Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20].O>CCO>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:9]3[S:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:16])[NH:19][N:20]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccsc1C(=O)c1ccncc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccncc2)c2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
The mixture of ethyl 2-isonicotinoylthiophene-3-carboxylate (200 mg, 0.77 mmol) from example 2.2 in NH2NH2.H2O (2 mL) and EtOH (10 mL) was stirred at room temperature for 30 min. The mixture was filtered and the solid dried to obtain the title compound (150 mg, 85.1% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[S]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:15][CH:16]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1nccn1-c1ccc(C2=CCCn3c2cnc3C)cc1
Agent: [S]
Solvent: Clc1ccccc1Cl
Product: Cc1nccn1-c1ccc(-c2cccn3c(C)ncc23)cc1
Temperature: 25 °C

Procedure:
Combine 24 g (82.7 mmol) of the product of Example III with 10 g (0.31 mol) of sulfur in 500 ml of 1,2-dichlorobenzene and heat to reflux under nitrogen for 13 hr. Cool to room temperature and extract with 2×500 ml of 10% hydrochloric acid. Combine the extracts and wash with 1 liter of methylene chloride and 500 ml of ethyl acetate. The aqueous phase is treated with charcoal, filtered, neutralized with sodium hydroxide, and extracted with 2×500 ml of methylene chloride. Dry the combined extracts over magnesium sulfate and charcoal treat. Concentrate under vacuum to 200 ml total volume and isolate the title compound by column chromatography on 300 g of silica gel using 2% methanol/methylene chloride as solvent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13]O.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in MeOH (10 mL, 247 mmol) was added sulfurous dichloride (0.232 mL, 3.22 mmol). The resulting mixture was stirred at 60° C. After 3 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with aq NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow oil of methyl 2-(4-bromo-3-fluorophenyl)acetate (500 mg, 1.774 mmol, 83.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.53 (t, J=8.0 Hz, 1H), 7.15 (dd, J=9.8, 1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 3.75-3.61 (m, 5H); ES-LCMS m/z 248.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:28]2[C:29]([C:30]#[N:31])=[C:32]([F:35])[CH:33]=[CH:34][C:27]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (820 mg, 4.4 mmol) in DCM (7 mL) was added triethyloxonium tetrafluoroborate (877 mg, 4.6 mmol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (7 mL). 3-Amino-6-fluoro-2-(pyridin-2-ylamino)benzonitrile (620 mg, 2.7 mmol) was added and the reaction heated at 75° C. for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (563 mg, 54%). LCMS (Method C): RT=3.20 min, [M+H]+=382.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])[C:3]=1[O:32][CH:33]([CH3:35])[CH3:34].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])[C:3]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C)=C\C(=O)O

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-bromo-8-tert-butyl-3-isopropoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-164, 46 mg, 0.08 mmol) in ethanol was treated with a solution of 1 N NaOH to produce the title compound after purification by recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10](=[O:11])[N:9]([NH2:12])[C:8](SC)=[N:7][N:6]=1)([CH3:4])[CH3:3].[CH2:15]([NH2:17])[CH3:16]>>[NH2:12][N:9]1[C:10](=[O:11])[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[N:6][N:7]=[C:8]1[NH:17][CH2:15][CH3:16]
Reactant: CCN
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Product: CCNc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 25 °C

Procedure:
A mixture of 150 g of technical metribuzin 200 g water and 100 g of 70% aqueous ethylamine was heated 90° for 7.0 hours in a stirred autoclave. The contents were cooled to room temperature, the solid filtered off and dried in a circulating air oven at 60°. The crude product was recrystallized from toluene to give 74 g of analytically pure product, m.p. 177°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]>>[CH3:31][C:15]1([CH3:14])[O:20][C:19]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([N:2]([CH3:1])[CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][C:5]=3[CH3:13])=[O:29])[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Reactant: CNCc1c(C)oc2ccccc12
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Yield: 81.3 %

Procedure:
According to the procedure of Example 43d, methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (124 mg, 0.71 mmol) and 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (160 mg, 0.64 mmol) were coupled to yield the title compound (211 mg, 81%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 11.39 (is, 1H), 8.20 (1s, 1H), 7.92 (is, 1H), 7.54-7.58 (m, 2H), 7.46-7.48 (m, 1H), 7.17-7.25 (m, 3H), 4.72-4.93 (m, 2H), 3.32 (s, 3H), 3.04 (s, 2H), 2.47 (s, 3H), 1.43 (1s, 6H); MS (ESI) m/e 406 (C23H23N3O4+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:4]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1.[BH4-].[Na+].C(Cl)(Cl)Cl.[Na+].[Cl-]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:4]([CH:20]([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:3]=1
Reactant: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COCOc1cccc(OC)c1-c1ccc(N)cc1C(O)c1ccccc1
Yield: 79 %

Procedure:
The compound of Example 5D (4.84, 13.31 mmol) in ethanol (45 mL) was heated at 65° C. with NaBH4(2.03 g, 53.42 mmol). After 1 hour Chloroform and aqueous NaCl was added. The organic phase was separated, washed with aqueous KHCO3, dried (Na2SO4), filtered and the solvent removed under reduced pressure to provide the titled compound (3.844 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46]C(C3OC(C#N)=CC=3)=O)=[C:42]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[CH:41]=2)[CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:42]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[CH:41]=2)[CH2:38][CH2:39]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCCCC3)c2)CC1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(N3CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To 62 mg (0.44 mmol) of 4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (107 mg, 0.560 mmol), hydroxybenzotriazole (HOBt) (65 mg, 0.48 mmol), and 4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (as prepared in Example 5, step (b), 100 mg, 0.370 mmol) and the mixture stirred for 24 h at RT. The mixture was poured into satd aq sodium bicarbonate (50 mL) and extracted with dichloromethane (2×20 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4 and the solvent was removed in vacuo. Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane yielded 63 mg (44%) of the title compound as a tan solid. 1H-NMR (400 MHz, CDCl3): δ 11.09 (br s, 1H), 9.11 (s, 1H), 8.25 (d, 1H, J=8.9 Hz), 7.45 (d, 1H, J=1.3 Hz), 6.88 (d, 1H, J=1.1 Hz), 6.81 (d, 1H, J=2.6 Hz), 6.75 (dd, 1H, J=8.9, 2.6), 3.21 (m, 4H), 2.84 (m, 4H), 2.62 (m, 4H), 2.38 (s, 3H), 1.78 (m, 5H). LC-MS (ESI, m/z): Calcd. for C22H29N6O, 393.2 (M+H); found: 393.2.
Reaction SMILES: [C:1]([C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[C:5](=O)[NH:6][C:7]1=O)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:2][CH2:1][C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[CH2:5][NH:6][CH2:7]1
Reactant: N#CC12C=CC(CC1)C1C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC12C=CC(CC1)C1CNCC12

Procedure:
15.4 g (76.2 mmol) of 1-cyano-4-azatricyclo[5.2.2.02,6 ]undec-8-ene-3,5-dione are reduced with LiAlH4 as described under Z 1-B and the mixture is worked up accordingly.
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:24]([O:26]C)=O)=O.Cl.NC.[BH3-][C:32]#[N:33].[Na+]>CO>[CH3:32][N:33]1[C:24](=[O:26])[C:4]2[C:3](=[C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[CH2:1]1
Reactant: [BH3-]C#N
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c(C=O)c(C(=O)OC)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(C)C2
Yield: 49.8 %

Procedure:
A sealed tube was charged with a solution of dimethyl 4-formyl-5-(4-(methylsulfonyl)phenoxy)-isophthalate (210 mg, 0.535 mmol) in MeOH and aminomethane hydrochloride (72.3 mg, 1.07 mmol). After stirring the reaction at room temperature for 2 hours, NaCNBH3 (84.1 mg, 1.34 mmol) was added. The mixture was then stirred at 65° C. for 14 hours. The solvent was evaporated and replaced with ethyl acetate. The organic layer was then washed with brine (3×), dried over MgSO4, and concentrated. The crude sample was introduced into a silica gel column chromatography and eluted with 5-10% MeOH/CHCl3 to provide the desired product (100 mg, 50% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.09 (s, 3 H) 3.21 (s, 3 H) 3.94 (s, 3 H) 4.36 (s, 2 H) 7.07-7.21 (m, 2 H) 7.84 (d, J=1.13 Hz, 1 H) 7.90-8.03 (m, 2 H) 8.37 (d, J=1.13 Hz, 1 H); LC-MS (ESI)+ m/z=376.00 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](O)=[O:33]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:25][CH:24]=2)=[O:9])=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C(O)c1ccccn1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC(=O)c2ccccn2)cc1

Procedure:
mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 443.3 (M)+.
Reaction SMILES: CC[C@@H]([C@H](NC([C@@H](NC(CN)=O)CC1C=CC(O)=CC=1)=O)C(NCC(N[C@H](C(N[C@H](C(O)=O)CCCN=C(N)N)=O)CO)=O)=[O:7])C.[CH2:47]([CH2:76][N:77]=[C:78]([NH2:80])[NH2:79])[CH2:48][C@H:49]([NH:71][C:72]([CH2:74][NH2:75])=[O:73])[C:50]([NH:52][CH2:53][C:54]([NH:56][C@H:57]([C:62](N[C@H](C(O)=O)CO)=[O:63])[CH2:58][C:59]([OH:61])=[O:60])=[O:55])=[O:51]>>[CH2:47]([CH2:76][N:77]=[C:78]([NH2:80])[NH2:79])[CH2:48][CH:49]([NH:71][C:72]([CH2:74][NH2:75])=[O:73])[C:50]([NH:52][CH2:53][C:54]([NH:56][CH:57]([C:62]([OH:63])=[O:7])[CH2:58][C:59]([OH:61])=[O:60])=[O:55])=[O:51]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O
Reactant: NCC(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O
Product: NCC(=O)NC(CCCN=C(N)N)C(=O)NCC(=O)NC(CC(=O)O)C(=O)O

Procedure:
GYIGSRY; GRGDF, GRGDY; GREDV; GYIGSR; GREDVY; and GRGDS;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][NH:16][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]2[CH2:31][C@@H:30]([CH2:32][C:33](O)=[O:34])[C:29](=[O:36])[N:28]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:27][C:21]2=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[CH2:31][C@@H:30]([CH2:32][C:33](=[O:34])[N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[C:12](=[O:13])[NH:11][C:10]5[CH:14]=[CH:15][NH:16][C:9]=5[CH:8]=4)[CH2:5][CH2:6]3)[C:29](=[O:36])[N:28]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:27][C:21]2=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)O)C1=O
Reactant: O=c1[nH]c2cc[nH]c2cc1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)N2CCC(c3cc4[nH]ccc4[nH]c3=O)CC2)C1=O
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To 6-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (60.0 mg, 0.276 mmol) was added (S)-2-(7-chloro-2-neopentyl-3-oxo-1,2,3,4,5,8-hexahydroazepino[3,4-e]indol-4-yl) acetic acid (100 mg, 0.276 mmol), EDC (58.3 mg, 0.304 mmol), HOBT (41.0 mg, 0.304 mmol), DMF (2.0 ml) at rt, followed by diisopropylethylamine (0.192 ml, 1.10 mmol). The resulting mixture was stirred at rt over night, partial of the solvent was removed under N2, and the residue was purified on reverse phase PrepHPLC to afford the expected products(25.2 mg, 16%), (S)-7-chloro-2-neopentyl-4-(2-oxo-2-(4-(5-oxo-4,5-dihydro-1H-pyrrolo [3,2-b]pyridin-6-yl)piperidin-1-yl)ethyl)-1,2,4,5-tetrahydroazepino [3,4-e]indol-3 (8H)-one, as a tan solid. 1H-NMR (400 MHz, MeOD) d 0.79 (d, J=5.29 Hz, 11H) 1.52-1.62 (m, 1H) 1.81 (s, 1H) 2.38-2.49 (m, 1H) 2.75 (s, 1H) 3.01 (d, J=13.35 Hz, 1H) 3.09-3.21 (m, 4H) 3.66 (d, J=13.85 Hz, 1H) 3.96 (s, 3H) 3.99-4.06 (m, 1H) 4.24 (s, 1H) 4.65 (d, J=17.37 Hz, 2H) 5.46-5.55 (m, 1H) 6.27 (dd, J=5.29, 3.02 Hz, 1H) 7.22 (s, 1H) 7.36 (dd, J=7.81, 3.02 Hz, 1H) 8.24 (s, 1H); Mass spec 562.48 (MH+) calc for C31H36ClN5O3 561.25.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](N)=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][CH2:34][CH3:35])(=[O:3])[CH3:2].C[Si]([Cl:41])(C)C.N#N>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:41])=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][CH2:34][CH3:35])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCCc1nccn1-c1nc(N)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N#N
Solvent: ClCCl
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-(2-propylimidazol-1-yl)purine (2.37 g, 4.72 mmol) in CH2Cl2 (120 mL) was added TMSCl (5.3 mL, 4.54 g, 42.5 mmol) dropwise under N2, and then BTEANO2 (7.1 g, 29.8 mmol) in CH2Cl2 (40 mL). Evolution of gas was observed, and when this subsided, additional TMSCl (5.3 mL) was added. The mixture was then stirred at ambient temperature for 3 h. The solution was diluted with CH2Cl2 and washed (NaHCO3/H2O, 2×200 mL+100 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4), and volatiles were evaporated in vacuo. The residue was chromatographed (MeOH/CH2Cl2, 1:99-1:90) to give crude product (1.40 g, 57%, contaminated with Ph3PO), which was recrystallized (i-PrOH) to give 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine: mp 126-127.5° C.; UV (MeOH) max 217, 287 nm (∈ 25 300, 15 000), min 238, 261 nm (∈ 4200, 6200); 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J=1.8 Hz, 1H), 8.25 (s, 1H), 7.11 (d, J=1.5 Hz, 1H), 6.27 (d, J=5.5 Hz, 1H), 5.83 (t, J=5.5 Hz, 1H), 5.60-5.62 (m, 1H), 4.49-4.51 (m, 1H), 4.43-4.44 (m, 2H), 3.29 (t, J=7.7 Hz, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.86 (sext, J=7.6 Hz, 2H), 1.07 (t, J=7.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 169.9, 169.7, 154.6, 153.8, 151.6, 148.4, 142.5, 129.3, 123.0, 120.5, 86.6, 81.0, 73.5, 70.8, 63.2, 33.2, 21.6, 21.1, 20.8, 20.7, 14.2; HRMS m/z 520.1476 (M+[C22H25ClN6O7]=520.1473). Anal. Calcd For C22H25ClN6O7: C, 50.73; H, 4.84; N, 16.13. Found: C, 50.58; H, 4.87; N, 16.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][C:7]([O:9][CH3:10])=[CH:6][CH2:5][CH:4]=1.[Li][CH2:12][CH2:13][CH2:14]C.C(I)(C)C>C1COCC1.CCCCCC>[CH:13]([CH:8]1[C:3]([O:2][CH3:1])=[CH:4][CH2:5][CH:6]=[C:7]1[O:9][CH3:10])([CH3:14])[CH3:12]
Reactant: [Li]CCCC
Reactant: COC1=CCC=C(OC)C1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)I
Product: COC1=CCC=C(OC)C1C(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 1,5-dimethoxy-cyclohexa-1,4diene (7 g, 50 mmol) in dry THF (140 mL) was added dropwise nBuLi solution (2.5 M, 30 mL) in hexane at −20° C. The orange colored reaction mixture was stirred for 0.5 hours at −20° C., then isopropyl iodide (17 g, 100 mmol) was added dropwise. The reaction mixture was stirred for 1 hour, while the temperature was raised to 0° C. Excess nBuLi was destroyed cautiously with methanol. Cold water (140 mL) was added to the reaction mixtures, then the product was extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a light yellow liquid (8.5 g, 93.4%). 1H NMR CDCl3): δ 0.90 (d, 6H, 2×CH3), 2.1 (m, 1H, CH), 2.76 (m, 3H, CH2 and CH), 3.53 (s, 6H, 2×OCH3), 4.73 (t, 2H, olefinic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([S:24][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(SCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a solution of 25 g of 3,4-difluorobenzonitrile in 100 ml of N,N-dimethylformamide is added 25 g of potassium carbonate and 22.3 g of benzylmercaptan. The mixture is stirred for 3 hours at room temperature and water is added. The crystals are filtered off, washed with water and pentane and dried to give 41 g of 4-benzylthio-3-fluorobenzonitrile in the form of crystals melting at 87° C.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[CH2:18][N:19]([CH3:21])[CH3:20])[N:11]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)Cl.CO>[ClH:1].[CH3:21][N:19]([CH2:18][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([OH:3])=[CH:9][CH:8]=3)[NH:14][N:13]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:20]
Reactant: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n[nH]2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccc(O)cc3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of {3-[5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-dimethylamine hydrochloride (1:1) (100 mg, 0.29 mmol) in CH2Cl2 (5 ml) at −78° C. was treated with boron tribromide (1M CH2Cl2 1.5 ml, 1.5 mmol, 5.2 eq.). Over 16 hrs. the temperature was raised gradually to r.t. After addition of methanol (1 ml) and saturated Na2CO3 (10 ml) the pH was adjusted to 9 with 2N HCl. After extraction with CH2Cl2, then EtOAc, the combined extracts were dried with Na2SO4 and the solvent evaporated. The residue was dissolved in EtOH, 1.45M HCl/EtOH added (0.17 ml, 1.1 eq.) and stirred for 30 min. then evaporated to dryness and the product obtained was dried under high vacuum at 20° C., affording the title compound (70 mg, 73% yield) as a light yellow solid. MS: m/e=295.3 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[NH:5][C:4]=1[C:10]([OH:12])=[O:11])#[N:2].[CH3:13][Si](C=[N+]=[N-])(C)C.CCOCC>C1COCC1>[CH3:13][O:11][C:10]([C:4]1[NH:5][C:6]([CH2:8][CH3:9])=[CH:7][C:3]=1[C:1]#[N:2])=[O:12]
Reactant: CCc1cc(C#N)c(C(=O)O)[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C#N)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Cyano-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 31) (500 mg) was dissolved in anhydrous THF (5 ml) and cooled to 0° C. (Trimethylsilyl)diazomethane/ether (2 ml) was added. The mixture was stirred at room temperature under nitrogen gas for 1 h. The solvent was removed in vacuo and MeOH was added. The mixture was stirred for a further 15 min, the solvent was removed in vacuo and the solid was dried under vacuum to give the title compound (580 mg).