Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: Nn1cccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 15 g of sodium bicarbonate and 9.2 g of (N-amino)pyrrole in 50 ml of dichloromethane was treated over a period of fifteen minutes with 11.4 ml of ethyl chloroformate. The reaction mixture was then stirred at ambient temperature for four hours and filtered. The filtrate was washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Concentration afforded 17 g of N-(1H-pyrrol-1-yl)carbamic acid ethyl ester, m.p. 60°-61° C.; MS(EI)M+ @154(100%); IR(CHCl3)--NH @ 3430 cm1, C=O @ 1755 cm-1.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H][H]>C1COCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Fc1ncccc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: C1CCOC1
Product: Fc1ncccc1C1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of 2-fluoro-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (7.99 g, 34.0 mmol) in THF (40 mL) under argon atmosphere was added palladium on carbon (10% activated, 0.80 g). The mixture was placed under 1 atmosphere of hydrogen and stirred for 5 h at 40° C. After placing the mixture back under argon atmosphere, the mixture was filtered through celite and the filtrate was concentrated in vacuo to give 2-fluoro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine MS (ESI, pos. ion) m/z: 238.1.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)N(NCCCCCC(O)=[O:28])C(=O)C=C1>CN(C=O)C>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:28])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCCCCNN1C(=O)C=CC1=O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One equivalent (2.24 g, 0.01 mole) of HNSA was mixed together - with one equivalent (2.06 g, 0.01 mole) of dicyclohexylcarbodiimide and one equivalent (2.10 g, 0.01 mole) of N-maleimido-6-aminocaproic acid in 25 ml of DMF at room temperature overnight. A white precipitate of dicyclohexyl urea was formed. The precipitate was filtered and 300 ml diethyl ether was added to the mother liquor. After about 10 minutes to four hours a gummy solid that precipitated from the mother liquor was formed. This solid was found to contain 58% of active HNSA ester and 42% of free HNSA by the analysis described above. The product was positively identified as mal-sac-HNSA ester by its reactivity with amines. The yield of the pure ester was estimated to be approximately 30% of theoretical; the purified material consisted of 99% ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24][CH3:25])=[O:23])=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: COC(=O)c1ccccc1S
Product: COC(=O)c1ccccc1SC1=C/C(=C2/C(=O)NN=C2C)Nc2ccccc21

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and methyl 2-mercaptobenzoate using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.88 (s, 3H) 6.77 (s, 1H) 7.50-7.72 (m, 3H) 7.76-7.92 (m, 3H) 7.96 (d, J=8.12 Hz, 1H) 8.16 (d, J=8.18 Hz, 1H) 10.39 (s, 1H) 13.20 (bs, 1H); ESI-MS: m/z calc'd for C21H17N3O3S 391.10. found 392.3 (M+H)+.
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:24])[C:8](=O)[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22])CCC.Cl.[NH2:26][OH:27].C(N(CC)CC)C>C(O)C>[OH:5][C:6]1[C:7](=[O:24])[C:8](=[N:26][OH:27])[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22]
Reactant: CCCCOc1c(C=C2N(C)c3ccccc3C2(C)C)c(=O)c1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1C(=Cc2c(O)c(=O)c2=NO)C(C)(C)c2ccccc21

Procedure:
A mixture of 200 mg (0.61 mmol)of 3-butoxy-4-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-3-cyclobutene-1,2-dione (18), 50 mg (0.72 mmol) of hydroxylamine hydrochloride and 90 μl (0.64 mmol) of triethylamine is stirring in 8 ml of absolute ethanol at room temperature for 1 h and 30 min at 40° C. The solvent is removed under reduced pressure by a rotary evaporator. The obtained residue is column purified (Silica gel 60, 0–10% methanol-chloroform) to give 2-hydroxy-4-hydroxyimino-3-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-2-cyclobuten-1-one (19a) as an yellow solid. Yield: 80 mg (46%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].[O:13]=[S:14]1(=[O:26])[CH2:18][CH2:17][CH2:16][N:15]1[CH2:19][CH2:20]OS(C)(=O)=O>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:20][CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][S:14]2(=[O:26])=[O:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CS(=O)(=O)OCCN1CCCS1(=O)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OCCN2CCCS2(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3,5-dimethylphenol (1.25 g, 6.17 mmol) and sodium hydride (60% on mineral oil, 160 mg, 3.95 mmol) are suspended in dry N,N-dimethylacetate (25 mL) and stirred for 30 minutes at room temperature. Methanesulfonic acid 2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl ester (Patent EP1479684 A1, 600 mg, 2.47 mmol;) is added and the mixture stirred at 80° C. for 5 hours. The mixture is concentrated under vacuum, diluted with water and extracted with ethyl acetate. The organic phase is dried and the solvent removed. The residue is purified by flash chromatography (0-50% ethyl acetate in cyclohexane) to give the title compound. (Yield: 350 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:14][C:12]([O:11][CH3:10])=[O:13]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (2.44 g) in toluene (25 ml) was added methoxycarbonylmethylene-triphenylphosphorane (6.68 g) and the mixture was stirred for 3 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with ethyl acetate - n-hexane (1:1)] to give methyl 3-(2-hydroxyphenyl)acrylate (2.47 g).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:22])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:19][CH2:20][Cl:21])[CH2:16][CH2:17][Cl:18])=[CH:11][CH:10]=1)[NH2:7]>>[Cl:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][Cl:21])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@@H:6]([C:5]([OH:22])=[O:4])[NH2:7])=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Product: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Temperature: 0 °C

Procedure:
Concentrated hydrochloric acid (425 ml, 5 volume) was added to the crude 4-[bis(2-chloroethyl)-amino]-L-phenylalanine methyl ester hydrochloride (III) obtained in Example 1 and the reaction mixture was heated at 80° C. to 85° C. After completion of the reaction, as monitored by HPLC, the mixture was treated with activated carbon and filtered through hyflo bed. The filtrate was cooled to 0° C. and the pH of the filtrate was adjusted to pH 6.0 by addition of aqueous ammonia solution (450 ml). The product was filtered, washed with water and the wet 4-[bis(2-chloroethyl)-amino]-L-phenylalanine free base (IV) was used as such for preparation of the hydrochloride salt.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCOCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:15]#[N:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)O)cc1C#N
Temperature: 60 °C
Yield: 97.8 %

Procedure:
A mixture of methyl 4-tert-butyl-3-cyano-benzoate (380 mg, 1.75 mmol), LiOH (3.5 mL of 2.0 M, 7.0 mmol) and 1,4-dioxane (3.5 mL) was heated at 60° C. for 2 h. The reaction mixture was made acidic and was washed with dichloromethane (2×8 mL). The organics were combined, dried over sodium sulfate and evaporated to dryness to give 4-tert-butyl-3-cyanobenzoic acid (348 mg, 98%). 1H NMR (400 MHz, CD3CN) δ 9.77 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.17 (dd, J=8.4, 1.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:5][CH2:4][C:2](=[O:3])[CH3:1]
Reactant: C=CC(C)=O
Reactant: c1ccoc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CCc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
Methylvinylketone (14 g, 0.2 mol) was added dropwise over a period of about 2 hours to furan (150 ml), containing a trace of p-toluene-sulphonic acid, boiling under reflux. The dark brown reaction mixture was stirred for about 16 hours at room temperature. The excess furan was removed by distillation, after which the residue was distilled under vacuum giving 4-(2-furyl)butan-2-one (18.5 g, 67% yield). In a way analogous to that described in Example II, the ketone was reduced to the corresponding alcohol and subsequently converted to the mesylate (28 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([CH3:18])[C:11]=2/[C:10](=[N:24]/[NH:23][C:20]([NH2:22])=[NH:21])/[CH2:9]1
Reactant: Cc1ncnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ncnc2c1/C(=N/NC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 141.9 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinazolin-5-one (40 mg) and aminoguanidine hydrochloride (16 mg) were added ethanol (3 ml) and 6N hydrochloric acid (0.025 ml), and the mixture was stirred at 90° C. for 3 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinazoline hydrochloride (Compound 89) (38 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]>>[CH3:16][O:17][C:18]([CH:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: COC(=O)C1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C

Procedure:
Intermediate 1 was coupled with piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 447.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([N:21]2[CH2:20][CH2:19][CH:18]([O:17][C:15]3[S:16][C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[N:14]=3)[CH2:23][CH2:22]2)[CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(N2CCC(Oc3nc4c(s3)CNCC4)CC2)C1
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (2.0 grams, 5 mmol, obtained in above step) in dichloromethane (30 mL) was treated with trifluroacetic acid (5.0 mL, 50 mmol) at 0° C. Reaction mass was stirred for 4 hours. After completion of reaction, the reaction mass was quenched into ice cold water and adjust pH to 10, by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3×50 mL), combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum to obtain the title compound (1.3 grams).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:11][CH2:12][C:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[CH:14][C:15](OCC)=[O:16])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8]>C(#N)C>[CH3:1][O:2][C:3](=[O:28])[CH:4]([N:11]1[CH2:12][C:13]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:14][C:15]1=[O:16])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=O)C=C(CNC(CCC(F)(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 180 °C
Yield: 71.4 %

Procedure:
A solution of 2-[2-(2-chloro-phenoxy)-3-ethoxycarbonyl-allylamino]-5,5,5-trifluoro-pentanoic acid methyl ester (1.43 g, 3.78 mmol) in acetonitrile (4 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 180° C. for 3 h. The mixture was then cooled and concentrated in vacuo with silica gel (3 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid methyl ester (1.02 g, 50% over two steps) as a an amber oil: HR-ES-MS m/z calculated for C16H15NO4ClF3 [M+H]+ 378.0715, observed 378.0716.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH:28][C:29](=[O:42])[C@H:30]([C:35]([S:38]([CH3:41])(=[O:40])=[O:39])([CH3:37])[CH3:36])[NH:31][C:32](=[S:34])[NH2:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][CH:46]=O>C(O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH:28][C:29](=[O:42])[C@H:30]([C:35]([S:38]([CH3:41])(=[O:40])=[O:39])([CH3:37])[CH3:36])[NH:31][C:32]1[S:34][CH:45]=[CH:46][N:33]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=CCCl
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(N)=S)C(C)(C)S(C)(=O)=O
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Nc1nccs1)C(C)(C)S(C)(=O)=O
Yield: 38 %

Procedure:
A stirred solution of 255 mg (0.4 mmol) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(thiocarbamoyl)-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide in 5 ml of ethanol was treated with 0.1 ml of chloroacetaldehyde (50% solution in water) and heated at reflux for 4 hours. The volatiles were evaporated and the residue partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane and the combined organic phase was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a solid which was chromatographed on silica eluting with dichloromethane/methanol (19:1) to give 100 mg (38%) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(2-thiazolyl)-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide as a white solid, [M+H]+ 662.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(Cl)cc23)CC1

Procedure:
(23.0 mg, 65%); from 5-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5e, 25 mg, 0.10 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), HRMS-FAB+ for C21H21N2OCl, calculated MH+ : 353.14206; found: 353.14033.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[NH:6]2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[C:13]([F:14])([F:15])[F:16])[N:30]=2)[CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1Cl
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C(F)(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1Cl

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 228B) and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.51 (s, 1H), 8.03-7.95 (m, 1H), 7.94-7.86 (m, 1H), 7.52 (s, 1H), 5.99 (s, 2H); MS (ES) m/z 539 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]([CH3:37])[S:35][CH:36]=2)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])C1C=CC=CC=1>C(O)C.[Pd]>[F:27][C:24]([F:25])([F:26])[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:32]3[N:33]=[C:34]([CH3:37])[S:35][CH:36]=3)[CH:30]=[CH:31][C:9]=2[OH:8])[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1
Reactant: Cc1nc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2ccc(O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Reaction time: 3.5 h
Yield: 77.2 %

Procedure:
2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide (160 mg, 0.3 mmol) and 10% Pd—C (240 mg) were dissolved in ethanol (10 ml) and stirred for 3.5 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (103.4 mg, 79.2%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][CH:4]=[CH2:5].C([O-])(=O)C.[Na+].Br[C:13]1[C:14]([NH:16][C:17](=[O:19])[CH:18]=1)=[O:15]>CO>[CH2:2]([NH:6][C:13]1[C:14]([NH:16][C:17](=[O:19])[CH:18]=1)=[O:15])[CH2:3][CH:4]=[CH2:5]
Reactant: O=C1C=C(Br)C(=O)N1
Reactant: C=CCCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCCNC1=CC(=O)NC1=O
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To 3-butenylamine hydrochloride (200 mg, 1.12 mmol) and sodium acetate (184 mg, 2.24 mmol) in methanol (15 mL) was added bromomaleimide (200 mg, 1.12 mmol) dropwise in methanol (15 mL). After 10 minutes, solvent was removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow waxy solid (142 mg, 0.85 mmol) in 76% yield. δH (500 MHz, CDCl3) 7.10 (s, 1H, NH), 5.77 (tdd, 1H, J=6.9, 10.7 and 17.4, H-2), 5.38 (s, 1H, NH), 5.18-5.15 (m, 2H, H2-1), 4.83 (d, 1H, J=1.3, H-6), 3.24 (t, 2H, J=6.7, H2-4), 2.40 (dtd, 2H, J=1.2, 6.8 and 6.9, H2-3); δC (125 MHz, CDCl3) 171.94 (C═O), 167.45 (C═O), 149.53 (C5), 133.89 (C2), 118.51 (C1), 85.80 (C6), 43.30 (C4), 32.68 (C3); IR (solid, cm−1) 3290 (m), 1703 (m), 1629 (s); MS (ES−) m/z (relative intensity): 165 ([M−H], 100); Exact Mass Calcd for [C8H10N2O2]−H requires m/z 165.0659 Found 165.0664 (ES−); m.p. 68-76° C.; UV (Acetonitrile) ε241=8300 and ε348=6100 cm−1M−1 d3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:14][CH2:15][CH2:16][N:17]1[CH:21]=[C:20]([CH:22]=O)[CH:19]=[N:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:22][C:20]3[CH:19]=[N:18][N:17]([CH2:16][CH2:15][OH:14])[CH:21]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=Cc1cnn(CCO)c1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCCn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.789 g, 4.01 mmol) and 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.562 g, 4.01 mmol) in DCE (35 mL) add sodium triacetoxyborohydride (1.28 g, 6.02 mmol) and acetic acid (0.382 mL) and stir at room temperature for 20 hr. Add saturated aqueous sodium bicarbonate, separate the layers, extract the aqueous layer twice with DCM, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 6:94 methanol (with 2N ammonia):DCM to give the title preparation as a yellow oil (1.16 g, 90%). MS (ES): m/z=323 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].S([C:45]#[N:46])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:45]#[N:46])[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(Sc2c(C)n(C#N)c3c(F)c(Cl)ccc23)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.50 g, 1.37 mmol) in THF (10 mL) at RT was added sodium bis(trimethylsilyl)amide (0.76 mL of a 2.0M solution in THF, 1.51 mmol). After 30 minutes, tosyl cyanide (0.279 g, 1.54 mmol) was added, and the reaction was stirred for 2 hrs, then subjected to standard aqueous workup. The crude residue was purified on silica gel (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11](Cl)(=O)[CH3:12]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8][CH:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NCCc1ccc(Cl)cc1
Product: CC1NCCc2ccc(Cl)cc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 4-chlorophenethylamine and acetyl chloride, 7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 67%) The product was used in the subsequent step without further purification.