Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@:2]1([C:15]([OH:17])=[O:16])[CH2:6][CH:5]([OH:7])[CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:18]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:11]([O:10][C:8]([N:3]1[CH2:4][CH:5]([O:7][C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][C:42]=2[F:44])[CH2:6][CH:2]1[C:15]([O:17][CH3:18])=[O:16])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@@]1(C)C(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccc(F)cc2F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirred solution of methyl 1-(tert-butoxycarbonyl)-4-hydroxyproline (4.0 g, 16.3 mmol), Ph3P (5.14 g, 19.6 mmol), and 2,4-difluorophenol (2.55 g, 19.6 mmol) in THF (50 ml) was added DIAD (3.9 ml, 19.6 mmol), and the mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was concntrated in vacuo and the residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) to give methyl 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylate (5.82 g, quant) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[Br:19]Br>C(Cl)Cl>[Br:19][C:3]1[C:4](=[O:18])[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: O=c1c(Br)c(O)c2cccnc2n1-c1ccccc1
Yield: 65.4 %

Procedure:
To a suspension of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1 g) in CH2Cl2 (20 mL) was added, dropwise and with stirring, a solution of bromine (0.7 g) in CH2Cl2 (5 mL). The mixture was stirred at room temperature overnight, after which time the product was filtered off, dried in air and recrystallized from acetonitrile to yield 0.87 g of the product, m.p. 280° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].C(O)C.C(O)(=O)C>[Fe].CCOC(C)=O>[NH2:21][C:17]1[CH:16]=[C:15]([C:10]2[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=[C:2]([F:1])[CH:3]=3)[CH:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Temperature: 92 °C

Procedure:
To 3-fluoro-N-(6-methyl-3′-nitrobiphenyl-3-yl)-5-(trifluoromethyl)benzamide (4.09 g, 9.78 mmol) was added ethanol (93.2 mL) followed by iron (3.0 g, 54 mmol) and acetic acid (9.32 mL, 164 mmol). The solution was heated at 92° C. for 2 h using the rotovap motor/heating bath. To the reaction mixture was added EtOAc and the mixture was then filtered and was concentrated in vacuo. The residue was used in the next reaction without purification. MS (EI) m/z=389 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.Cl.[C:32](N1C=CC=N1)(=[NH:34])[NH2:33].C(N(CC)CC)C>CO>[ClH:30].[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([C@H:6]3[CH2:7][CH2:8][C@@H:3]([NH:2][C:32]([NH2:34])=[NH:33])[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: N=C(N)n1cccn1
Reactant: N[C@H]1CC[C@@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(N)N[C@H]1CC[C@@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Yield: 161.6 %

Procedure:
A solution of 1-(cis-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg), 1-amidinopyrazole hydrochloride (47 mg) and triethylamine (100 mg) in methanol (10 ml)was stirred at room temperature for 1 day. The reaction solution was concentrated, and to the residue was added dichloromethane. The mixture was washed with 1 N sodium hydroxide aqueous solution, dried and concentrated. The residue was dissolved in ethyl acetate and transformed into hydrochloride with hydrochloric acid to give a colorless solid of the title compound (88 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Product: CSc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-(4-methylthiophenyl)isoquinolin-1-one (0.73 g) was reacted with phosphorus oxychloride (5 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-methylthiophenyl)isoquinoline. Then, N-ethylpiperazine (10 ml) and potassium carbonate (0.36 g) were added to the resulting product as it was. The resulting mixture were reacted at 100° C. overnight. The reaction solution was evaporated, and the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.95 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([OH:18])[CH2:16][CH:15]2[CH2:27][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([OH:18])[CH2:16][CH:15]2[CH2:27][CH:12]1[CH2:13][CH2:14]2)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: COc1cccc(C2(O)CC3CCC(C3)C2CN(C)C)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (100 mg, 5.56 mmol) and TMSCl (361 mg, 3.34 mmol) to a solution of 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol (877 mg, 3.03 mmol) in 2-butanone (60 mL). Stir the mixture at ambient temperature for 12 hours. Concentrate the mixture under vacuum to give 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol hydrochloride as white solid (986 mg, Yield: 100%). 1H NMR (400 MHz, D2O) δ 7.23-7.27 (t, J=16.4, 1H), 7.00-7.02 (d, J=8.0, 1H), 6.95-6.96 (t, J=4.0, 1H), 6.78-6.80 (d, J=10.4, 1H), 3.71 (s, 3H), 3.05-3.19 (m, 1H), 2.52-2.58 (m, 4H), 2.14-2.26 (m, 4H), 2.09-2.14 (m, 2H), 2.05-2.06 (d, J=2.4, 1H), 1.89-1.92 (m, 1H), 1.78-1.80 (m, 1H), 1.51-1.68 (m, 4H), 1.40-1.52 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][CH2:17][CH3:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:12]=[C:11]([O:16][CH2:17][CH3:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Solvent: Cc1cc(C)cc(C)c1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12

Procedure:
5.1 g (15.6 mmol) 7-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole and 13.4 g (155.8 mmol) piperazine were heated in 80 ml mesitylene to 150° C. for 7.5 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 5.8 g (99%) of the title substance was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([C:22]([O:24]C)=[O:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Li+].CO>C1COCC1.O>[CH2:15]([O:14][C:12]([N:3]1[C:2]([CH3:1])([C:22]([OH:24])=[O:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1(C)Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
Step-3: To a solution of 2-benzyl 3-methyl 3-methyl-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate in THF (1.2 mL) was added lithium hydroxide (50.5 mg, 1.204 mmol) in water (0.6 mL). Methanol (0.72 mL) was added till homogeneous solution was obtained and the reaction was heated at 60° C. overnight. The reaction was concentrated, acidified to pH 2 using 2 N HCl, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford the crude product which was purified by preparative TLC using hexane/ethyl acetate mixture (1:1) to afford 2-((benzyloxy)carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. MS (ES+): m/z 326.15 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:11].[N:12](OCCC(C)C)=[O:13]>C(O)C.C(OCC)C>[C:8](/[C:7](=[N:12]\[O-:13])/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:9].[Na+:11]
Reactant: CC(C)CCON=O
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: N#C/C(=N\[O-])c1ccccc1
Reaction time: 2 h
Yield: 56.6 %

Procedure:
Phenylacetonitrile (9.72 g, 82.97 mmol) was metered into a suspension of 3.31 g (82.97 mmol) of NaOH in 60 ml of ethanol. Following the complete addition, 11.66 g (99.56 mmol) of isopentyl nitrite were metered in dropwise at temperatures of 15° C. The mixture was then stirred for a further 2 hours at this temperature. The reaction mixture was diluted with 300 ml of diethyl ether, and the precipitated solid was filtered off and washed twice with in each case 50 ml of diethyl ether. The white salt sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide (7.89 g, 56% yield) can be dried in vacuo or be further used directly. 1.49 g (6.24 mmol) of but-3-yn-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate and 103 mg (0.624 mmol) of potassium iodide were added to a solution of 1.05 g (6.24 mmol) of sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide in 25 ml of acetonitrile and 10 ml of DMF. The reaction mixture was stirred for 7 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in 100 ml of ethyl acetate. The organic phase was washed with water and dried over MgSO4. After removing the solvent, 2.21 g (99% yield, only 1 oxime isomer) of but-3-yn-1-yl{6-[({[(Z)-cyano(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate were isolated as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][C:28](O)=[O:29])=[C:21]2[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH:16][C:28](=[O:29])[CH2:27][C:22]1[NH:23][C:24]2[C:20]([C:21]=1[CH3:31])=[CH:19][C:18]([F:17])=[CH:26][CH:25]=2
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Reactant: Cc1c(CC(=O)O)[nH]c2ccc(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CC(=O)NC2CC3(CCC3)Oc3ccc(F)cc32)[nH]c2ccc(F)cc12

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and (5-fluoro-3-methyl-1H-indol-2-yl)acetic acid (200 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.145 mmol), HOBt (221 mg, 1.145 mmol) and triethylamine (401 μl, 3.003 mmol) in dichloromethane (10 ml) as described in Example 1 to give 18 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.74 (m, 4H), 1.88-1.95 (m, 2H), 2.08-2.25 (m, 2H), 2.40 (s, 3H), 3.70 (s, 2H), 5.23 (q, J=8.7 Hz, 1H), 5.68 (d, J=9.0 Hz, 1H), 6.61-6.66 (m, 2H), 6.72-6.89 (m, 2H), 7.07-7.18 (m, 2H), 8.01 (s, 1H); ESI-MS (m/z) 397.33 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:38])[C@@H:10]([NH:20][C:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C@H:10]([NH:20]/[C:21](/[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:22]/[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:38])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of di-tert-butyl {[((1S)-2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}-2-oxoethyl)amino]methylylidene}biscarbamate (1.72 g) in dichloromethane (17 ml) was added trityl chloride (931 mg). To the mixture was added triethylamine (0.53 ml) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate. The solution was washed with water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give di-tert-butyl {(Z)-[((1S)-{[(tert-butoxycarbonyl)amino]methyl}-2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoethyl)amino]methylylidene}biscarbamate (2.25 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])(C)(C)C.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1.CCCCC.C(OCC)C>[CH3:14][Sn:15]([CH3:17])([CH3:16])[SH:1]1[CH:5]=[C:4]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[C:3]2[S:6][CH:7]=[CH:8][C:2]1=2
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2sccc2s1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Sn](C)(C)C1=C[SH]([Sn](C)(C)C)c2ccsc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
1 g (7.1 mmol) thieno[3,2-b]thiophene are dissolved in 40 ml anhydrous THF under argon and cooled to −78° C. 11 ml (17.6 mmol) of a 1.6 M tert-butyllithium solution in pentane are added slowly. The mixture is stirred for 2 hours at −78° C., then 4 g (20 mmol) trimethyltin chloride are added as solid. The solution is warmed to room temperature and, stirred for one hour. The solution is diluted with 100 ml diethylether, extracted with aqueous sodium bicarbonate solution, dried and evaporated. The residue is crystallized from acetonitrile at −20° C. to yield 1.9 g (58%) of colorless crystals. Mp=130° C., MS (FD, 8 kV) m/z=465.4 g/mol—calculated: 465.9 g/mol for C12H20S2Sn2; 1H-NMR (300 MHz, CD2 Cl2, RT): δ 7.28 (s, 2H), δ 0.41 (s, 2H); 13C-NMR (75 MHz, CD2Cl2, RT): δ 148.0, 142.0, 16.6, −8.0; elemental analysis: found 30.91%, 4,48% H, 13.61% S—calculated: 30.94% C, 4.33% H, 13.77% S.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:18])([CH3:17])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][CH2:25][NH:26][C:34](=[O:36])[CH3:35])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC(C)(C)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COCc1nc2c(N)nc3cc(CCCNC(C)=O)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
A solution of 1-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.25 g, 3.50 mmol) in triethylamine (2.4 mL, 17.5 mmol) was cooled to 0° C. in an ice water bath and acetic anhydride (393 mg, 3.85 mmol) was added. The solution was stirred for approximately 18 hours while warming to ambient temperature. The solution was concentrated under reduced pressure and the residue was partitioned between 1% aqueous sodium carbonate (125 mL) and chloroform (50 mL). Successive chloroform extractions were performed until no product was present in the aqueous layer. The combined organic fractions were concentrated under reduced pressure and dissolved in methanol (100 mL). To this solution was added solid potassium carbonate (3 tsp) and the reaction was heated to reflux temperature for 2 hours. After cooling to ambient temperature, the mixture was filtered, concentrated and partitioned between water (50 mL) and chloroform (50 mL). Crude product was extracted from the aqueous fraction through successive chloroform extractions until no product remained in the aqueous layer. The combined organic extracts were concentrated and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-30% CMA over 1500 mL, followed by 30% CMA over 1000 mL) to provide 578 mg of N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}acetamide as a white semi-solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:14][NH2:15].C1COCC1>>[Cl:9][C:6]1[N:5]=[C:4]2[C:10](=[O:12])[N:15]([CH3:14])[CH2:2][C:3]2=[CH:8][CH:7]=1
Reactant: COC(=O)c1nc(Cl)ccc1CBr
Reactant: CN
Solvent: C1CCOC1
Product: CN1Cc2ccc(Cl)nc2C1=O

Procedure:
2-Chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one was prepared according to the general procedure in Example 7 Step 1 using methyl 3-(bromomethyl)-6-chloropyridine-2-carboxylate (0.40 g, 1.49 mmol) and methylamine, 2 M in THF (10 mL, 20 mmol) as the starting materials.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3[N:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:29][C:25]=3[C@@H:24]([NH:34]C(OC(C)(C)C)=O)[C@H:23]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=3[F:49])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3[N:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[S:29][C:25]=3[C@@H:24]([NH2:34])[C@H:23]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=3[F:49])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2sc(C(F)(F)F)nc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1c2sc(C(F)(F)F)nc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Reaction time: 2 h
Yield: 89.8 %

Procedure:
(4R,7S,8S)-8-(tert-butoxycarbonylamino)-7-(2,3-difluorophenyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-4-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (3.5 mg, 4.94 μmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (0.5 mL, 6.49 mmol) at rt. The reaction was stirred for 2 h. The solvent was removed under vacuum and the crude product was partitioned between sodium bicarbonate(sat.) and ethyl acetate. The organic layer was separated, dried (sodium sulfate), filtered and concentrated in vacuo. Flash chromatography, eluting with methanol in methylene chloride from 0 to 10% gave the desired product (2.7 mg, 90%) as a white solid: LCMS (M+Na=631.04).
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=O.Cl.[NH2:27][OH:28].C(OCC)(=O)C.O>CN(C)C=O>[OH:28][N:27]=[CH:1][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc2occ(C=NO)c(=O)c2cc1Oc1ccccc1
Reaction time: 1 h
Yield: 72 %

Procedure:
4 g of 3-formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 20 ml of N,N-dimethylformamide. Thereto was added 850 mg of hydroxylamine hydrochloride. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was mixed with 50 ml of ethyl acetate and 100 ml of water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from ethanol to obtain 3.0 g (yield: 72.3%) of 3-hydroxyiminomethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 199°-200° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:11](OC(=O)C)(=[O:13])[CH3:12].O.C(OCC)(=O)C>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:11](=[O:13])[CH3:12]
Reactant: NCc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-bromobenzylamine hydrochloride (5.20 g) in pyridine (30 ml) was added acetic anhydride (3.2 ml) at 0° C. and the mixture was stirred at room temperature for 24 h. Water and ethyl acetate were added to the reaction mixture for partitioning, and the organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (4.00 g) as colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)(=O)C>O1CCOCC1>[CH2:35]([NH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2NCc2ccccc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2-amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (170 mg, 0.379 mmol) in anhydrous dioxane (3 mL) was added a 1 M solution of potassium t-butoxide (0.42 mL, 0.42 mmol). The reaction mixture was stirred at room temperature for 10 minutes and benzyl bromide (130 mg, 0.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 2-benzylamino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-bromopyrazine 112 (165 mg, 0.307 mmol).