Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C1C=CC=CC=1>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:18]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:19])=[CH:11][C:10]=1[C:9]([F:8])([F:20])[F:21]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) is converted to free base by adding 5 ml. of 50% NaOH and extracting into benzene. After drying over K2CO3, the benzene solution is stirred at room temperature and 11.08 g. (0.05 mole) of 3-trifluoromethyl-4-chlorophenylisocyanate [prepared according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasski, 70 (4), 491-4 (1967)] dissolved in about 50 ml. of anhydrous benzene is added dropwise to this solution. After one-half of the amount is added cloudiness occurs and then solid precipitates. The mixture is stirred at room temperature overnight. The solid is collected, 1-(4-chloro-3-trifluoromethylphenyl)-3-(1-methyl-2-pyrrolidylidene)urea, and recrystallizations from ethyl acetate yields the pure product, m.p. = 175° C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-nitrophenyl)propenoic acid; MS (ES+) 302 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[NH2:28][OH:29]>CO>[CH3:21][C:17]1([CH3:22])[C:18]2[C:13](=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][C:4]([C:3]([NH:28][OH:29])=[O:2])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:14]([CH3:24])([CH3:23])[CH2:15][CH2:16]1
Reactant: NO
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(C(=O)NO)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-terephthalamic acid methyl ester 7 (0.20 g, 0.55 mmol) in MeOH (2 mL) was added an hydroxylamine solution (1.76 M, 2 mL) in MeOH and the reaction mixture was stirred 1 h at room temperature under magnetic stirring. The reaction mixture was adjusted to pH=5, concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was dried with Na2SO4 and the product was crystallized by dissolving the mixture at 80° C. in CH3CN to give N-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)-N′-hydroxyterephthalamide EHT 7706 (0.05 g, 25% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH:22]1[N:23]=[CH:24][N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>ClCCCl>[CH:22]1[N:23]=[C:24]([C:6]([C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: c1ccn2cncc2c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.5 g (0.053 mol) of 3-methoxy-4-nitrobenzoyl chloride and 7.8 ml (0.056 mol) of triethylamine are added to 3 g (0.025 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is concentrated under reduced pressure and the residue is then taken up in dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in dichloromethane and purified by filtration through a bed of silica gel. After evaporation, 7.1 g of a yellow solid are collected. Melting point: 183° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.35-7.40 (1H, m), 7.47-7.54 (1H, m), 7.97 (1H, s), 8.06-8.11 (3H, m), 8.15 (1H, s), 9.77 (1H, d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([CH2:22][CH3:23])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O>CCOCC>[CH3:8][CH:9]([CH2:22][CH3:23])[CH2:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCC(C)Cc1ccccc1
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Phenylmagnesium bromide-ether solution was prepared from bromobenzene (64.5g, 0.41m), magnesium turnings (9.85g, 0.41m), and anhydrous ether (500ml). The reagent was cooled and (+)-β-methylbutyl-4-toluenesulfonate (200g, 0.82m) in ether (800ml) was added in drops. When the addition was complete, the reaction mixture was stirred for two hours, refluxed for two hours and left to stand overnight. Aqueous sulfuric acid was added until a clear solution was formed. The layers were separated. The aqueous layer was extracted with ether (3×250ml), and the combined organic layers were washed with sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was steam-distilled. Fractional distillation of the crude product at reduced pressure yielded (+)-β-methylbutylbenzene (38.7g, 64.8%), bp. 74°-77° C at 12 mm pressure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[Li][C:13]#[N:14].P(C#N)(OCC)(OCC)=O.C(O)(C)(C)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][C:13]#[N:14])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: [Li]C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: N#CCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-indolecarboxaldehyde (1.0 g, 6.90 mmol) and LiCN 1.5THF (72.5 mg, 0.69 mmol) in 50 ml THF, was added (EtO)2P(O)CN (1.36 ml) at 0° C. The reaction was stirred at rt overnight, and then t-butanol (0.79 ml) was added. The mixture was cannulated into a flask containing an 0.1 M solution of SmI2 in THF (159 ml). Additional SMI2 (10 mol %) was added until no color change was observed. The mixture was stirred for 30 min, and then concentrated and the residue poured into ethyl acetate. The organic layer was washed with 1.0 N HCl, saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography with Hexane:Ethyl acetate=2:1, to give (1H-Indol-7-yl)-acetonitrile as white solid, (300 mg, 30%). MS (m/z) 157.0 (M++1), 155.0 (M+−1). 1HNMR (DMSO) 11.26 (s, 1H), 7.50 (d, J=6.0 Hz, 1H), 7.39 (m, 1H), 7.06 (d, J=5.4 Hz, 1H), 6.97 (dd, J=5.4 Hz, 1H), 6.46 (m, 1H), 4.18 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cccc(NC(=O)OC(C)(C)C)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2cccc(N)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}carbamate (103 mg, 0.337 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.2 mL, 16 mmol) at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium carbonate was added to adjust to pH˜9. The mixture was then extracted with ethyl acetate (3×) and the combined organics were dried over magnesium sulfate, filtered, and concentrated to afford 6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-amine that was used without further purification. MS ESI calc'd for C11H19N4 [M+H]+ 207. found 207. 1H NMR (500 MHz, CD3OD) δ 7.46-7.40 (m, 1H), 6.66 (d, J=7.2 Hz, 1H), 6.47 (d, J=8.3 Hz, 1H), 3.47 (s, 2H), 2.85-2.46 (m, 8H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(N)ncnc2Cl)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Oc3cc(O)cc(NS(C)(=O)=O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 70 °C
Yield: 31 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (81 mg, 0.27 mmol), 3-hydroxy-5-(methylsulfonamido)phenyl 4-amino-6-chloropyrimidine-5-carboxylate (104 mg, 0.29 mmol), DIEA (323 μl, 1.85 mmol) and cesium fluoride (121 mg, 0.80 mmol) were suspended in tert-butanol (8 ml) and the mixture was heated at 70° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 50 mg (31% yield) as a solid. Purity 97%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])[CH:12]=2)[N:7]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])[CH:12]=2)[N:7]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][C:35]=2[Cl:44])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C(C)=O)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C(F)(F)F)cc2Cl)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Reaction time: 0.5 h

Procedure:
4-Acetyl-1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (0.048 g, 0.072 mmol) was dissolved in 1 mL of DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes. The material was concentrated, dissolved in acetonitrile and loaded onto an ion exchange column (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc (made by adding acetyl chloride to a MeOH/EtOAc mixture). The second filtrate was concentrated to afford 4-acetyl-1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.42 (s, 1 H), 8.12 (d, J=1.7 Hz, 1 H), 7.90 (dd, J=1.6, 8.4 Hz, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.31 (d, J=7.9 Hz, 1 H), 6.21 (d, J=8.8 Hz, 1 H), 3.96 (t, J=4.6 Hz, 2 H), 3.68 (br. s., 2 H), 2.24 (s, 3 H). m/z (ESI) 517.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([N:11]([CH3:23])[C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:8]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[OH:28])([CH3:4])[CH3:3].C([Li])CCC.[C:34](Cl)(=[O:36])[CH3:35].O>O1CCCC1>[C:34]([O:28][C:6]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:10][C:9]([N:11]([CH3:23])[C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CN(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccn(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(N(C)c2ccn(-c3ccccc3)n2)cc1C(C)(C)C
Reaction time: 16 h

Procedure:
To 2,6-bis (1,1-dimethylethyl)-4-(N-methyl-N-[1-phenyl-1H-pyrazol-3-yl]amino)phenol (0.6 g) in dry tetrahydrofuran (15 ml) at -78° under nitrogen was added butyl lithium (1.29 ml of 1.4M hexane solution). After 10 minutes acetyl chloride (0.2 ml) was added. The reaction was left for 16 hours, poured into water and extracted with ethyl acetate. Evaporation, and chromatography (silica, dichloromethane/hexane [1:1]) of the residue, followed by recrystallisation from hexane at -20° gave the title compound (0.35 g), mp 102°-103°.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
To a solution of 5-benzyl-3-methyl-6-propyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 8) (369 mg, 1.23 mmol) and sodium acetate (1 g) in acetic acid (5 mL) at 100° C., a solution of the bromine (318 mg, 2 mmol) in acetic acid (10 mL) was added dropwise over a period of 20 minutes. The reaction mixture was cooled after the addition and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×60 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (60 mL), water (100 mL), brine (100 mL) and dried over Na2SO4. Concentration of the organic layer provided the pure 5-benzyl-6-(1-bromo-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one, (460 mg, 100%) as white crystalline solid. 1H NMR (300 MHz) δ 0.76 (t, 3H), 2.1-2.47 (m, 2H), 2.84 (s, 3H), 4.62 (t, 1H), 4.88 (d, 1H), 6.20 (d, 1H), 7.10-7.40 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:26])[NH:44][CH:41]5[CH2:43][CH2:42]5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)NC1CC1
Yield: 39.9 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (250 mg), 1,1′-carbonyldiimidazole (130 mg) and cyclopropylamine (45 mg) were treated as in Example 151 to give the title compound (110 mg) as a white powder (yield: 40%).
Reaction SMILES: [F:1][C:2]([F:18])([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][NH2:16])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].Cl.[C:20](N)(=N)[CH3:21].C(O)(=O)C>CN(C)C=O>[CH3:20][C:21]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:18])([F:1])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=2)[C:14](=[O:17])[NH:15][N:16]=1
Reactant: CC(=N)N
Reactant: NNC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1n[nH]c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
4-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]semicarbazide (6.0 g) and 10.6 g of acetamidine hydrochloride were dissolved in 100 ml of dimethylformamide. The solution was stirred for one hour at room temperature. After adding 6.6 g of acetic acid, the reaction solution was heated at 80° C. for seven hours and concentrated under reduced pressure. The residue was dissolved in a mixture of 200 ml of ethyl acetate and 40 ml of water. The separated organic layer was washed with water and saturated sodium chloride solution, dried and distilled off to remove the solvent. The residue was recrystallized from ethyl acetate to give 3.6 g of 5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless needles.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C@H:4]([CH3:12])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:37][C:16]([F:15])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23](/[CH:26]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH3:12])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:22][CH2:21]1
Reactant: C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)alaninamide (646 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.08 g).
Reaction SMILES: [CH:1]1([C:5]2[C:6]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)=[C:7]([NH2:17])[N:8]([CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N=[C:27]=[O:28])C>N1C=CC=CC=1>[CH:1]1([C:5]2[C:6]3[C:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[C:27](=[O:28])[NH:17][C:7]=3[N:8]([CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=O
Reactant: Nc1c(C2=CCCCC2)c(C2CCC2)nn1Cc1cccnc1
Solvent: c1ccncc1
Product: O=c1[nH]c2c(c(C3CCC3)nn2Cc2cccnc2)c2c1CCCC2
Temperature: 50 °C

Procedure:
To a solution of Example 85C (4 g, 18 mmol) in anhydrous pyridine (50 mL) was added ethyl isocyanate (3 mL) under nitrogen. The solution was heated at 50° C. for 6 h and under reflux overnight. The volatile were removed and the residual solid was purified by flash chromatography to give Example 85D. Yield: 4.2 g (70%). MS (DCI): m/z 335 (M+H)+, 1H NMR (300 MHz, CDCl3) δ 1.58 (s, 1H), 1.72-1.86 (m, 5H), 1.87-2.17 (m, 2H), 2.27-2.61 (m, 6H), 2.84 (s, 2H), 3.62-3.90 (m, 1H), 7.20 (dd, J=7.80, 4.75 Hz, 1H), 7.78 (d, J=7.80 Hz, 1H), 8.48 (d, J=3.05 Hz, 1H), 8.77 (s, 1H).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:22])=O>>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Piperidine-1,4-dicarboxylic acid monobenzyl ester (VI) (5.0 g, 19 mmol) was suspended in thionyl chloride (10 ml) and stirred at room temperature for one hour. Excess thionyl chloride was distilled out and the obtained crude 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (VII) was used for the next reaction immediately.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>C(N(CC)CC)C.C(OC(=O)C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, Example 9 (100 mg, 0.186 mmol), Pd(PPh3)4 (10 mg, 0.0093 mmol), CuI (1.8 mg, 0.0093 mmol) and Ethynyltrimethylsilane (32 ul, 0.223 mmol) in triethylamine (0.4 ml) was heated to 80° C. for 4 hours. The mixture was cooled to room temperature, diluted with ethylacetate, filtered and the solvent was removed in vacuo. The crude brown oil was purified on SiO2 (Heptane/AcOEt 0%-40%,15 minutes) to provide the title compound (50 mg, 53%, yellow foam); M+H=590.2.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)=[O:4].[N:13]1[NH:14][C:15]([NH2:18])=[CH:16][CH:17]=1>C(O)(=O)C>[N:13]1[N:14]2[C:15]([N:18]=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]3=[C:3]2[OH:4])=[CH:16][CH:17]=1
Reactant: Nc1ccn[nH]1
Reactant: COC(=O)C1CCCCCC1=O
Solvent: CC(=O)O
Product: Oc1c2c(nc3ccnn13)CCCCC2
Yield: 83.7 %

Procedure:
A solution of 2-oxo-cycloheptanecarboxylic acid methyl ester (5 g, 29.4 mmol) and 2H-pyrazol-3-ylamine (2.44 g, 29.4 mmol) in acetic acid (5 mL) was heated at 100° C. for 1 hour and resulted in the formation of a colorless precipitate. The solid was collected via filtration and washed with ethanol and ethyl ether to give 6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol (5 g, 85% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:31][C:32]([OH:34])=[O:33])[C@@H:12]([CH2:13][O:14]CC2C=CC=CC=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:31][C:32]([OH:34])=[O:33])[C@@H:12]([CH2:13][OH:14])[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](CO)C1=O
Yield: 80 %

Procedure:
A 10% palladium-carbon catalyst (3.93 g) was added to a solution of (3S,4S)-4-benzyloxymethyl-3-carboxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.93 g, 8.41 mmol) in methanol (84.0 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for three days. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give 2.54 g of the title compound.