Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]1[C@@H:27]([C:28](O)=[O:29])[CH2:26][NH:25][C:24]1=[O:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:28]([C@H:27]3[CH2:26][NH:25][C:24](=[O:31])[N:23]3[CH3:22])=[O:29])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Reactant: CN1C(=O)NC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc(-c2cc(NC(=O)[C@H]3CNC(=O)N3C)nn2-c2ccccc2)c1
Yield: 49.1 %

Procedure:
To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (56 mg) prepared according to the same procedures as Preparation 8 in N,N-dimethylformamide (0.6 ml) were sequentially added (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid (38 mg) prepared in Preparation 9, HOBt.H2O (46 mg) and WSC.HCl (58 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added a saturated aqueous solution of sodium hydrogen carbonate and water, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (40 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I-].[K+].[CH3:40][C:41]([CH2:43]C(C)C)=O>>[CH2:43]([N:11]1[CH2:12][C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:41]=[CH2:40]
Reactant: CC(=O)CC(C)C
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: C=CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (1.025 g, 2.5 mmol) was dissolved in methylisobutylketone (15 ml). Triethylamine (0.53 ml, 3.8 mmol) and potassium iodide (0.04 g) were added. The mixture was stirred under a nitrogen atmosphere for 4 hours at 80° C. and 24 hours at room temperature and evaporated in vacuo. Water (40 ml) was added and extraction with methylene chloride (3×40 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded a yellow oil. Purification of the crude product on a silica gel column (Eluent: Heptane/ethyl acetate (9: 1)) gave (2R,3R,4R)-1-allyl-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (0.91g, yield: 81%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][OH:8])([O-:3])=[O:2].N1C=CN=C1.ClCCl.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.C(OCC)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][O:8][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Add 2-nitrophenethyl alcohol (20 g, 120 mmol) and imidazole (11.4 g, 167 mmol) to dichloromethane (200 mL). Cooled to 0° C. and add solid tert-butyldimethylsilyl chloride (23.4 g, 155 mmol). Stir the mixture at 20° C. for 2 hours and dilute with 1:1 ethyl acetate:diethyl ether. Wash with distilled water, aqueous 3% acetic acid, aqueous 0.5 molar sodium hydrogen carbonate, and saturated sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to give 32.4 g (96%) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, 1H, J=8.0, 1.2 Hz), 7.50 (dt, 1H, J=7.2, 1.6 Hz), 7.37 (m, 2H), 3.89 (t, 2H, J=6.4 Hz), 3.12 (t, 2H, J=6.4 Hz), 0.83 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:23][CH2:24][N:25]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:26][CH2:27]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1
Reactant: CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 80 °C

Procedure:
Ethyl chloroformate (40.4 mL; 45.9 g; 0.423 mol) was added slowly to a hot (-80° C) toluene solution (320 mL) of the 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (45.7 g; 0.141 mol) from Example 1E containing the two corresponding fluoro-substituted compounds of the invention. Following complete addition, the temperature was maintained at 80° C. for 1 h. The reaction mixture was cooled to ambient temperature and the toluene solution washed with water which was adjusted to pH 10 with aqueous sodium hydroxide. The organic layer was concentrated to a residue which was dissolved in hot acetonitrile and decolorized with charcoal. The solution was concentrated to a crystalline slurry which was cooled (5° C). 8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta [1,2-b]pyridine containing the two corresponding fluoro-substituted compounds of the invention as discussed in Examples 1G below was isolated by filtration yielding 42.4 g: m.p. 134.5°-136° C.; NMR (400 MHz, CDCl3)δ1.25 (t,3H,J=8 Hz), 2.3-2.4 (m,3H), 2.4-2.5 (m,1H), 2.7-2.9 (m,2H), 3.1-3.2 (m,2H), 3.3-3.4 (m,2H), 3.81 (br s, 2H), 4.13 (q,2H,J=8 Hz), 7.1-7.3 (m,4H), 7.43 (dd,1H,J=9,2 Hz), 8.40 (d,1H,J=5 Hz); mass spectrum, m/e (relative intensity) 385M+3 (35), 383 M+1 (100). Anal. Calcd. for C22H23N2ClO2 : C,69.00; H,6.05; N,7.32; Cl9.26. Found: C,69.37; H,6.09; N,7.35; Cl 9.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[C:11]([CH:18]2[C:20]3([C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[O:22][C:21]3([CH3:29])[CH3:28])[O:19]2)[CH:10]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.Cl([O-])(=O)(=O)=O.[Li+]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[C:11]([CH:18]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[O:22][C:21]([CH3:29])([CH3:28])[C:20]2=[O:19])[CH:10]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Temperature: 27 °C
Yield: 15.8 %

Procedure:
To a mixture of 2-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one (17.80 g, 0.041 mol) and ytterbium triflate (2.20 g, 4.41 mmol) is added a solution of 5M lithium perchlorate (prepared from 42 ml diethyl ether and 22.30 g lithium perchlorate). The resulting suspension is stirred at room temperature for 17 days, at which stage further diethyl ether (42 ml), lithium perchlorate (22.3 g, 0.21 mol) and ytterbium triflate (19.8 g, 0.035 mol) is added. The reaction mixture is then heated at 27° C. (internal temperature) for 1 day, followed by partitioning between diethyl ether and distilled water. The two phases are separated, the aqueous phase is extracted with diethyl ether (×2), and then all organic fractions are combined, washed with brine then dried over magnesium sulphate. The suspension is filtered and the filtrate is concentrated in vacuo. The crude material is purified by flash column chromatography (ethyl acetate/hexane eluant) to give an oil which is triturated with hexanes to afford 4-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (2.80 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[O:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: CC(=O)c1ccco1
Reactant: C1COCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(c1ccco1)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
2-Acetylfuran (20 mmol) and morpholine (20 mmol) were added to neat titanium isopropoxide (32 mmol) and the reaction stirred under N2 at room temperature for 3 h. Methanol (90 ml) was then added followed by the careful portionwise addition of NaBH4 (32 mmol). After stirring at room temperature for 10 mins, the reaction was quenched by addition of 0.1M NaOH and the resultant mixture filtered through a celite pad. The filtrate was extracted twice with DCM, dried over Na2SO4 and concentrated in-vacuo. Flash chromatography of the residue (silica, 5 to 20% EtOAc in Heptane) yielded pure 4-(1-furan-2-yl-ethyl)-morpholine as a golden oil: m/z in MS ES+=182 [M+H]+, 2.76 mmol, 14% yield.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.[CH2:9]([N:11]1[C:19]2[C:14](=[N:15][C:16]([C:20](OC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:24](=[O:42])[NH:25][CH:26]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=1)[C:27]([F:30])([F:29])[F:28])[CH3:10]>ClCCl>[CH:1]1([NH:4][C:20]([C:16]2[N:15]=[C:14]3[CH:13]=[C:12]([C:24]([NH:25][CH:26]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:39])([F:40])[F:41])[CH:32]=4)[C:27]([F:29])([F:28])[F:30])=[O:42])[N:11]([CH2:9][CH3:10])[C:19]3=[CH:18][CH:17]=2)=[O:21])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)NC(c2ccc(F)c(C(F)(F)F)c2)C(F)(F)F)cc2nc(C(=O)OC)ccc21
Reactant: NC1CC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCn1c(C(=O)NC(c2ccc(F)c(C(F)(F)F)c2)C(F)(F)F)cc2nc(C(=O)NC3CC3)ccc21
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon protective gas, cyclopropylamine (58.1 mg, 1.02 mmol) was added to one ml of dichloromethane, and trimethylaluminium (73.4 mg, 1.02 mmol) was added dropwise using a syringe. The mixture was stirred for another 30 minutes, and methyl 1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate, dissolved in one ml of dichloromethane, was then added dropwise. The reaction mixture was then heated under reflux for six hours and subsequently cooled and hydrolysed, and the residue was, after removal of the volatile components under reduced pressure, chromatographed on silica gel cyclohexane/ethyl acetate (ethyl acetate 0% to 60%). This gave 20 mg (35% of theory) of the target product. HPLC-MS: log P=3.78; mass (m/z): 517.1 (M+H)+; 1HNMR (D6-DMSO): δ 0.54-0.76 (m, 4H), 1.22-1.30 (t, 3H), 2.88-2.94 (m, 1H), 4.48-4.59 (q, 2H), 6.32-6.42 (m, 1H), 7.42 (s, 1H), 7.65-7.71 (t, 1H), 7.98-8.02 (d, 1H), 8.14-8.20 (m, 1H), 8.20-8.24 (d, 1H), 8.26-8.32 (m, 1H), 8.56-8.62 (d, 1H), 9.91 (s, 1H).
Reaction SMILES: [ClH:1].[C:2]([CH:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)([OH:4])=[O:3].S(Cl)([Cl:20])=O>>[ClH:20].[C:2]([CH:5]([Cl:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)([OH:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(O)CCCCCCn1ccnc1
Agent: Cl
Product: O=C(O)C(Cl)CCCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 140 mg of 1-(7-carboxy-7-hydroxyheptyl)imidazole hydrochloride (prepared in Example 6(a)) was added dropwise 0.193 ml of thionyl chloride at from 0° C. to 3° C., and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. Ice was added to the obtained residue, and the mixture was stirred for 5 minutes, and concentrated under reduced pressure. A small amount of water was added to the residue, and insoluble materials were removed off, and the solution thus obtained was concentrated under reduced pressure to give 149 mg of the title compound having the following physical characteristics:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)([OH:14])[CH2:9]1)=O)(C)(C)C.C=O>C(O)=O>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Br)cc2)C1
Agent: C=O
Solvent: O=CO
Product: CN1CCCC(O)(c2ccc(Br)cc2)C1
Temperature: 150 °C
Yield: 92.8 %

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.39 g, 3.9 mmol), formic acid (18.4 mL) and formaldehyde (1.6 mL) was heated under microwave irradiation at 150° C. for 5 minutes. The cooled reaction mixture was loaded onto a 70 g SCX-2 cartridge which was washed with methanol (200 mL) and then eluted with 2N ammonia in methanol (200 mL). Concentration of the combined basic fractions in vacuo afforded the title compound (978 mg, 93%) as a brown oil. LCMS (Method B): RT=1.84 min, M+H+=270.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([O:33][CH:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCOCC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OC4CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1
Yield: 27 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 188 as a white solid (12 mg, 27%). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 8.25 (dd, J=8.6, 3.9 Hz, 1H), 8.17-8.09 (m, 1H), 7.85 (s, 1H), 7.40-7.00 (br s, 2H), 7.20 (d, J=11.6 Hz, 2H), 5.30 (d, J=48 Hz, 1H), 4.92-4.86 (m, 2H), 4.11-4.00 (m, 2H), 3.92-3.84 (m, 2H), 3.75 (s, 3H), 3.62-3.50 (m, 3H), 2.07 (m, 4H), 1.95-1.70 (m, 2H), 1.68-1.55 (m, 2H). LCMS (ES+) m/z 564 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[C:27]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[N:24]([CH3:27])[C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c(n3C)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 34.4 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.10 g, 0.28 mmol), K2CO3 (0.13 g, 0.92 mmol), and MeI (0.027 mL, 0.43 mmol) in DMF (4 mL) was stirred at 50° C. in 24 h. The reaction mixture was cooled, added H2O, the solid was filtered, dried and purified by ISCO (0-30% EtOAc/DCM) to give the title compound (35 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71-7.78 (1H, m), 7.40-7.50 (1H, m), 7.35 (1H, t, J=7.6 Hz), 6.86 (1H, br. s.), 6.22 (1H, s), 5.87 (1H, s), 3.39-3.50 (3H, m), 3.11-3.21 (2H, m), 2.77 (2H, t, J=6.8 Hz), 2.51 (3H, s), 1.28 (9H, s). m/z (ESI, +ve) 364.0 (M+H)+.
Reaction SMILES: [O-]Cl=O.[Na+].[CH:5]([C:7]1[N:8]=[C:9]([CH3:12])[NH:10][CH:11]=1)=[O:6].CC(=CC)C.CC([OH:22])(C)C>O.C1COCC1.CCOC(C)=O>[CH3:12][C:9]1[NH:10][CH:11]=[C:7]([C:5]([OH:22])=[O:6])[N:8]=1
Reactant: CC(C)(C)O
Reactant: Cc1nc(C=O)c[nH]1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of NaClO2 (2.5 g, 27.5 mmol) and NaH2PO4.H2O (2.3 g, 16.3 mmol) in water (6.1 mL) was added to a solution of 4-formyl-2-methylimidazole (0.30 g, 2.72 mmol), 2-methyl-2-butene (17.0 mL of a 2M solution in THF, 34.0 mmol), tBuOH (2.0 mL), and THF (8.5 mL). The solution was stirred at RT for 3 h. EtOAc (10 mL) was added and the resulting solid was filtered and dried to provide 2-methyl-1H-imidazole-4-carboxylic acid (0.33 g, 97%) as a white solid which was used without further purification. A solution of the above acid (0.035 g, 0.28 mmol) in oxalyl chloride (0.15 mL, 1.67 mmol) was heated under reflux for 1 h and then evaporated to dryness. The residue was stirred with 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.061 g, 0.28 mmol) in CH3CN (3. mL), DMF (1 mL), and DIEA (0.4 mL, 2.3 mmol) at RT overnight. Aqueous Na2CO3 was added, and the solution was extracted with 9:1 CH2Cl2:MeOH. The organic phase was dried (Na2SO4), filtered, and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to provide the title compound (0.010 g, 7%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (br. s., 1H), 7.93 (s, 1H), 7.83 (t, J=1.47 Hz, 1H), 7.49-7.55 (m, 2H), 7.48 (t, J=2.11 Hz, 1H), 7.39 (t, J=7.97 Hz, 1H), 4.55 (d, J=5.59 Hz, 2H), 2.54 (s, 3H). ES-LCMS: m/z 419.3, 421.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[N:7][CH:8]=1)#[N:2].[BH4-].[Na+].O>S(Cl)(Cl)=O.O1CCOCC1>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([S:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(Sc2cccc(C(=O)O)c2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: O
Product: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Dissolve 3-(5-cyano-pyridin-2-ylsulfanyl)-benzoic acid (1.25 g, 4.88 mmol) in thionyl chloride (50 mL) and stir. Heat to reflux. After 2 hours, concentrate under reduced pressure to give a residue. Dissolve residue in dioxane (100 mL) and add sodium borohydride (1.85 g, 48.8 mmol). Heat to 50° C. After 2 hours, cool to ambient temperature and add water. Extract with ethyl acetate, combine organic layers, dry with sodium sulfate, filter and concentrate to give the title compound as a yellow oil (670 mg, 57%): 1H NMR (DMSO-d6) δ 4.56 (d, 2H), 5.33 (t, 1H), 7.06 (d, 1H), 7.49 (m, 3H), 7.57 (m, 1H), 8.08 (dd, 1H), 8.82 (dd, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:24]=[O:25])=[N:20][C:21]=1[O:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:24]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[OH:25])=[N:20][C:21]=1[O:22][CH3:23]
Reactant: COc1nc(C=O)ccc1Cl
Reactant: CSc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(C(O)c2ccc(SC)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
n-Butyllithium (2.64 M, 2.9 mL) was added to a solution of 4-bromothioanisole (1.61 g) in tetrahydrofuran (20 mL) at −78° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.14 g) in tetrahydrofuran (10 mL) was added to the reaction solution, followed by stirring for one hour. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→4:1) to give (5-chloro-6-methoxypyridin-2-yl)[4-(methylsulfanyl)phenyl]methanol as a pale yellow oil (1.42 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[K+].O>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Methyl 5-methoxyvalerate (7.33 g, 50.2 mmol) and KOH (14.4 g, 0.256 mol) were dissolved into a mixture of 50 ml of water and 150 ml of MeOH. The solution was stirred at 0° C. for 2 hrs then MeOH was removed in vacuo. After washed by CHCl3 (50 ml), the aqueous layer was acidified to pH=1 by 2N HCl and extracted by Et2O (2×100 ml). Organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 5-methoxyvaleric acid (5.27 g, 79.6%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:35]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH:20]4[CH2:22][CH2:21]4)[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>CO.CCOC(C)=O>[C:24]([O:23][C@@H:17]1[C@@H:18]([CH:20]2[CH2:21][CH2:22]2)[CH2:19][N:14]([C:13]2[C:12]([NH2:35])=[CH:11][N:10]=[C:9]3[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]=23)[CH2:15][C@H:16]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:26])[CH3:25]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C2CC2)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C2CC2)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 96.8 %

Procedure:
A solution of 4-{(3R,4R,5S)-4-(acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.055 g, 0.11 mmol) in MeOH (5.0 mL) and EtOAc (1.0 mL) was deoxygenated and purged with nitrogen prior to the addition of 10% palladium (dry basis) on activated carbon (wet, Degussa type E101 NE/W) (0.025 g). The reaction mixture was stirred under an atmosphere of hydrogen, introduced via a balloon, for 2 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the solids were washed thoroughly with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to afford the sub-title compound (0.052 g, 100%). LCMS (ESI) m/z calc. for C25H37N4O6 489.3 [M+H]+. found 489.0.