Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]#[CH:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([Li])CCC.IC>C1COCC1>[CH2:24]([C@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][C:13]([CH3:15])([CH3:16])[N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:25]#[C:26][CH3:27]
Reactant: C#CC[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
A solution of (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(prop-2-ynyl)oxazolidine-3-carboxylate (0.60 g, 1.6 mmol) in THF (5 mL) was cooled to −78° C. and butyllithium (0.75 mL, 1.9 mmol) was added dropwise. After 5 min, the mixture was re-cooled to −78° C. and iodomethane (0.15 mL, 2.3 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h and brought to RT and stirred for 15 h. The reaction mixture was quenched with sat NH4Cl, filtered, concentrated, and chromatographed on silica gel eluting with hexanes to afford a light yellow oil as (4S,5S)-tert-butyl 4-(but-2-ynyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.463 g, 74% yield). MS m/z: 298 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N=C(Nc1c(Cl)cccc1Cl)SCc1ccccc1
Reaction time: 4 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetyl-thiourea, 1.7 g of (0.012 M) of ground potassium carbonate 2.6 ml (0.024 M) of benzylchloride and 80 ml of acetone are boiled in a reflux being energetically shaken for 4 hours. The acetone is distilled off. The product in the flask is washed with water and is filtered. After drying N-(2,6-dichlorophenyl)-N'-acetyl-S-benzylisothiourea is obtained with a melting point of 84°-95° C. After being recrystallized twice from ethanol it has a melting point of 99°-101° C., whereby 1.7 g are isolated (24% of the theoretical yield).
Reaction SMILES: [CH2:1]([C:10]([C:21]#[N:22])([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.Cl[C:24]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[CH2:1]([C:10]1([C:21]#[N:22])[CH2:11][CH2:12][C:13](=[O:15])[CH:17]([C:18]([O:20][CH3:24])=[O:19])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: COc1cccc(CC(C#N)(CCC(=O)O)CCC(=O)O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(Cc2cccc(OC)c2)CCC1=O
Yield: 99 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 30.34 gm. (0.0951 mole) of the dimethyl ester of 4-(m-anisyl)-4-cyanopimelic acid (prepared in Part A, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 620 ml. of the tetrahydrofuran, 21.3 gm. (0.19 mole) of the potassium tert-butoxide, and 150 ml. of the 2.5 N glacial acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 29.1 gm. (99% yield) of 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclohexanone as a gum.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.[OH-].[Na+].Cl>O>[CH3:13][Si:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cccc([Si](C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[Si](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 130 mg (0.676 mmol) of 3'-trimethylsilylacetophenone and 127 mg (0.774 mmol) of methyl 4-formylbenzoate in 4.5 ml of tetrahydrofuran(THF) were added 128 mg (3.20 mmol) of NaOH and 3 ml of hot water, and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted with 7 ml of 0.5N-HCl to pH6, and then the aqueous solution was extracted with ethyl acetate. The extract was washed with 0.05N-HCl and H2O, dried and evaporated. The residue was purified by column chromatography affording 133 mg of pale yellow powder (yield 61%), which was recrystallized from a mixture of methylene chloride, methanol and n-hexane to give 98 mg of pale yellow needles, m.p.179°-180° C. (yield 45%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][CH:12]=[C:13]([C:19]([O-])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]2[OH:11]
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: Nc1ccccc1Br
Product: CCOC(=O)c1cnc2c(Br)cccc2c1O
Yield: 80.8 %

Procedure:
A solution of 2-bromoaniline (2.5 g, 14.62 mmol) and ethyl ethoxymethylenemalonate (3.16 g, 14.62 mmol) was heated at 100° C. for 3 h. Then the volatiles were removed by passing a stream of nitrogen and the molten mass was added slowly onto boiling diphenyl ether (10 mL) and the mixture was heated at reflux for 2 h. Then petroleum ether was added to the reaction mixture at rt and the precipitated solid was collected by filtration and dried to afford 3.5 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 11.65 (br s, 1H), 8.45 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.39-7.34 (t, J=7.8 Hz, 1H), 4.26-4.19 (q, J=7.2, 14.1 Hz, 2H), 1.30-1.26 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[N:37]=[C:38]=[O:39]>O1CCCC1>[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[NH:37][C:38]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:39]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1onc(-c2ccccc2)c1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 5-methyl-3-phenyl-4-isoxazolyl isocyanate (244 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 229 mg (63.3%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 72.2 %

Procedure:
A stirred solution of 6-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue was recrystallized from ethyl acetate and hexanes to afford a yellow solid (721 mg, 72%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.Cl>O.CN(C)C=O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CC(C)CCNc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of N-(3-methylbutyl)-4-phenyl-1,3-thiazol-2-amine (370 mg), sodium hydride (60% oil, 50 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by preparative HPLC (gradient cycle A) to give the title compound (250 mg, yield 47%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([S:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH3:26])[CH:29]=2)(=[O:36])=[O:35])[CH2:9][CH2:8][N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(S(=O)(=O)c2cccc(OC)c2)CCN1Cc1ccccc1
Yield: 82.5 %

Procedure:
A solution of 1-benzyl-piperazine-2-carboxylic acid ethyl ester (300 mg) in DMF (13 mL) was treated with triethylamine (0.5 mL) and 3-methoxybenzene sulfonyl chloride (274.6 mg) at RT for 2 hours. Water was added, and the inorganic layer was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and evaporated to yield 1-benzyl-4-(3-methoxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester as a colorless oil (417 mg), MS: 419.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(C)(C)C)=[C:11]([F:22])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl>CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:10][C:11]=1[F:22]
Reactant: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(N)c2)cc1F
Agent: Cl
Solvent: CO
Product: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 53.6 %

Procedure:
A solution of N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide (70 mg, 0.23 mmol) in 3 mL of MeOH was added 2 mL of 6 N HCl. The mixture was then heated at reflux for 48 h. After cooling down, the solvent was removed under reduced pressure and the residue was purified by solid extraction (Waters Oasis MCX extraction cartridge) to give 4-(4-amino-3-fluorophenoxy)pyridin-2-amine (27 mg, 54% yield). MS (ESI+): m/z 220.21 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][O:14][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:8][C:7]=1[F:15]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cc(F)cc(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cc(F)cc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3,5-difluorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C1(S(O[CH:11]2[CH2:24][N:23]3[C:14](=[N:15][C:16]4[C:21]([C:22]3=[O:25])=[CH:20][CH:19]=[C:18]([Br:26])[CH:17]=4)[CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[CH3:27][NH:28][CH3:29]>C(#N)C.O>[Br:26][C:18]1[CH:17]=[C:16]2[C:21]([C:22](=[O:25])[N:23]3[CH2:24][CH:11]([N:28]([CH3:29])[CH3:27])[CH2:12][CH2:13][C:14]3=[N:15]2)=[CH:20][CH:19]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccccc1)CC2
Reactant: CNC
Solvent: O
Solvent: CC#N
Product: CN(C)C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl benzenesulfonate (0.15 g, 0.34 mmol, 1 equiv) and excess aq. dimethylamine in acetonitrile (6 mL) was stirred at 70° C. for 3 hours. After it was cooled to rt, the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][C:7](=[O:13])[C:6]([CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])=[O:16])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:6]2[C:7](=[O:13])[O:8][C:9]3[C:4]([C:5]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][C:2](/[CH:37]=[CH:36]/[C:35]([O:39][CH3:40])=[O:38])=[C:11]([CH3:12])[CH:10]=3)=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: Cc1cc2oc(=O)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(-c3ccccc3)c2cc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1C
Temperature: 120 °C
Yield: 72 %

Procedure:
A solution of 2-(6-bromo-7-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide (Example 177) (500 mg) in DMF (5 mL) was combined with methyl acrylate (0.14 mL), Et3N (0.21 mL), Pd(OAc)2 (5 mg) and triphenylphosphine (10 mg) under argon atmosphere, and stirred with heating at 120° C. for 10 hours. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid followed by an aqueous solution of NaHCO3 and water, and then dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a colorless crystal (360 mg, yield: 72%). An aliquot was recrystallized from ethyl acetate to measure a melting point. Melting point: 233-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:16])=[CH:10][C:11]=3[C:12](SC)=[N:13][C:4]=2[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:16])=[CH:10][C:11]=3[C:12]([N:27]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)=[N:13][C:4]=2[CH:3]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2sc(C)cc21
Solvent: CC(C)O
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1
Temperature: 79.5 °C
Yield: 69 %

Procedure:
Combine 7-chloro-2-methyl-10-methylsulfanyl-4H-3-thia-4,9-diaza-benzo[f]azulene (42.74 g, 145 mmol) and (s)-2-(2-methoxy-ethyl)-piperazine (26.1 g, 181 mmol) in isopropyl alcohol (190 mL). Heat to 78-81° C. for 3-4 days, and then allow cooling to ambient temperature. Filter the solids and rinse with 1:1 MTBE/Ligroin (2×300 mL). Drying at 30° C. affords 39.1 g (69.5%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 1.52 (bm, 2H), 2.27 (s, 3H), 2.45 (bt, 1H), 2.65 (bm, 2H), 2.75 (bt, 1H), 2.86 (bd, 1H), 3.20 (s, 3H), 3.38 (m, 2H), 3.80 (m, 1H), 3.90 (m, 1H), 6.33 (s, 1H), 6.67 (d, 1H), 6.75 (d, 1H), 6.82 (dd, 1H), 7.70 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 15.07, 25.49, 33.28, 45.11, 47.36, 52.55, 57.92, 69.18, 118.38, 119.81, 122.29, 122.56, 126.41, 126.99, 128.43, 142.54, 142.90, 152.84, 157.82. MS (ES+) M+H calcd for C19H23ClN4OS 390.94; found 391.96.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][O:27][CH2:28][CH3:29].O[N:31]1[C:52](=[O:53])[NH:51][C@H:50]2[C@@H:32]1[CH2:33][S:34][C@H:35]2[CH2:36][CH2:37][CH2:38][CH:39](N1C(=O)CCC1=O)[C:40](=O)[OH:41]>C(Cl)(Cl)Cl>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][NH:9][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]3[CH:50]4[CH:32]([NH:31][C:52](=[O:53])[NH:51]4)[CH2:33][S:34]3)[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Yield: 13.3 %

Procedure:
Triethylamine (1.2 g, 11.4 mmol) was added in a single portion to a slurry of 1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (3.39 g, 10.53 mmol) in chloroform (150 mL). The reaction mixture became clear. N-hydroxysuccinimidobiotin (3.0 g, 8.79 mmol) was then slowly added. After 2 hours the turbid reaction mixture was heated to reflux. The reaction mixture was maintained at reflux overnight and became clear. The reaction mixture was allowed to cool to ambient temperature and then it was quenched with water. The layers were separated. The organic layer was dried over magnesium sulfate and then concentrated to provide an off-white solid. This material was recrystallized from 8:2 ethanol:water to provide a white solid. A portion of this material was purified by prep HPLC eluting with water/acetonitrile/trifluoroacetic acid to provide 0.6 g of N1-[2-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as the ditrifluoroacetate salt, m.p. 171-175° C. Analysis: Calculated for: C25H33N7O3S.2 C2HF3O2: % C, 47.09; % H, 4.77; % N, 13.26. Found: % C, 47.06; % H, 5.17; % N, 13.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:10]1.[OH-].[Na+]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:10]1
Reactant: CCOC(=O)c1ccc(-c2cc(C3CC(C)(C)OC(C)(C)C3)nn2-c2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To a solution of ethyl 4-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-benzoate (Example 17) (200 mg, 0.43 mmol) in 3 mL of methanol was added 0.07 mL of 50% NaOH soln (1.30 mmol) and the mixture heated at 50° C. for 8 hrs. The mixture was diluted with 50 mL of EtOAc and washed with 50 mL of 1N HCL and 50 mL of brine. The organic layer was dried over Na2SO4 and concentrated to give 185 mg (93%) of a white solid.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[CH:8]=[N:9][C:10]([S:15][CH3:16])=[N:11][C:12]=2[CH2:13][CH2:14]/1)[CH3:3].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2C(N)=[CH:28][CH:27]=[N:26]2)=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>CO.C(O)(C)C>[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:12]5[N:11]=[C:10]([S:15][CH3:16])[N:9]=[CH:8][C:7]=5[C:6]=4[C:28]=3[CH:27]=[N:26]2)=[CH:22][CH:21]=1
Reactant: CSc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: CO
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(SC)ncc2-4)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
To a mixture of (E)-6-((dimethylamino)methylene)-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (8 g, 32 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (7.2 g, 35 mmol) was added trifluoroacetic acid (3 mL). The reaction mixture was heated at 100° C. for 16 hours. The reaction was cooled to room temperature and diluted with a 1:1 mixture of methanol and isopropanol (40 mL). The mixture was stirred for 30 minutes and filtered. The solid obtained was then further purified using flash column chromatography (SiO2, gradient from 100% chloroform to 2% EtOAc in chloroform) to give the desired product (3.0 g, 24%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.52 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.64 (s, 2H), 3.78 (s, 3H), 3.16 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.2 Hz, 2H), 2.65 (s, 3H); LCMS [M+H]: 390.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1.[NH4+:18].[OH-]>CN(C)C=O.O>[Cl:7][C:8]1[C:13]([C:14]([NH2:18])=[O:15])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Oxalyl chloride (7.70 mL, 88.3 mmol) was added over 1 hour to a suspension of 4,6-dichloronicotinic acid (8.47 g, 44.1 mmol) in dimethylformamide (200 mL) at room temperature. The reaction mixture was stirred for an additional 3 hours at room temperature then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) followed by the dropwise addition of NH4OH (8.3 mL, 130 mmol) over 30 minutes [Note: reaction is exothermic upon addition of NH4OH and care was taken to control the rate of addition so that the reaction temperature did not exceed 25° C.]. The reaction mixture was stirred for an additional 1 hour at room temperature then diluted with water (600 mL) and extracted with EtOAc (4×600 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light brown solid (8.05 g, 95% yield). This material was carried forward without further purification.