Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.Cl.[CH2:15](N=C=NCCCN(C)C)[CH3:16].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:15]([O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:13])[CH3:16]
Reactant: Cn1ccc2ccc(C(=O)O)cc21
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccn(C)c2c1
Reaction time: 15 h
Yield: 88.6 %

Procedure:
A solution of 1.05 g (6.0 mmol) of 1-methyl-1H-indole-6-carboxylic acid in 15 mL of methylene chloride was added to a stirring solution of 1.905 g (10 mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.20 g (10 mmole) of 4-dimethylaminopyridine in 20 mL of methylene chloride at room temperature. Ethanol was added and the reaction stirred for 15 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with brine and dried on anhydrous magnesium sulfate. Chromatographic purification of this material gave 1.08 g (89%) of 1-methyl-1H-indole-6-carboxylic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH2:8]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:12]>>[CH:1]1([NH:6][CH2:7][CH2:8][Cl:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCNC1CCCC1
Product: ClCCNC1CCCC1

Procedure:
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2,3-dichlorophenyl isothiocyanate according to Method C1d to afford 2-(2,3-dichlorophenylimino)-3-cyclopentyl-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][C@@H:59]1[CH2:63][CH2:62][CH2:61][NH:60]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:60]2[CH2:61][CH2:62][CH2:63][C@@H:59]2[CH2:58][O:57][CH3:56])=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: COC[C@@H]1CCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC[C@H]1CCCN1C(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (S)-(+)-2-(methoxymethyl)pyrrolidine (46 mg, 2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1
Reactant: [I-]
Reactant: Cc1nnc(SCCl)s1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCI)s1
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (730 mg: 4 mMol.) in acetone (6 ml) is added sodium iodide (1.2 g: 2.0 equivalents: 8 mMol.), and the mixture is stirred at 55° C. for 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated to give 5-iodomethylthio-2-methyl-1,3,4-thiadiazole (1.05 g) as yellow oil.
Reaction SMILES: [CH2:1]([Sn:11](Cl)([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[S-:33][C:34]#[N:35].[K+].C1C=CC=CC=1>O>[CH2:1]([Sn:11]([N:35]=[C:34]=[S:33])([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccccc1C(F)(F)F)c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(N=C=S)c1ccccc1C(F)(F)F)c1ccccc1
Yield: 96.2 %

Procedure:
Dineophyl-orthotrifluoromethylphenyltin chloride (6 g, 10.6 mmol) prepared in Example 5, potassium thiocyanate (1.5 g, 15.9 mmol), benzene (40 g) and water (10 g) were charged into a flask and the mixture was refluxed for 2 hours. The aqueous layer was removed and the organic layer was washed with water and filtered. Evaporation of the benzene under reduced pressure gave 6.0 g of dineophyl-orthotrifluoromethylphenyltin isothiocyanate as a colorless viscous liquid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH:13](Br)[CH3:14]>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes ) provided the title compound (3.79 9). 1H NMR (400 MHz, CDCl3) δ6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:22])[CH2:20][OH:21])[CH:14]=1)=[O:12].[C:32]([O-])([O-])([O:34][CH3:35])[CH3:33].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:20][O:21][C:32]([O:34][CH3:35])([CH3:33])[O:22]2)[CH:14]=1)=[O:12])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24]
Reactant: COC(C)([O-])[O-]
Reactant: O=C(C(C(=O)c1cccc(C(O)CO)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC1(C)OCC(c2cccc(C(=O)C(C(=O)c3cccc(F)c3)=C3Nc4ccccc4N3)c2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A 6 ml portion of THF solution containing 0.21 g of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione and 0.3 g of methyl orthoacetate was mixed with 63 mg of pyridinium p-toluenesulfonate and then stirred at room temperature for about 30 minutes. After evaporation of the solvent, the residue was mixed with an appropriate amount of sodium bicarbonate aqueous solution, extracted several times with ethyl acetate, dried with anhydrous magnesium sulfate and concentrated. The thus formed residue was purified by a silica gel column chromatography to obtain 162 mg (68%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(2-methoxy-2-methyl-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione (Example 3-1) as a pale yellow foam from an ethyl acetate-hexane (1:2) eluate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCC(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCC(=O)NCCCCn1c(CC)nc2c(N)nc3ccccc3c21
Yield: 62.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with butyryl chloride (0.40 mL, 3.9 mmol) to provide 0.77 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide as a light brown solid, m.p. 147.7-148.8° C. Analysis: Calculated for C20H27N5O.0.4H2O: % C, 66.60; % H, 7.77; % N, 19.42; Found: % C, 66.84; % H, 7.77; % N, 19.36.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1Cl.[CH3:18][C:19]1([CH3:29])[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([OH:28])[C:21]=2[O:20]1>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[O:28][C:27]1[C:21]2[O:20][C:19]([CH3:29])([CH3:18])[CH2:23][C:22]=2[CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cccc(Oc3ccc([N+](=O)[O-])cc3Cl)c2O1
Temperature: 110 °C
Yield: 95.8 %

Procedure:
To a mixture containing 32.63 g (0.236 mole) of anhydrous potassium carbonate and 30.41 g (0.158 mole) of 3,4-dichloro-1-nitrobenzene in 250 ml of dry DMF at room temperature and under an atmosphere of nitrogen was added 30.88 g (0.188 mole) of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran. The reaction mixture was then placed in an oil bath and heated to 110° C. for 20 hours The reaction mixture was cooled to room temperature. The DMF was removed under vacuum. The residue was dissolved in 1.5 L of 1:1 ethylacetate:ether and 300 ml of water. The layers were separated. The organic layer was washed twice with 5% NaOH, twice with H2O and once with a saturated aqueous NaCl solution. After drying over anhydrous Na2SO4, removal of the solvents afforded 48.42 g of a light tan solid. This was recrystallized from hexane:ethyl acetate to afford 44.19 g of white crystals mp 132°-133° C. NMR (CDCl3): δ1.42 (s, 6H), 3.05 (s, 2H), 6.5-7.2 (m, 4H), 7.95 (doft, J=9, 2 Hz, 1H), 8.28 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([C:20]#[N:21])[C:18]#[N:19].N1CCCCC1>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
14.22 g (67 mmol) of 4-benzyloxybenzaldehyde and 5.31 g (80.4 mmol) of malonodinitrile were suspended in 80 ml of isopropanol in the presence of 0.2 ml of piperidine. In so doing the mixture increased in temperature from 19 to 31° C. A solution resulted, from which a solid was finally obtained. This was filtered off after stirring for 30 min. There were obtained 10.3 g (59%) of 2-(4-benzyloxy-benzylidene)-malononitrile with m.p. 146-148° C.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH2:40][CH3:41])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: CCCOC(=O)Cl
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
120 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 120 mg of potassium carbonate were dissolved in 1.5 ml of water and 7.5 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.034 ml of propyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: Cl[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[SH-:19].[Na+].Cl>C(O)C>[SH:19][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: [SH-]
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(S)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 14 g. (.05 moles) of α, 2'-dichloro-4-biphenylylacetic acid and 5 g. of sodium hydrosulfide in 100 ml. of absolute ethanol and under a nitrogen atmosphere is stirred for 15 hours. The mixture is then acidified with 6 N hydrochloric acid. The solvent is removed in vacuo and the residue is extracted into ether, washed with water, saturated sodium chloride solution, dried and evaporated to dryness to obtain α-mercapto-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: NC1C([Br:12])=CC=CC=1C(OC)=O.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[C:48]([Br:12])=[CH:47][CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: COC(=O)c1cccc(Br)c1N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-bromobenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 595 (M+H).
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([C@@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (150 mg, 0.44 mmol) was dissolved in 3 mL of dry dichloromethane. To this solution was added triethylamine (30 μL, 0.22 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (83 mg, 0.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The reaction mixture was shaken overnight at ambient temperature, concentrated under reduced pressure and passed through a silica gel column (2 g) using 1:1 hexanes/ethyl acetate as eluant. The dichloromethane/hexanes/ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by preparative reverse phase High Pressure Liquid Chromatography (HPLC) using a solvent gradient going from 100% water to 100% acetonitrile to give 85 mg of the title product, a compound of the present invention as an oil. 1H NMR (CDCl3) δ 0.9-1.1 (br m, 3H), 1.7-1.9 (m, 2H), 1.9-2.2 (m, 4H), 2.31 (s, 3H), 2.7-3.0 (m, 4H), 3.2-3.4 (m, 2H), 3.9-4.6 (br m, 2H), 4.96 (br s, 2H), 5.6-6.0 (m, 1H), 6.3 (s, 1H) 7.20-7.45 (m, 5H), 7.8 (s, 1H).
Reaction SMILES: [Si]([O:8][C@@H:9]([C:40](=[O:42])[NH2:41])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C>ClCCl>[CH2:38]([NH:30][CH:27]1[CH2:28][CH2:29][CH:24]([O:23][C:14]2[C:13]3[C:12]4[C@@H:11]([CH2:10][C@@H:9]([OH:8])[C:40]([NH2:41])=[O:42])[CH2:22][CH2:21][C:20]=4[S:19][C:18]=3[N:17]=[CH:16][N:15]=2)[CH2:25][CH2:26]1)[CH3:39]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Solvent: ClCCl
Product: CCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](O)C(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-[(2R)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (200 mg, 0.32 mmol, 1.00 equiv), hydrogen chloride(conc.) (0.3 mL) in dichloromethane (3 mL). The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water WITH 50 mL NH4CO3 and CH3CN (5.0% CH3CN up to 44.5.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); detector: 254/220 nm. 57.4 mg product was obtained. This resulted in 57.4 mg (44%) of (2R)-3-[(3R)-12-[[4-(ethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2-hydroxypropanamide as a white solid. MS: m/z 405 (M+H)+. 1H-NMR (300 MHz, CD3OD): δ 8.474 (1H, s), 5.25-5.22 (1H, m), 4.00-4.03 (1H, t), 3.61 (1H, m), 3.07-3.10 (1H, m), 2.94-2.98 (1H, m), 2.52-2.68 (4H, m), 2.18-2.39 (2H, m), 1.64-1.71 (3H, m), 1.26-1.34 (2H, m), 1.08-1.13 (3H, d).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2)([OH:3])=[O:2].OS(O)(=O)=O.[CH3:20]O>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2)([O:3][CH3:20])=[O:2]
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2nc(C)ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 6-carboxy-2-methyl quinoline in MeOH (600 ml) was added concentrated H2SO4 and stirred for 3 days at room temperature. The reaction mixture was evaporated and the residue was diluted with H2O (250 ml) and ethyl acetate (250 ml), and transferred to a separatory funnel. A solution of saturated sodium bicarbonate in water (1 L) was added and extraction with ethyl acetate afforded a purple solid which was chromatographed on column of flash silica gel using hexane-ethyl acetate (2:1) as eluant to provide the title compound as a yellow solid: m.p. 98-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:33]>O1CCCC1>[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([N:34]([C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH3:33]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)N(Cc1ccc(F)cc1)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-propionic acid (37 g, 195 mmol) in dry tetrahydrofuran (250 mL) at 0° C. was added 4-methyl morpholine (21.5 mL, 195 mmol) followed by isobutylchloroformate (25.3 mL, 195 mmol). The reaction was allowed to warm to ambient temperature and stirred for two hours. This was followed by the addition of (S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (43.2 g).
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 53.9 %

Procedure:
Following the procedure of Example 3, step 4, 40.0 mg (0.214 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in anhydrous DMF (2 ml) was reacted with 32.5 mg (0.235 mmol) of anhydrous potassium carbonate and 25.4 ml (0.214 mmol) of benzyl bromide. Chromatography on flash silica, eluting with 10-15% ethyl acetate/petroleum ether, gave 32.0 mg (54%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 244°-248° C. (dec). NMR δ(D2O) 1.49-1.84 (4H, m), 2.68 (2H, m), 2.89-2.99 (3H, m), 3.23 (1H, m), 3.53 (1H, m), 3.73 (1H, m), 4.37 (2H, m), 7.23-7.27 (3H, m), 7.33 (1H, m), 7.54 (5H, s). m/z (CI+, NH3) 278 (M+H)+, 186 (M-CH2Ph)+, 184, 110.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[C:7]3[C:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[C:7]3[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a mixture of 7-chloro-3-((t-butoxy)carbonylmethyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (0.26 g, 0.72 mmol) in methylene chloride (6 mL) was added trifluoroacetic acid (6.38 g, 56 mmol) via syringe. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated via rotary evaporator to give a solid which was recrystallized from dimethylformamide and dried at 100° C. to yield the title compound (0.14 g, 64%, mp 297.3-299.6° C.).