Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][CH:18]=[CH:19][C:10]=3[C:9]=2[CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:3][O:4][C:5]([C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([Br:1])=[CH:19][C:10]=3[C:9]=2[CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 100 °C
Yield: 103.9 %

Procedure:
Bromine (6.76 ml, 132.0 mmol) was added to a mixture of 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (10.0 g, 44.0 mmol) and sodium acetate (11.2 g, 136.4 mmol) in acetic acid (360 mL) and then the reaction mixture was heated at 100° C. for 90 minutes. The reaction mixture was then cooled to ambient temperature and the solvent removed under reduced pressure then the residue was treated with saturated sodium thiosulfate solution (40 mL) followed by water (100 mL) and then the pH of the aqueous solution was adjusted to 7 by the addition of saturated sodium hydrogen carbonate solution. The resultant precipitate was collected by filtration and the solid was washed with water (20 mL) then dried at 60° C. until constant weight was achieved, to afford the desired material as an off-white solid (14.0 g, quantitative yield). 1H NMR (DMSO-D6, 300 MHz): 9.13 (d, J=2.3 Hz, 1H), 9.00 (d, J=2.0 Hz, 2H), 8.70 (d, J=2.3 Hz, 1H), 3.92 (s, 3H). LCMS (Method B): RT=2.92 min, M+H+=306/308.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:19][C:11]2[NH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[CH2:1]([CH:8]1[CH2:19][C:11]2[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CC(Cc1ccccc1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CC(Cc1ccccc1)C2
Yield: 38.9 %

Procedure:
The title compound was synthesized from methyl 5-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.017 g, 0.065 mmol) and lithium hydroxide monohydrate (0.019 g, 0.45 mmol) according to General Procedure 7. The crude product was purified by reverse phase HPLC (40-100% MeOH: water, 0.1% formic acid), to give 5-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (23) as a light brown solid (6.1 mg, 39%). Rf (1:1 EtOAc:heptane)=0.12; 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.30-2.49 (m, 2H), 2.62-2.90 (m, 4H), 3.08-3.20 (m, 1H), 6.57 (s, 1H), 7.16-7.30 (m, 5H); LCMS-MS (ESI+) 242.3 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1>FC(F)(F)CO>[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
1-Methylpiperazine (0.50 mL, 4.51 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 750 mg, 1.75 mmol) in 2,2,2-trifluoroethanol (15 mL) and the mixture was heated in a microwave at 120° C. for 1 h and then 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). This organic solution was washed with sat. NaHCO3 (100 mL), water (2×100 mL) and then brine (100 mL). The solution was then dried (MgSO4) and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% CH3OH in CH2Cl2 gave the title compound (772 mg, 87%) as a orange solid; 1H NMR: (CDCl3) 2.37 (3H, s), 2.59-2.65 (4H, m), 3.07-3.14 (4H, m), 3.90 (3H, s), 3.99 (3H, s), 6.63 (1H, s), 7.25-7.3 (1H, m) partially obscured by chloroform peak, 7.31-7.36 (1H, m), 7.39 (1H, d), 7.56 (1H, s), 8.22 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.18 (1H, s); m/z: ES+ MH+ 508.19.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]=1[F:18])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17]2)[C:7]=1[F:18])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 2-fluoro-3-piperidin-4-ylphenyl methanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 4), 287 (16), 286 (bp), 236 (2), 207 (41).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([NH2:16])[C:4]=2[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]2[CH2:31]N[CH2:29][CH2:28][NH:27]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C@@H:26]2[NH:27][CH2:28][CH2:29][N:16]([C:5]3[C:4]4[N:3]=[C:2]([CH3:1])[S:11][C:10]=4[NH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[N:6]=3)[CH2:31]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(CC[C@H]2CNCCN2)cc1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(F)cc2)C1
Yield: 38.3 %

Procedure:
By a similar method to the method of Example 460, using 2-methyl4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.21 g, 5.25 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (1.09 g, 5.25 mmol) to give 0.848 g of the title compound as a tan solid: mass spectrum (ion spray): m/z=422 (M+1); Analysis for C23H24FN5S(0.3 H2O): calcd: C, 64.70; H, 5.81; N, 16.40; found: C, 64.97; H, 5.86; N, 16.15.
Reaction SMILES: [CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10][C:9](=S)[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:21][NH2:22]>O>[CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10]/[C:9](=[N:21]\[NH2:22])/[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Reactant: NN
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
The mixture of 8-cyclobutyl-3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (0.6 g, 2.0 mmol) in 20 M of hydrazine in water (20 mL) was stirred at 100° C. overnight. After cooling to room temperature, the solid formed was filtered and dried Cooled down, the solid was isolated to give yield the desired product (230 mg, 38.6%). LCMS calculated for C14H23N6O (M+H): 291.2. Found: 291.2.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([CH2:28][S:29]C(=O)C)[CH:6]([C:14]1[CH:15]=[N:16][C:17]([NH:20]C(OC(C)(C)C)=O)=[CH:18][CH:19]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>Cl>[NH2:20][C:17]1[N:16]=[CH:15][C:14]([CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]([CH2:28][SH:29])[C:4]([OH:33])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(CSC(C)=O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: Cl
Product: Nc1ccc(C(Cc2ccccc2)C(CS)C(=O)O)cn1

Procedure:
2-Acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)4-phenyl-butyric acid ethyl ester (0.14 g, 0.3 mmol) was dissolved in conc. HCl (5.0 mL). The solution was heated to reflux for 4.5 h under argon. Concentration under reduced pressure gave the title compound as the hydrochloride salt (100 mg, 98%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 96 %

Procedure:
4-Chlorobenzonitrile (141 mg, 1.02 mmol) reacted with p-trifluoromethylphenylboronic acid using by 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (182 mg, 3.00 mmol) in THF solvent to give the title compound (236 mg, 96%) as a white solid after recrystallization from hexane: 1H-NMR (500 MHz, CDCl3): δ 7.78 (d, 2H, J=8.23 Hz), 7.76 (d, 2H, J=8.48 Hz), 7.71 (app.d, 4H, J=8.18 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 111.92, 118.57, 142.61, 144.09, 123.95 (q, J=270.2 Hz), 126.04 (q, J=3.6 Hz), 127.60, 127.93, 130.63 (q, J=32.5 Hz), 132.76. 19F{1H}-NMR (MHz, CDCl3): δ −63.0. GC/MS(EI): m/z 247 (M+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][NH:2][CH2:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2c(c1)CCNC2
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)CNCC2
Yield: 50 %

Procedure:
This example shows how to make example compounds of the present invention. More specifically, this example demonstrates how to make four aromatic nitro isomers of 6-position nitro-1,2,3,4-tetrahydroisoquinolinylpurine ribosides NBMPR analogues (compounds 2-5). Several literature methods are employed to synthesize the required nitro-1,2,3,4-tetrahydroisoquinoline (compounds 6-9), which are subsequently reacted with the commercially available 6-chloropurine riboside (10) according to Scheme 1 to obtain the target compounds. The commercially available 5-nitroisoquinoline (11) is reduced using sodium borohydride in ethanol to afford the 5-tetrahydroisoquinoline (6) intermediate in good yield (about 90%). The 7-nitrotetrahydroisoquinoline intermediate (8) is prepared in about 50% yield by nitration of the commercially available 1,2,3,4-tetrahydroisoquinoline using KNO3 in concentrated sulfuric acid according to the method of Ajao et al. (1985) (Scheme 3). The 6- and 8-nitro-1,2,3,4-tetrahydroisoquinoline intermediates 7 and 9, are prepared following reaction Scheme 4 according to the report by Tercel et al. (1996) as follows.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:39])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:15][CH:14]=2)[N:7]([C:40]2[CH:45]=[CH:44][C:43]([O:46][Si](C(C)C)(C(C)C)C(C)C)=[C:42]([Cl:57])[CH:41]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:39])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:15][CH:14]=2)[N:7]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([Cl:57])[CH:41]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCOCC4)c3)c3ccccc23)cc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCOCC4)c3)c3ccccc23)n(-c2ccc(O)c(Cl)c2)n1
Reaction time: 16 h

Procedure:
To a solution of N-(4-(4-(3-(3-tert-butyl-1-(3-chloro-4-(triisopropylsilyloxy)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)morpholine-4-carboxamide (70 mg, 0.078 mmol) in dry THF (2.0 mL) was added TBAF (1.0 M in THF, 116 μL, 0.116 mmol) and the reaction mixture kept at RT for 16 hr. The reaction mixture was diluted with MeOH (1.0 mL) and after 5 min was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 4 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Example 12, as a pink solid (20 mg, 39%); Rt 3.97 min (Method 1 basic); m/z 655 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 3.36 (4H, m), 3.52 (4H, m), 6.37 (1H, s), 6.61 (1H, dd), 7.12 (1H, d), 7.31 (1H, d), 7.35 (1H, dd), 7.37 (1H, d), 7.54 (1H, d), 7.57 (1H, m), 7.64 (1H, m), 7.84 (1H, d), 7.91 (1H, br s), 8.06 (1H, d), 8.12 (1H, d), 8.74 (1H, s), 9.09 (1H, s), 9.26 (1H, s), 10.62 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(c2nncc3cc(Br)ccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C)CC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 6-bromo-1-(4-methylpiperazin-1-yl)phthalazine (0.13 g, 0.42 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.13 g, 0.42 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.021 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4: 1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.15g) as a yellow solid. Found MS (ES+): 402(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=3)[N:18]=1)[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2

Procedure:
Was prepared according to method A from 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-chloro-6-nitroquinoline. Decomp.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C(=Cc1ccccc1)COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 5-hydroxyindole (0.25 g) in acetonitrile (10 mL) was added cesium carbonate (1.22 g) and cinnamyl bromide (0.37 g). The suspension was stirred under nitrogen at ambient temperature overnight. Cesium salts were removed by filtration and washed with acetone. The residue left on concentrating the combined filtrate and washings was chromatographed over silica eel with a mixture of ethyl acetate and hexanes and crystallized from ether with hexanes to give 0.23 g of the title compound. MS CI (MH+)=250
Reaction SMILES: [S:1]1[C:9]2[C:8](=[O:10])[CH2:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:10][C:8]2[C:9]3[S:1][CH:2]=[CH:3][C:4]=3[CH:5]=[N:6][CH:7]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CN=Cc2ccsc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cncc3ccsc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of thieno[3,2-c]pyridin-7(6H)-one (110 mg, 0.728 mmol, 1.0 equiv) in THF (5.00 mL) was added NaH (35 mg, 0.873 mmol, 1.2 equiv) followed by TsCl (180 mg, 0.946 mmol, 1.3 equiv). The reaction mixture was stirred at rt for 2 h, then quenched with water and extracted with ethyl acetate. Purification by column chromatography using 20% ethyl acetate in hexanes elution gave 180 mg of a white solid, 81%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]([S:14][CH3:15])[N:4]=1.[CH3:16][NH2:17]>CO>[CH3:15][S:14][C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:11])[N:17]([CH3:16])[CH2:2][C:3]=2[N:4]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1CCl
Solvent: CO
Product: CSc1ncc2c(n1)CN(C)C2=O
Reaction time: 15 h
Yield: 18 %

Procedure:
79 g (320 mmoles) of 4-chloromethyl-5-ethoxycarbonyl-2-methylthiopyrimidine was dissolved in 300 ml of methanol, and 50 g (640 mmoles) of a 40% methanol solution of methylamine was added dropwise over 15 minutes, and the mixture was stirred for 15 hours. The product was separated by filtration and dried to give 11 g (yield 18%) of 2-methylthio-6-methyl-5-oxo-5,6-dihydro(7H) pyrrolo[3,4-d]pyrimidine. The resulting product (1.5 g; 7.7 mmoles) and 3.4 g (38.5 mmoles) of morpholine were dissolved in 20 ml of n-amyl alcohol, and the solution was heated under reflux for 7 hours. The reaction mixture was cooled, and the precipitated crystals were separated by filtration to give 0.75 g (yield 42%) of the desired compounds.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH2:27][S:28][CH3:29])[NH2:25]>>[CH2:1]([C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:25][CH:24]([CH2:26][CH2:27][S:28][CH3:29])[C:23]([O:22][CH3:21])=[O:30])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cc1ccccc1
Agent: Cl
Product: COC(=O)C(CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1Cc1ccccc1

Procedure:
Compound 29 (2.45 mmol) was coupled with L-methionine methyl ester hydrochloride (540 mg, 2.7 mmol) to give methyl 2-[(2-benzyl-4-nitro-benzoyl)amino]-4-methylsulfanyl-butyrate (compound 30).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]([NH2:27])[CH3:26])=[N:23][CH:24]=3)[C:11]=2[F:28])[CH:7]=[CH:8][CH:9]=1.O.[O-:30][C:31]#[N:32].[Na+].Cl>C(OCC)C.C(O)(=O)C>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]([NH:27][C:31]([NH2:32])=[O:30])[CH3:26])=[N:23][CH:24]=3)[C:11]=2[F:28])[CH:7]=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(Cc2ccc(C(C)N)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Cc2ccc(C(C)NC(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 1-[5-(3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethylamine dihydrochloride (P-606, 55 mg, 0.124 mmol), water (800 uL), glacial acetic acid (400 uL) followed by sodium cyanate (32.2 mg, 0.496 mmol). The mixture was stirred at room temperature for 18 hours and then slowly quenched with a saturated solution of sodium bicarbonate (3 mL) and extracted with dichloromethane (3×4 mL). The organic portions were combined, dried (MgSO4), concentrated and purified by a 10 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 2-20% MeOH/dichloromethane to produce 13 mg of P-613 (free base) as an off-white solid in 25% yield. To P-613 (free base) (13 mg, 0.0314 mmol) was added diethyl ether (1 mL) and 2M HCl in diethyl ether (300 uL). The mixture was allowed to stir at room temperature for 10 minutes, concentrated and dried to produce 14 mg of P-613HCl salt as an off-white solid in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 1.36 (d, J=7 Hz, 3H), 3.73 (s, 3H), 4.06 (s, 2H), 4.82 (m, 1H), 5.53 (br s, 2H), 6.69 (br s, 1H), 6.97 (d, J=9 Hz, 1H), 7.29 (br d, J=6 Hz, 1H), 7.38-7.47 (m, 4H), 7.60 (br d, J=8 Hz, 1H), 8.02 (br d, J=8 Hz, 1H), 8.58 (s, 1H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:16].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:16].[CH3:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-t-butoxycarbonyl-4-methoxypiperidine (2.84 g) in ethyl acetate (20 ml) was added 4N hydrochloric-acid-ethyl acetate solution (20 ml) and the mixture was stirred at ambient temperature for 1 hour. The solution was evaporated in vacuo to give 4-methoxypiperidine hydrochloride as a colorless amorphous powder (2.03 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11].[H-].[Na+].[F:25][C:26]([F:30])([F:29])[CH2:27]I>CN(C=O)C>[Cl:22][C:21]1[C:16]([CH:14]2[CH2:13][N:12]([C:10]([C:2]3[N:3]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)=[O:11])[CH2:15]2)=[N:17][CH:18]=[CH:19][N:20]=1
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2Cl)C1
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1nc2ccccc2n1CC(F)(F)F)N1CC(c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone (84), as prepared in Preparation 36 below, (314 mg, 1.0 mmol) in dry DMF (10 mL) was added sodium hydride (applied as 60% dispersion in oil, 62 mg, 1.5 mmol)) at 0° C. under N2 atmosphere. After 0.5 h, 1,1,1-Trifluoro-2-iodo-ethane (418 mg, 2.0 mmol) was added slowly. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with water (10 mL) at 0° C. and extracted with EtOAc (3×20 mL). The combined organics were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography to provide (85) (355 mg, 0.90 mmol, 90% yield) as white solid.