Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>CO>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])/[C:24]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c (53 mg, 0.2 mmol) was dissolved in 1 ml of methanol under stirring, and added with 5-chloro-1,3-dihydro-indol-2-one (34 mg, 0.2 mmol) and piperidine (0.1 ml) to the solution. Upon the completion of the addition, the mixture was stirred to mix well in dark, heated to reflux for 2 hours and lots of precipitate was formed. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with ethanol and dried to obtain the title compound (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 23 (62 mg, yield 75%) as an orange powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2cccc(Br)c2)CC1
Yield: 62.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].C(C(C)=O)C(C)C>C(N(CC)CC)C>[C:8]([O:13][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)O
Reactant: O=C1OCCC1Br
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=C(C)C(=O)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
After charging 100 parts of α-bromo-γ-butyrolactone and 104.4 parts of methacrylic acid (2.0 times in mole based on α-bromo-γ-butyrolactone), a three times amount of methyl isobutyl ketone based on α-bromo-γ-butyrolactone was added thereto to form a solution. To this solution was added dropwise 183.6 parts of triethylamine (3.0 times in mole based on α-bromo-γ-butyrolactone). Then, the solution was stirred at room temperature for about 10 hours. After filtration, the organic layer was washed with 5% aqueous sodium hydrogen carbonate-solution and then washed twice with water. The organic layer was concentrated to give α-methacryloyloxy-γ-butyrolactone represented by the following formula in 85% yield:
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][C:12]1([CH3:20])[CH2:17][CH:16]([CH3:18])[C:15](=[O:19])[CH:14]=[CH:13]1.[Cl-].[NH4+]>C(OCC)C>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]2([OH:19])[CH:16]([CH3:18])[CH2:17][C:12]([CH3:20])([CH3:11])[CH:13]=[CH:14]2)=[CH:5][CH:4]=1
Reactant: CC1CC(C)(C)C=CC1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CC(C)(C)C=CC1(O)Cc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of magnesium turnings (66 g, 2.73 g atoms) in diethyl ether (300 ml) was added a solution of 4-chlorobenzyl chloride (418 g, 2.6 moles) in diethyl ether (1500 ml) at such a rate as to maintain gentle reflux. After a further 30 minutes, a solution of 4,4,6-trimethylcyclohex-2-en-1-one (340 g, 2.46 moles) in diethyl ether (350 ml) was added, again maintaining a gentle reflux. After 1 hour the mixture was added into saturated aqueous ammonium chloride (4 liters) and the phases separated. The ether phase was back-washed with water (1 liter) and used directly in the next reaction. A small portion of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-2-en-1-ol was isolated for characterisation (gas chromatography analysis showed two isomers in approximately equal amounts).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11](O)=O)=[CH:9][N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=1[NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH:14]1([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[NH:29][C:21]4[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=4[N:19]=3)=[CH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ncnc2c1c(C(=O)O)cn2C1CCCC1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Nc1ncnc2c1c(-c1nc3ccc([N+](=O)[O-])cc3[nH]1)cn2C1CCCC1
Reaction time: 6 h
Yield: 28.8 %

Procedure:
4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (ID, 12.0 g, 488 mmol), 1,2-diamino-4-nitrobenzene (11.2 g, 73.1 mmol), and HATU (26.0 g, 73.1 mmol) were combined and stirred in 242 mL of anhydrous NMP under N2 at 50° C. After 6 hrs, reaction was monitored by LCMS confirming the loss of the starting material and the formation of a new component. The reaction mixture was decant into ten 50 mL centrifuge tubes and concentrated overnight in the GeneVac. Dark brown oil was taken up in EtOAc (1.6 L) and extracted using 1.2 L H2O. The organic layer was washed with H2O (3×900 mL) and then concentrated. The residue (dark brown gum) was triturate in ˜900 mL CH2Cl2, 10.02 g of a reddish black solid was collected after filtration and vacuum drying. 1H NMR suggested it contained the coupling product plus 20-30% impurity. The solid was again taken up in 1.5 L EtOAc, washed with H2O (5×900 mL). The organic layer was concentrated and residue triturated in ˜900 mL CH2Cl2, filtered and dried to furnish 7.65 g of a yellow solid. 1H NMR and LCMS suggested the coupling product plus minor impurities (88% pure by LCMS at 210 nm, M/Z 381.5, retention time 2.3 min. with analytical HPLC method 1).
Reaction SMILES: [C:1]([C:5](=[CH2:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O:3]C)=[O:2].C[O-].[Na+].CO>O>[C:1]([C:5](=[CH2:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: C=C(Cc1ccc(-c2cccc3cncn23)cc1)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(Cc1ccc(-c2cccc3cncn23)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 20 mg of 5-[p-(2-carbomethoxyprop-2-enyl)phenyl]imidazo[1,5-a]pyridine and 20 mg of sodium methoxide in 2 ml. of methanol is stirred under nitrogen for 1 hour at 25°. To the reaction mixture 2 ml. of water is added, and the homogenous solution is stirred at room temperature for 18 hours. The solvent is evaporated and the residue is redissolved in 5 ml of water and washed with 3 ml of ether. Acidification to pH=5, extraction with 10 ml of methylene chloride, drying over magnesium sulfate and evaporation yields 5-[p-(2-carboxyprop-2-enyl)phenyl]imidazo[1,5-a]pyridine, m.p. 171°-172°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:45][CH:46]=[CH:47][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:45][CH:46]=[CH:47][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)cc1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CNC(C)C)c3ccc(Cl)cc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.013 g, 0.020 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.009 g, 72% yield) as the dihydrochloride salt. MS ESI (+) m/z 563 detected.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>ClCCl>[N+:7]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:9][CH:10]=1)[CH2:17][CH2:16][CH2:15][CH2:14]2)([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: c1ccc2c(c1)CCCC2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a suspension of 85% nitronium tetrafluoroborate (52 g, 0.333 mol) in dichloromethane (500 mL) was added dropwise a solution of tetralin (40 g, 0.303 mol) in dichloromethane (400 mL) over 45 min at 0° C. The mixture was stirred for 30 min at 0° C. and quenched by addition of ice-water (700 mL). The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 30:1~5:1 hexane/toluene to give 14.15 g of the title compound: 1H NMR (CDCl3) δ7.91 (s, 1H), 7.88 (d, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.6 Hz), 2.84 (m, 4H), 1.83 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[N:12][NH:13][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])[N:13]=[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]ncc2n(CCCC)c1=O
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(=O)c2nn(S(=O)(=O)CCCCl)cc2n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To 222 mg (0.84 mmol) of 4,6-dibutyl-1,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-dione in 10 mL CH2Cl2 was added 0.22 mL (163 mg, 1.26 mmol) of i-Pr2NEt followed by 0.11 mL (164 mg, 0.924 mmol) of 3-chloro-n-propanesulfonyl chloride. The resulting solution was stirred at 23° C. for 16 h after which time TLC shows that all starting material had been consumed. The reaction mixture was poured into brine, extracted with 2×50 mL EtOAc, and the combined organics were washed with 1×50 mL brine, dried over MgSO4, filtered and evaporated to a yellow solid. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (40/1 to 20/1) gave the title compound. Recrystallization from hot hexanes/EtOAc gave 168 mg (0.415 mmol, a 49% yield) of the title compound as a white crystalline solid. mp: 67-68° C.; 1H NMR (300 MHz, CDCl3); δ 0.92-1.02 (m, 6H), 1.34-1.49 (m, 4H), 1.56-1.79 (m, 4H), 2.21-2.34 (m, 2H), 3.65 (t, J=6.1 Hz, 2H), 3.79-3.88 (m, 4H), 4.17 (t, J=7.3 Hz, 2H), 7.87 (s, 1H); IR (KBr, cm-1): 3137w, 2958w, 1718m, 1677s, 1626w, 1380m, 1166m; MS (ES) m/z (relative intensity): 405 (M+ +H, 100); Anal. Calcd. for C16H25ClN4O4S: C, 47.46; H, 6.22, N, 13.84. Found: C, 46.80; H, 6.06; N, 13.24.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:36][NH2:37]>CS(C)=O.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([NH:37][CH3:36])=[N:3][C:4]([C:32]([F:33])([F:35])[F:34])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:24][CH:25]=1
Reactant: CN
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Solvent: O
Solvent: CS(C)=O
Product: CNc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (26 mg, 0.05 mmol) in DMSO (0.5 mL) and 40 wt. % methylamine in water (0.5 mL) was heated in a microwave oven at 200° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (10 mL×2). The combined EtOAc extracts were concentrated under reduced pressure. The crude product was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 16 mg (63%) of the title compound as a yellow powder. HPLC/MS: retention time=3.28 min, [M+H]+=511.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[Na+].O>CN(C)C=O>[CH2:18]([NH:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 30 g of 6-(4-chlorobutoxy)-carbostyril, 103 ml of benzylamine and 33 g of sodium iodide in 300 ml of dimethylformamide was stirred at 80° C. for 8 hours. The reaction mixture was allowed to cool and then poured into water. The resulting precipitate was collected by filtration. The precipitate was washed with water and diethyl ether in this order to obtain 29.1 g of 6-(4-benzylaminobutoxy)carbostyril.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[CH2:9][CH2:10][C:11]([NH:13][O:14]C2CCCCO2)=[O:12])=[CH:4][C:3]=1[CH3:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:21][CH3:22])[CH2:9][CH2:10][C:11]([NH:13][OH:14])=[O:12])=[CH:4][C:3]=1[CH3:23]
Reactant: COC(CCC(=O)NOC1CCCCO1)c1ccc(F)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H](CCC(=O)NO)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To the solution of 4R)-4-(4-fluoro-3-methylphenyl)-4-methoxy-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (66 mg, 0.2 mmol) in 4 mL DCM was slowly added 2 mL TFA and the resulting solution stirred for 30 min at 25° C. The solvent was evaporated and the product isolated by flash column chromatography eluting with 0% to 10% methanol/DCM gradient solvent to give 32 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][S:9]2(=[O:16])=[O:15])[CH:5]=[C:4]([F:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:40])(=O)=O.O>O1CCCC1>[F:17][C:4]1[CH:5]=[C:6]([N:8]2[C@H:12]([CH2:13][O:14][CH3:40])[CH2:11][CH2:10][S:9]2(=[O:15])=[O:16])[CH:7]=[C:2]([F:1])[C:3]=1[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:24][CH2:25]1)=[O:19]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H]1CCS(=O)(=O)N1c1cc(F)c(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
(S)-[2,6-difluoro-4-(3-hydroxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (270 mg) described in Example 35 was dissolved in tetrahydrofuran, sodium hydride (48 mg) was added, and the mixture was stirred at room temperature for 30 min. Then, to the reaction mixture was added methyl tosylate (203 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (5 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:38][C:39]([F:47])([F:46])[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>N12CCCN=C1CCCCC2.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([N:43]3[CH2:44][CH2:45][CH:40]([C:39]([F:47])([F:46])[F:38])[CH2:41][CH2:42]3)=[N:20][CH:19]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCC(C(F)(F)F)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 34.1 %

Procedure:
A mixture of 150 mg (0.28 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.16 g (0.84 mmol) 4-(trifluoromethyl)piperidine hydrochloride in 2 ml 1,8-diazabicyclo[5.4.0]undec-7-ene was heated at 140° C. for 20 h. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 62 mg (34%) of the title compound as a light yellow solid.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH2:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: COC(=O)C1(C)CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(C)CCC(N)CC1
Reaction time: 20 h
Yield: 68.9 %

Procedure:
0.2 g of 10% palladium-carbon was added to a solution of 3.1 g of methyl 4-(N-benzylamino)-1-methyl-1-cyclohexanecarboxylate (Example 15) in 200 ml of methanol. The solution was reacted at room temperature under normal-pressure hydrogen gas. The reaction was stopped after 20 hours, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. As a result, 1.4 g of methyl 4-amino-1-methyl-1-cyclohexanecarboxylate was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].C1COCC1.Br[CH2:20][C:21]([CH3:23])=[CH2:22]>CCOC(C)=O.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:22][C:21]([CH3:23])=[CH2:20]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=C(C)CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccccc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a well stirred mixture of 3-chloropropiophenone (10.0 g, 59.3 mmol), zinc powder (4.0 g, 1.03 equiv), satd aq NH4Cl solution (150 mL), THF (70 mL), a solution of the 3-bromo-2-methylprop-1-ene (16 g, 2 equiv) was added slowly. The reaction was exothermic mildly. After the addition, the mixture was heated to reflux for 1.5 h. After being cooled to rt, the mixture was diluted with EtOAc (200 mL), separated, washed with brine (35 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120 g silica gel column, eluted with a 0-10% methanol in CH2Cl2 gradient, to afford 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (8.67 g product, 65% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH3:2].Cl.[NH2:17][OH:18]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCOCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCOCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Ethoxypentyl)-4-piperidone oxime is prepared from 1-(5-ethoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:7][CH:8]=2)[NH:3]1.[Cl:19][C:20]1[CH:27]=[C:24]([CH:25]=O)[C:23]([OH:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:13])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C1Cc2ccc(NC(=O)C3CCCC3)cc2N1
Product: O=C1Nc2cc(NC(=O)C3CCCC3)ccc2C1=Cc1cc(Cl)ccc1O

Procedure:
Cyclopentanecarboxylic acid (2-oxo-2,3-dihydro-1H-indol-6-yl)-amide was condensed with 5-chlorosalicylaldehyde using method B to give cyclopentanecarboxylic acid [3-(5-chloro-2-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amide which was reducted using method D to give 34.4 mg (68%) cyclopentanecarboxylic acid [3-(5-chloro-2-hydroxybenzyl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amide as an off-white crystalline solid.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 39 %

Procedure:
In analogy to the procedure described for the preparation of example 3, (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) was reacted with ethyl chloroformate to give the title compound as a off-white powder in 39% yield. MS: 322.2 (M+H+).