ethanol. The red disodium salt intermediate was then converted to the title compound as described in Example 17. Two recrystallizations of the final product from DMF-water yielded yellow needles of mpt. 290°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1416 g, 0.70 mmol) is added to a slurry of pentane-washed NaH (0.0400 g, 0.0010 mol) in DMF (2 mL) and after stirring for 30 min, p-fluorobenzyl bromide (0.11 mL, 0.88 mmol) is added. After the mixture had stirred for 2.3 h, it is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (100 mL) using first dichloromethane (100%) and then methanol/dichloromethane (2/98). The product fractions are combined and rechromatographed on silica gel (50 mL) using acetone/heptane/NH4OH (15/85/0.25) and then recrystallized using ethyl acetate/hexane to give 0.0932 g (43%) of the title compound; mp 177-178° C.; MS (ESI−) for C19H15F2NO m/z 310.1 (M−H)−; IR (drift) 1638, 1630, 1509, 1496, 1459, 1436, 1413, 1361, 1249, 1222, 1194, 1158, 1125, 830, 790 cm−1; 1H NMR (CDCl3) δ2.24, 2.58, 2.86, 5.47, 6.89-7.02, 7.16, 8.06. Anal. Calcd for C19H15F2NO: C, 73.30; H, 4.86; N, 4.50. Found: C, 73.40; H, 4.83; N, 4.50.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[O:4][CH2:1][CH2:2][O:3]2)=[N:21][CH:22]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.9 %

Procedure:
Ethyleneglycol (14.88 g, 0.24 mol) and p-toluenesulfonic acid (3 g, 0.16 mol) are added to a solution of 5-bromopyridine-2-carbaldehyde (30 g, 0.16 mol) in toluene (150 ml) at room temperature and the mixture is stirred for 10 hrs at refluxing temperature. After cooling to room temperature, the mixture is quenched with saturated aqueous NH4Cl, extracted with CH2Cl2 and washed with H2O. The aqueous layer is extracted with CH2Cl2 and the combined organic extract is washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane-AcOEt (9:1 VAT)) to afford 5-bromo-2-(1,3-dioxolan-2-yl)pyridine (30.9 g, 84%) as a colorless oil). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.87 (m, 1H), 7.45 (m, 1H), 5.83 (s, 1H), 4.13 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:28])=[C:18]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:31])C>[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:28])=[C:18]([CH2:20][C:21]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[O:31])[N:19]=2)=[CH:11][CH:10]=1
Reactant: CCO
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCN1CCC[C@H]1C
Agent: [Pd]
Product: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of 2-(4-Benzyloxy-phenyl)-5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (See Example 55) (0.48 g, 1.3 mmol) and 5% Pd/C (0.046 g) in absolute ethanol (25 mL) is shaken under a hydrogen atmosphere (65 psi) for 18 h. The mixture is filtered and concentrated to provide the title compound (0.35 g, 94%) as a yellow oil, which was used without purification. MS (m/e): 287.3 (M+1)
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH:23](OCC)[O:24]CC)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3].ClCCl.[BH4-].[Na+]>C1COCC1>[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH2:23][OH:24])[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc2c(-c3cc(OCCO)c(Cl)cc3Cl)nc(N)nc2s1
Reaction time: 18 h

Procedure:
Hydrochloric acid was added to a solution of 2-Amino-4-(2,4-dichloro-5-(2,2-diethoxyethoxy)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in THF and the solution stirred for ˜18 hrs. Dichloromethane was added and the mixture stirred, sodium borohydride was added and the resulting suspension stirred for ˜5 hrs. Dichloromethane was added and the mixture washed with saturated ammonium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude product was purified by preparative HPLC, to give the product as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=O)[N:5]=[CH:4]1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=[S:16])[N:5]=[CH:4]1)[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1nc2c([nH]1)c(=O)ncn2CC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)c(=S)ncn2CC
Yield: 63.7 %

Procedure:
The product of stage (i) (8.65 g) and phosphorus pentasulfide (12.0 g) was refluxed in 150 ml of pyridine for 1 hr. Under cooling 59.4 ml of 2N NaOH was added dropwise, the solid filtered off and washed with water. The filtrate was concentrated in vacuo to dryness and the residue suspended in 200 ml of water and collected. The filtrate was extracted three times with 600 ml of chloroform. The residue of the organic phase was combined with the solid collected (total 6.08 g), dissolved in 500 ml of chloroform and filtered through 24 g of silicagel. Fractions 2 and 3 eluted 4.63 g of crude product which was crystallized from 120 ml of methanol to give 3,8-diethyl-6-thiohypoxanthine (3.58 g) with mp (sublimation at 210° C.) 250-270° C. under decomposition A second crop gave 0.58 g.
Reaction SMILES: [NH2:1]C1C2C(=CC=CC=2)C(O)=C(C(NCCCCOC2C=CC(C(CC)(C)C)=CC=2C(CC)(C)C)=O)C=1.[C:37]([NH:40][C:41]1[C:50]2[C:45](=[C:46]([N:52]=[N:53][C:54]3[CH:59]=[CH:58][C:57]([S:60]([Cl:63])(=[O:62])=[O:61])=[CH:56][CH:55]=3)[CH:47]=[CH:48][C:49]=2[OH:51])[C:44]([S:64]([Cl:67])(=[O:66])=[O:65])=[CH:43][CH:42]=1)(=[O:39])[CH3:38].Cl.[C:69]([NH:72][C:73]1[C:82]2[C:77](=[CH:78][CH:79]=[C:80](N=NC3C=CC(S(=O)(=O)N)=CC=3)[C:81]=2[OH:83])[C:76]([S:96]([O-:99])(=[O:98])=[O:97])=[CH:75][CH:74]=1)(=[O:71])[CH3:70].[Na+:100].ClS(O)(=O)=O>N1C=CC=CC=1>[C:37]([NH:40][C:41]1[C:50]2[C:45](=[C:46]([N:52]=[N:53][C:54]3[CH:55]=[CH:56][C:57]([S:60]([Cl:63])(=[O:61])=[O:62])=[CH:58][CH:59]=3)[CH:47]=[CH:48][C:49]=2[OH:51])[C:44]([S:64]([Cl:67])(=[O:65])=[O:66])=[CH:43][CH:42]=1)(=[O:39])[CH3:38].[C:69]([NH:72][C:73]1[C:82]2[C:77](=[C:78]([N:52]=[N:53][C:54]3[CH:59]=[CH:58][C:57]([S:60](=[O:62])(=[O:61])[NH2:1])=[CH:56][CH:55]=3)[CH:79]=[CH:80][C:81]=2[OH:83])[C:76]([S:96]([O-:99])(=[O:97])=[O:98])=[CH:75][CH:74]=1)(=[O:71])[CH3:70].[Na+:100]
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)[O-])c2ccc(N=Nc3ccc(S(N)(=O)=O)cc3)c(O)c12
Agent: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2c(N=Nc3ccc(S(=O)(=O)Cl)cc3)ccc(O)c12
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)[O-])c2c(N=Nc3ccc(S(N)(=O)=O)cc3)ccc(O)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1.95 g. (0.004 mol) of 4-amino-N-[4-(2,4-di-tert-pentylphenoxy)butyl]-1-hydroxy-2-naphthamide in 50 ml. of dry pyridine at 0° C., under nitrogen, was added 1.95 g. (0.004 mol) of 4-acetamido-8-(4-chlorosulfonylphenylazo)-5-hydroxy-1-naphthalenesulfonyl chloride. The solution was stirred at 0° C. for one hour, poured into 75 ml. of concentrated hydrochloric acid and 75 ml. of ice. The solid was collected on a filter funnel and dried. It was then chromatographed on a silica column, eluting with ethyl acetate to remove the product. The eluents were concentrated to dryness and the resulting solid reprecipitated from chloroform with hexane. The solid was collected on a filter funnel and dried to yield 1.1 g. (39%), m.p. 220°-2° C. dec. The 4-acetamido-8-(4-chlorosulfonylphenylazo)-5-hydroxy-1-naphthalenesulfonyl chloride was prepared by heating a solution of 9.7 g. (0.02 mol) of sodium 4-acetamido-5 -hydroxy-6-(4-sulfamoylphenylazo)-1-naphthalenesulfonate in 150 ml. of chlorosulfonic acid on a steam bath for ninety minutes. The solution was cooled and poured onto ice. The solid was collected on a filter funnel and dried to yield 9.4 g. (94%). The sodium 4-acetamido-5-hydroxy-8-(4-sulfamoylphenylazo)-1-naphthalenesulfonate was prepared as in Example 1.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:15][C:16](Cl)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[F:20][C:21]([F:46])([F:45])[C:22]1[CH:23]=[C:24]([S:32]([NH:35][C:36]2[S:37][C:38]3[CH2:39][NH2+:40][CH2:41][CH2:42][C:43]=3[N:44]=2)(=[O:34])=[O:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH:10]1([CH2:15][C:16]([N:40]2[CH2:41][CH2:42][C:43]3[N:44]=[C:36]([NH:35][S:32]([C:24]4[CH:23]=[C:22]([C:21]([F:20])([F:45])[F:46])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=4)(=[O:34])=[O:33])[S:37][C:38]=3[CH2:39]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=S(=O)(Nc1nc2c(s1)C[NH2+]CC2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)CC1CCCC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCCC1)N1CCc2nc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)sc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIEA and cyclopentyl-acetyl chloride are added at 0° to a mixture of 75 mg of 2-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-5-ium hydrochloride salt in CH2Cl2. The mixture obtained is stirred at RT for 4 hours, 2 ml of 1 M aqueous NaHSO4 solution are added and two phases formed are separated. The organic layer obtained is concentrated and subjected to preparative HPLC (RP-18). N-[5-(2-Cyclo-pentyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-3,5-bis-trifluoromethyl-benzene-sulfonamide is obtained.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([O:17][S:18]([OH:21])(=[O:20])=[O:19])[C:10]1=[O:22])=O)(C)(C)C.[K].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]1[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([O:17][S:18]([OH:21])(=[O:19])=[O:20])[C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(OS(=O)(=O)O)C12CCCC2
Agent: [K]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1C(=O)N(OS(=O)(=O)O)C12CCCC2
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
3[(t-Butoxycarbonyl)amino]-2-oxo-1-(sulfooxy)-1-azaspiro[3.4]octane, monopotassium salt (280 mg, 0.75 mmoles) was covered with 2 ml of dry dichloromethane, 0.8 ml of anisole was added, and the mixture cooled to -10° C. Trifluoroacetic acid (3 ml) was added, and the solution was stirred at -10° to -5° C. for 1.5 hours. After 0.75 hours a solid formed, becoming quite substantial by 1.5 hours. The volatiles were evaporated in vacuo and the solid residue triturated with ether to give 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.4]octane.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)n[nH]c12
Yield: 59 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with 4-fluorophenyl sulfonyl chloride (0.033 g, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.048 g of white solid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10]C(C)=O>>[CH:1]1([C:7]([CH3:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)=O
Reactant: O=C(O)C1CCCCC1
Product: CC(=O)C1CCCCC1

Procedure:
Using the apparatus, catalyst and method of Examples 16-18, cyclohexane carboxylic acid and acetone in a molar ratio of 1:2.76 was introduced into the system after purging with acetone. Methyl cyclohexyl ketone was produced and identified as in Examples 16-18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[F:20][C:21]([F:40])([F:39])[C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][N:31]=[C:30](Cl)[CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][C:21]([F:20])([F:40])[C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[C:28]1[CH:29]=[CH:30][N:31]=[C:32]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:17]([O-:19])=[O:18])[CH:33]=1
Reactant: CC1(C)OB(c2cc(F)ccc2[N+](=O)[O-])OC1(C)C
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Into a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(5-fluoro-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.8 g, 44.19 mmol, 3.00 equiv) in 330 mL of 10:1 DME/H2O, N-(3-(trifluoromethyl)benzyl)-2-chloroisonicotinamide (5 g, 15.92 mmol, 1.00 equiv), Pd(PPh3)2Cl2 (2.54 g, 3.62 mmol, 0.20 equiv), X-PHOS (2.5 g, 6.36 mmol, 0.20 equiv), and K3PO4 (20 g, 59.17 mmol, 4.00 equiv). The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5˜1). The product was obtained as 2 g (27%) of a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([NH:18][OH:19])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([N+:18]([O-:19])=[CH: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)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NO
Reactant: O=CCCCCCc1ccccc1
Solvent: CO
Product: CC(C)(C)[N+]([O-])=CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
To a solution of 6-phenyl 1-hexanal (4.93 g, 28.0 mmol, 1 equiv) in methanol (50 ml) was added N-tert-butylhydroxylamine (3.00 g, 33.6 mmol, 1.2 equiv), and the mixture was stirred at rt. for 4 h. Concentration of the mixture gave a light colored oil which was purified by flash chromatography (EtOAc) to give N-tert-butyl-C-(5-phenylpentyl)nitrone (4.39 g, 89.0%) as a colorless oil: 1H NMR (CD3OD) δ 7.28–7.11 (m, 6H), 2.66–2.24 (m, 4H,), 1.72–1.24 (m, 15H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15]I.CCCCCCC>C(#N)C>[Cl:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCI
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3-(3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.