Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH:1]1([NH:7][C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: S=C(Nc1ccc(Cl)cc1)NC1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of cyclohexylamine (1.75 g.) in chloroform (15 ml.) was added dropwise with stirring a solution of p-chlorophenylisothiocyanate (3.0 g.) in chloroform (15 ml.) at room temperature. After stirring 3 hours, the white solid was filtered off, washed with a little CHCl3 and recrystallised from toluene to give 1-cyclohexyl-3-(p-chlorophenyl)thiourea, m.p. 179°-180°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>C(Cl)Cl.CN(C=O)C.C(N(CC)C(C)C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC1CCCNC1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.3 %

Procedure:
To polymer N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (0.038 g) in an Alltech™ tube was added a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino)2-oxopyrrolidin-1-yl)propanoic acid (0.007 g) in DCM (0.9 ml) followed by 3-methylpiperidine (0.0025 g) in DMF (0.1 ml) and N,N-diisopropylethylamine (0.006 ml). The mixture was shaken at room temperature for 4 days. The tube was drained, the filtrate collected and the resin washed with DCM. The combined DCM solutions were concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.0023 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][C@H:35]([NH2:38])[CH2:36][OH:37])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][C@H:35]([CH2:36][OH:37])[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:39])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC[C@H](N)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.18 g (0.49 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.122 g (0.64 mmol) of tert-butyl[(2S)-2-amino-3-hydroxypropyl]carbamate (Example 251A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.123 g (0.64 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.N1C2C(=CC=CC=2)C=[C:16]([CH2:24][OH:25])C=1.[S:26](Cl)(Cl)=O>C1C=CC=CC=1>[C:24]([S:26][CH2:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:25])[CH3:16]
Reactant: ClCc1cnc2ccccc2c1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc2ccccc2c1
Agent: Cl
Solvent: c1ccccc1
Product: CC(=O)SCc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
3-Chloromethylquinoline hydrochloride—3-Quinolylmethanol (9.85 g) was taken up in dry benzene (200 ml) and stirred followed by the addition of thionyl chloride (14.69 ml). An immediate yellow precipitate was obtained. Stirring was maintained at rt for 2 h. A light yellow solid was filtered off and dried to give the subtitle compound (13 g).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].O.[NH2:25][NH2:26].O1CCOCC1>O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH:25][NH2:26])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=S)NN)cc3)CC2)cc1
Yield: 89 %

Procedure:
A mixture of 47.8 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 100 parts of hydrazine hydrate and 400 parts of 1,4-dioxane was stirred and refluxed for 1 hour. The reaction mixture was cooled and poured into water. The precipitated product was filtered off, washed with water and methanol and dried, yielding 46 parts (89%) of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]hydrazinecarbothioamide (int. 11).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH2:16])(=[O:4])[CH3:3].[C:17]([O:20][CH2:21][C:22](O)=[O:23])(=[O:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O1CCOCC1>[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH:16][C:22](=[O:23])[CH2:21][O:20][C:17](=[O:19])[CH3:18])(=[O:4])[CH3:3]
Reactant: CC(=O)OCC(=O)O
Reactant: COC(=O)c1ccc(NC(C)=O)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(C)=O)c(NC(=O)COC(C)=O)c1
Temperature: 0 °C
Yield: 678.9 %

Procedure:
Compound 16 (0.20 g, 0.96 mmol) was dissolved in a mixture of anhydrous DMF (2 mL) and anhydrous dioxane (5 mL), and the solution was cooled to 0°-5° C. in an ice bath. To this were added acetoxy acetic acid (0.124 g, 0.129 mmol) and DCC (0.198 g, 0.210 mL, 0.960 mmol). The reaction mixture was stirred for a few minutes at 0° C., the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The solid which separated was filtered and the filtrate was concentrated to dryness on a rotary evaporator. The solid residue was triturated with 5% HCl, filtered, and washed on the filter with water. The collected solid was then triturated with 5% NaHCO3, filtered, washed with water, and dried under vacuum to give 17 (270 mg, 70.9% yield) as a white solid: mp 182°-186° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11](Br)=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH3:2].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])/[CH:16]=[CH:17]/[CH3:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]([C:17]([CH3:18])=[CH:16][C:15]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH3:2]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(=O)Nc1ccc(Br)c2c1CCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)c1ccc(NC(C)=O)c2c1CCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetylamino-7-bromoindane (2.8 g, prepared according to the method of A. Courtin, Helv. Chim. Acta 1980, 63(8), pages 2280-2286), ethyl crotonate (2.51 g), palladium diacetate (150 mg), tri-ortho-tolyl phosphine (450 mg) and tributylamine (10 mL) in dimethylformamide (30 mL) was stirred at 120° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, then allowed to stand for 48 hours, then partitioned between ethyl acetate (500 mL) and aqueous hydrochloric acid (300 mL, 1M). The organic phase was washed with 5% aqueous sodium bicarbonate (150 mL) and then filtered. The clear yellow filtrate was dried over sodium sulfate then evaporated. The residue was subjected to normal phase HPLC on silica under gradient elution conditions using ethyl acetate, heptane and methanol mixtures (from 20:80:1 to 90/10/1, v/v/v) to give the title compound (1.9 g).
Reaction SMILES: O[NH:2][CH:3]=[N:4][C:5](=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(O)(=O)C.O1CCOCC1>[C:8]1(/[CH:7]=[CH:6]/[C:5]2[O:14][N:2]=[CH:3][N:4]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)N=CNO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C(=C/c1ncno1)\c1ccccc1
Yield: 7.7 %

Procedure:
N-[(Hydroxyamino)methylene]-cinnamamide (850 mg, 4.5 mmol) was dissolved in acetic acid/dioxane (20 mL 1:1 v:v), and heated to reflux for 2 h. The cooled solution was made basic (pH 8) with K2CO3, and partitioned between ethyl acetate and water. The organics were dried over Na2SO4, and concentrated in vacuo. The resultant solids were triturated with hot ethyl acetate, and the soluble portion was purified by flash column chromatography on silica eluting with 2:1 hexane:ethyl acetate to afford 5-[(E)-2-phenylethenyl]-1,2,4-oxadiazole (60 mg, 8% yield) as a white powder. M.p. 53–55° C. 1H NMR (CDCl3, 300 MHz) δ8.43 (s, 1H), 7.85 (d, J=16 Hz, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 7.05 (d, J=16 Hz, 1H). MS (EI ionization) 171 (M+−H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][N:14]([CH2:16][CH2:17][NH2:18])[CH3:15].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][N:14]([CH3:15])[CH2:16][CH2:17][NH:18][C:1]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=2)[CH2:27][CH2:28]1)=[O:2]
Reactant: CN(C)CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of 6.3 g (0.04 mole) of 1,1'-carbonyldiimidazole in 50 ml of tetrahydrofuran (THF) was added a solution of 3.4 g (0.04 mole) of unsym-dimethylethylenediamine in 75 ml of THF and the reaction mixture was stirred at ambient temperature for 1.5 hr. A solution of 7.0 g (0.04 mole) of 1-(4-fluorophenyl)piperazine in 50 ml of THF was added and the reaction mixture was heated at reflux for 20 hr. The solution was concentrated under reduced pressure and the residue was dissolved in 150 ml of benzene. The solution was washed thrice with 50 ml portions of water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which solidified. After trituration with petroleum ether (30°-60° C.), the collected solid was recrystallized from isopropyl alcohol/hexane to yield 7.8 g (68%) of title compound as a crystalline, white solid, m.p. 99°-101° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]1([N:29]=[C:30]=[S:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[S:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: S=C=NC1CCCCC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)NC1CCCCC1
Yield: 60 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was-reacted with cyclohexyl isothiocyanate (794 mg, 5.62 mmol) to provide 1.35 g of N-(3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylthiourea as a tan powder, m.p. 199–200° C. Analysis: Calculated for C23H32N6OS: % C, 62.70; % H, 7.32; % N, 19.07; Found: % C, 62.37; % H, 7.20; % N, 18.70.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH3:38]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Light yellow solid. MS (ISP) 538.1 [(M−H)−]; mp 259° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cnccn1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cnccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 117 mg of (2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.24 (s, 9H), 7.38 (dm, 2H, J=6.8 Hz), 7.50 (dd, 1H, J=9.2 Hz, 1.6 Hz), 7.70 (m, 2H), 7.76 (m,1H), 7.80 (m,1H), 8.62 (m,1H), 8.77 (m,1H), 9,06 (m,1H), 10.37 (s, 1H). MS: m/z 430.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:10]1[C:15]([O:17][CH3:18])=[O:16])=[O:8])=[O:4].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C:12]2([O:24][CH2:23][CH2:22][O:14]2)[CH2:13]1)=[O:8])=[O:4]
Reactant: OCCO
Reactant: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OC)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OC)OCCO2)C(C)C
Temperature: 110 °C
Yield: 41.7 %

Procedure:
In a 50 mL round-bottomed flask, (S)-methyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate (230 mg, 766 μmol, Eq: 1.00) and ethane-1,2-diol (238 mg, 214 μl, 3.83 mmol, Eq: 5) were combined with toluene (15 ml) to give a colorless solution. p-toluenesulfonic acid monohydrate (29.1 mg, 153 μmol) was added and the reaction mixture was heated to 110° C. with a Dean-Stark apparatus for 20 hr. After cooling, it was diluted with EtOAc (50 ml), washed with NaHCO3 (sat solution, 200 ml), dried and concentrated in vacuo. The crude mixture was purified on a silica gel column (CH2Cl2, 20%, 30%, 40% and 60% EtOAc/CH2Cl2) to afford (S)-methyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate as an oil (110 mg, 41.7%). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 0.95 (d, J=6.78 Hz, 8H) 1.05 (d, J=6.78 Hz, 7H) 1.57 (s, 2H) 2.22 (dd, J=13.18, 6.90 Hz, 3H) 2.37 (dd, J=13.05, 8.78 Hz, 2H) 3.62-3.70 (m, 11H) 3.71-3.87 (m, 10H) 3.93-4.03 (m, 11H) 4.25 (d, J=2.76 Hz, 4H) 4.59-4.78 (m, 2H) 5.23-5.51 (m, 2H) 5.26-5.51 (m, 2H)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][C:11]=1[CH3:12].[OH-].[Na+].CN([CH:18]=[O:19])C>O>[CH3:12][C:11]1[CH:10]=[C:9]([CH:18]=[O:19])[O:8][C:7]=1[CH3:6]
Reactant: CN(C)C=O
Reactant: Cc1ccoc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C=O)oc1C
Reaction time: 3 h
Yield: 76 %

Procedure:
According to the procedure of S. F. Martin, et al. J. Org. Chem. 1984, 49, 2512-2516, phosphorus oxychloride (10.7 mL, 114.4 mmol) was added dropwise to a stirred, ambient temperature solution of 2,3-dimethylfuran (10 g, 104 mmol) in DMF (150 mL) under a dry nitrogen atmosphere over a period of 30 min. After 3 h., the reaction mixture was hydrolized with 2.5 N aq. sodium hydroxide and further diluted with water (50 mL). Aqueous mixture was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were washed with water, dried with brine and purified by silica gel flash chromatography (eluent: ethyl acetate) to provide a yellow oil (9.8 g, 76%); MS (ESI): [M+H]+, 125.1.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH:48]2[CH2:50][CH2:49]2)[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH:48]2[CH2:49][CH2:50]2)[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C2CC2)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C2CC2)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (12 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-2-cyclopropyl-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (12 mL), N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized from dichloromethane and diisopropyl ether to give the title compound (0.70 g, 83%) as a colorless solid.
Reaction SMILES: C([Li])CCC.CCCCCC.CCOCC.[CH:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Br:31]Br>O>[Br:31][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: C#CCCCCCCCCCCCC
Reactant: BrBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCC#CBr
Yield: 80 %

Procedure:
A 250 ml, three-necked, round bottom flask was fitted with mechanical stirrer, thermometer, addition funnel and means for providing nitrogen atmosphere. To the flask was added 41 ml (0.10 mole) of 2.4 M butyl lithium/hexane solution and 40 ml of anhydrous ether. The resulting mixture was stirred vigorously and 17.2 g (0.090 mole) of tetradecyne was added over a period of 25 min at -10° C. After stirring at -10° to -15° C. for an additional 35 min, the reaction mixture was cooled in a Dry Ice/acetone bath. About 16.0 g (0.10 mole) of bromine was added dropwise over a period of 90 min at -60° C. to -68° C. After stirring at -40° C. for an additional 40 min, the reaction mixture was poured into 100 ml of water. The resulting mixture was extracted twice with 50 ml portions of ether. The combined ethereal layers were washed twice with 50 ml portions of sodium bicarbonate solution, dried, and concentrated, resulting in 21.9 g (80% yield) of light yellow liquid. I.R. (film/neat) in cm-1 : 2230 (C≡C), 1470 (CH2), 720 [--(CH2)n --, n≥4].
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>O.O1CCOCC1>[CH2:12]([O:19][C:20]([C:22]1([NH:27][S:48]([C:45]2[CH:44]=[CH:43][C:42]([C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:47][CH:46]=2)(=[O:49])=[O:50])[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-aminocyclopentanecarboxylic acid benzyl ester p-toluenesulfonic acid salt (12.1 grams, 30.9 mmol) and triethylamine (10.0 mL, 72 mmol) in water (150 mL) and 1,4-dioxane (150 mL) was added 4'-fluorobiphenyl-4-sulfonyl chloride (8.8 grams, 32.5 mmol). The mixture was stirred at room temperature for 16 hours and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed successively with dilute hydrochloric acid solution, water, and brine. The solution was dried over magnesium sulfate and concentrated to leave 1-(4'-fluorobiphenyl-4-sulfonylamino)cyclopentanecarboxylic acid benzyl ester as a solid, 12.33 grams (76%).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:25][CH2:24]4)=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:24][CH2:25]4)=[CH:13][C:14]([CH:21]=[O:30])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(C2CC2)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-vinylbenzoate (0.22 g) in a mixed solvent of acetone (4.40 ml)-acetonitrile (4.40 mL)-water (4.40 mL) were added osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.65 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.22 g) as a crude product. This compound was used in the next step without an additional purification.