Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:32]1([CH2:31][O:1][C:2]2[C:3](=[O:29])[C:4]([C:18]3[N:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:21]=[CH:20][CH:19]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=3)[CH:7]=2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(OCC2CC2)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), (bromomethyl)cyclopropane (0.048 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (103 mg, 91% yield) as colorless prisms: mp 72-78° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.32-0.47 (2H, m), 0.60-0.76 (2H, m), 1.26-1.39 (1H, m), 4.06 (2H, d, J=7.2 Hz), 7.04 (1H, dd, J=2.3, 8.3 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.99 (1H, s). LC-MS (ESI) m/z 453 [M+H]+. Anal. Calcd for C24H19F3N4O2.0.5H2O: C, 62.47; H, 4.37; N, 12.14. Found: C, 62.19; H, 4.41; N, 12.15.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[OH:9][C@H:10]1[CH2:14][NH:13][CH2:12][C@@H:11]1[CH2:15][OH:16].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][C@H:10]([OH:9])[C@@H:11]([CH2:15][OH:16])[CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@H]1CNC[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reaction time: 1 h

Procedure:
Sodium hydroxide (2.70 g) was dissolved in water (25 mL) and dioxane (15 mL) was added to the solution. (3R,4R)-(4-Hydroxypyrrolidin-3-yl)methanol (1.00 g) was then dissolved in the solution. While the mixture was chilled in an ice water bath, carbobenzoxy chloride (0.97 mL) was added dropwise. The reaction mixture was stirred at 5° C. or below for 1 hour and a second portion of carbobenzoxy chloride (0.97 mL) was added dropwise, followed by stirring at 5° C. or below for another hour and dropwise addition of a third portion of carbobenzoxy chloride (0.97 mL). The resulting mixture was stirred at 5° C. or below for 1 hour and then at room temperature for 1 hour. Subsequently, the reaction mixture was extracted with dichloromethane (2×100 mL). The dichloromethane layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=1:1->ethyl acetate: methanol=20:1) to give (3R,4R)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol as a milky white tar-like material (1.18 g).
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16][OH:17])[CH:10]=1.[Cl:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:35][O:36][CH2:37][CH3:38])[N:31]([CH2:32][C:33]#[CH:34])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:35][O:36][CH2:37][CH3:38])[N:31]([CH2:32][C:33]3[O:17][N:16]=[C:15]([C:11]4[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=4)[CH:34]=3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: ON=Cc1cccnc1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Temperature: 50 °C
Yield: 55.3 %

Procedure:
N-Chlorosuccinimide (1.09 g, 8.19 mmol) was added to a 6° C. solution of 3-pyridinecarboxaldehyde oxime (1.00 g, 8.19 mmol) in tetrahydrofuran (THF) (25 mL). The solution was heated at 50° C. for 2 h. 4-Chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part D of Example 3, 1.96 g, 6.55 mmol) and triethylamine (1.70 mL, 12.3 mmol) were added to the reaction, which was heated at 50° C. for 17 hours. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous layer was extracted multiple times with dichloromethane and chloroform. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 1:1 to 1:4 hexanes/ethyl acetate) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.52 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:18])[N:9]([CH3:19])[CH2:8][C:7]=2[CH:20]=1)=O.C([O-])(=O)C.[Na+].Cl.Cl.[NH2:28][CH2:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.C([BH3-])#N.[Na+]>CO>[N:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH:34][C:30]=1[CH2:29][NH:28][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:18])[N:9]([CH3:19])[CH2:8][C:7]=2[CH:20]=1
Reactant: COC(=O)CC1Nc2ccc(C=O)cc2CN(C)C1=O
Reactant: NCc1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)CC1Nc2ccc(CNCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
Methyl (±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (180 mg, 0.65 mmol) (prepared as in Example 14(b)) was suspended in anhydrous methanol, then sodium acetate (160 mg, 1.95 mmol), 2-(amino methyl)benzimidazole dihydrochloride (143 mg, 0.65 mmol) and 4 Å molecular sieves were added. After 30 min., sodium cyanoborohydride (45 mg, 0.71 mmol) was added in 2 portions over a period of 30 min. The reaction mixture was allowed to stir at RT overnight, then the methanol was removed under vacuum. The residue was diluted with CH2Cl2, and the solution was washed with saturated NaHCO3. Drying (MgSO4), concentration, and silica gel chromatography (90% CH2Cl2 /9% methanol/1% NEt3) gave the title compound (133 mg, 49%): 1H NMR (CDCl3, 400 MHz) δ 2.67 (dd, J=16.1, 6.1 Hz, 1H), 2.96 (dd, J=16.1, 6.8 Hz, 1H), 3.05 (s, 3H), 3.68 (d, J=16.4 Hz), 3.72 (br s, 2H), 3.75 (s, 3H), 4.11 (br s, 2H, 4.97 (dd, J=6.8 Hz, 6.1, 1H), 5.35 (d, J=16.4 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 7.05 (d, J=8.2 Hz, 1H), 7.20-7.26 (m, 2H), 7.57 (m, 2H); MS(ES) m/e 408 (M+H)+.
Reaction SMILES: COP(=O)OC.[C:7](=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([CH:25]=O)[N:22]=[C:21]2[CH3:27])=[CH:16][CH:15]=1>CO>[C:25]([C:23]1[N:22]=[C:21]([CH3:27])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH:24]=1)#[CH:7]
Reactant: Cc1nc(C=O)cn1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: CO[PH](=O)OC
Agent: [K+]
Solvent: CO
Product: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester is dissolved in methanol. Potassium carbonate is added. A solution of 1-(4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde in methanol is added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight. The desired compound 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[OH:17][CH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([O:17][CH2:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 100 °C

Procedure:
2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (702 mg, 2.32 mmol, from Example 21a), tert-butyl (2S)-2-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.32 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), 2-(di-t-butylphosphino)biphenyl (42 mg, 0.139 mmol) and Cs2(CO3) (1.51 g, 4.64 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 100° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the residue separated between EtOAc (250 ml) and water (250 ml). The organic phase washed with water (250 ml) and the combined aqueous phases were extracted with EtOAc (250 ml). The combined EtOAc phases were dried over Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 5-20% EtOAc in heptane yielded the title compound as a colorless oil. Yield: 729 mg (72%). 1H NMR (400 MHz, CDCl3) δ 7.43 (t, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.3 Hz), 6.44 (d, 1H, J=8.2 Hz), 4.57 (s, 2H), 4.48 (m, 1H), 4.25 (d, 2H, J=7.4 Hz), 3.91 (d, 1H, J=11.6 Hz), 2.76 (dt, 1H, J=13.3 Hz, J=2.0 Hz), 1.69 (d, 1H, J=12.0 Hz), 1.57-1.37 (m, 5H), 1.27 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: c1cc2cc(N3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A heterogeneous, tan solution of 1H-indol-5-amine (4.5547 g, 34.5 mmol), 1-chloro-2-(2-chloroethoxy)ethane (6.06 mL, 51.7 mmol) and Na2CO3 (14.61 g, 138 mmol) in t-BuOH (90 mL) in a sealed pressure tube was heated to 100° C. for 2 days. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a pad of CELITE®, and the filtrate was concentrated in vacuo. Water (50 mL) was added to the residue and basified to pH ˜11 with saturated aqueous NaHCO3; this was extracted with CH2Cl2 (4×75 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude product. This was triturated with Et2O to give the first crop of desired product (3.7495 g) as a tan solid. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using an ISCO 120 g column eluting with 20-50% EtOAc/hexanes to give the second crop of the desired product (1.9458 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[Cl:10].[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([C:11](=[O:13])[CH3:12])=[C:6]([OH:8])[CH:7]=1
Reactant: COc1ccc(Cl)c(Br)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(Cl)c(Br)cc1O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
The 2-bromo-1-chloro-4-methoxybenzene (25.0 g, 113 mmol) [Oakwood cat#035670] was dissolved in carbon disulfide (250 mL), and the acetyl chloride (12 mL, 170 mmol) and aluminum trichloride (37.6 g, 282 mmol) were added. The reaction was heated to reflux and monitored by LC/MS. After heating for 1 h, the reaction became two layers. The reaction allowed to cool to room temperature and poured over ice. The slurry was extracted with ethyl acetate 3×, the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-(4-bromo-5-chloro-2-hydroxyphenyl)ethanone as a solid (28.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 12.12 (s, 1H), 7.78 (s, 1H), 7.31 (s, 1H), 2.62 (s, 3H).
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3,3-difluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6): δ 8.54 (t, J=6.01 Hz, 1H), 7.89 (d, J=9.32 Hz, 1H), 7.54-7.61 (m, 2H), 7.04 (d, J=9.21 Hz, 1H), 4.16 (s, 1H), 3.96-4.03 (m, 2H), 3.45 (t, J=5.00 Hz, 2H), 3.27-3.28 (m, 2H), 2.56-2.59 (m, 3H), 1.73-1.75 (m, 1H), 1.52-1.61 (m, 4H), 1.46-1.47 (m, 1H), 1.34-1.38 (m, 1H), 1.18-1.19 (m, 1H), 0.84-0.87 (m, 4H). m/z: 438.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:18][CH:17]3[CH:10]([O:11][Si:12]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:13][Si:14]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:15][CH2:16]3)[C:9]2([F:32])[F:31])[C:4](=[O:33])[N:3]=1.[C:34](=O)([O:46]C1C=CC([N+]([O-])=O)=CC=1)[O:35][CH2:36][C:37]1[O:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>C1COCC1>[F:32][C:9]1([F:31])[CH:10]2[O:11][Si:12]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[O:13][Si:14]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:23])[CH3:24])[O:15][CH2:16][CH:17]2[O:18][CH:8]1[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:46])[O:35][CH2:36][C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[CH:41]=2)=[N:3][C:4]1=[O:33]
Reactant: CC(C)[Si]1(C(C)C)OCC2OC(n3ccc(N)nc3=O)C(F)(F)C2O[Si](C(C)C)(C(C)C)O1
Reactant: O=C(OCc1cc2ccccc2o1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)[Si]1(C(C)C)OCC2OC(n3ccc(NC(=O)OCc4cc5ccccc5o4)nc3=O)C(F)(F)C2O[Si](C(C)C)(C(C)C)O1
Temperature: 100 °C
Reaction time: 96 h
Yield: 87.3 %

Procedure:
To a stirred solution of 62 (300 mg, 0.59 mmol) in THF (5 mL) was added benzofuran-2-ylmethyl 4-nitrophenyl carbonate (223 mg, 0.71 mmol). The resulting solution was stirred at 100° C. for 4 days. Solvent was evaporated off in vacuo and the product was purified by preparative HPLC to give 63 (350 mg, 87%) as an oil. m/z=680.0 (M+H), 1359.49 (2M+H).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][CH2:21]Cl>C1COCC1>[CH2:6]([N:13]([CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:19][O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCCl
Reactant: C[Si](C)(C)CNCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(Cc1ccccc1)C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 34.85 mL, 55.76 mmol) was added to N-benzyltrimethylsilylmethylamine (10 g, 55.76 mmol) in dry THF (140 mL) and stirred at −78° C. under nitrogen atmosphere. After 45 minutes, methoxymethyl chloride (4.3 mL, 55.76 mmol) in THF (6 mL) was added and then stirred for another 3 hours. The THF was evaporated, and the residue was dissolved in hexane, washed with water, and dried over sodium sulfate. The solvent was evaporated to give under reduced pressure to give N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (10 g).
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23](=[O:32])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: NN1CCCC(NC(=O)OCc2ccccc2)([PH](=O)NC(=O)C=Cc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NN1CCCC(N)([PH](=O)NC(=O)CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Palladium black (20.0 mg) was added to a solution of (3S, P (SR))-3-benzyloxycarbonylamino-1-amino(cinnamoylamino)phosphinyl-2-piperidone (201.0 mg, 0.4404 mmol) in ethanol (6 mL), and the resulting mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2=[CH:10][N:11]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]([C:13]3[S:14][CH:15]=[C:16]([C:18](OCC)=[O:19])[N:17]=3)=[C:8]2[C:7](=[O:31])[N:6]([CH3:32])[C:5]1=[O:33].[Cl-].[Li+]>C(O)C.C1COCC1>[OH:19][CH2:18][C:16]1[N:17]=[C:13]([C:12]2[N:11]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH:10]=[C:9]3[C:8]=2[C:7](=[O:31])[N:6]([CH3:32])[C:5](=[O:33])[N:4]3[CH3:3])[S:14][CH:15]=1
Reactant: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2COCC[Si](C)(C)C)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(=O)c2c(-c3nc(CO)cs3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (0.856 g, 22.62 mmol) was added to a solution of ethyl 2-(1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thiazole-4-carboxylate (step 1) (5.254 g, 11.31 mmol) and lithium chloride (0.959 g, 22.62 mmol) in ethanol (145 ml) and THF (290 ml) at 0° C. The mixture was stirred at room temperature for 16 hours. Further portions of lithium chloride (0.959 g, 22.62 mmol) and sodium borohydride (0.856 g, 22.62 mmol) were added and the mixture stirred for a further 4 hours. The reaction was quenched with saturated NaHCO3 (aq) (250 ml), diluted with water (100 ml) and extracted with chloroform (3×350 ml). The combined organic extracts were washed with water (200 ml) and brine (2×200 ml), dried over sodium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:12])[CH:6]([CH3:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCN1c2nc(Cl)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
To a stirred solution of 2-chloro-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (2.0 g, 7.4 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 ml, 74 mmol), cupric acetate (2.70 g, 14.8 mmol) and phenylboronic acid (1.81 g, 14.8 mmol) followed by 4 Å molecular sieves (3.0 g). The reaction mixture was stirred for 48 h at room temperature with an air balloon. The mixture was then filtered over celite. The filtrate was washed with aqueous saturated sodium bicarbonate (2×50 ml), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel using 2% methanol in dichloromethane as eluent to give the titled product. (yield: 39%). 1HNMR (300 MHz, CDCl3): δ 0.91-1.01 (m, 6H), 1.49-1.75 (m, 6H), 3.12-3.20 (m, 1H), 4.18-4.21 (m, 1H), 4.30-4.45 (m, 1H), 7.10 (s, 1H), 7.20-7.39 (m, 2H), 7.42-7.65 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH2:9]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].[Ni]=O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:9]
Reactant: N#Cc1ccccn1
Reactant: O
Agent: O=[Ni]
Agent: [Cr+3]
Agent: [O-2]
Product: NC(=O)c1ccccn1
Temperature: 87.5 °C

Procedure:
In a four neck round bottom flask fitted with thermo well, agitator and reflux condenser, 2-cyanopyridine (100 g), de-mineralized water (150 g) isopropyl alcohol (10 g) and chromium oxide-nickel oxide catalyst (1 g) prepared in Example 2 is charged. The mixture is heated up to 85-90° C. for 4-6 h. The completion of reaction is monitored by HPLC. After the completion of reaction the crude product is cooled and filtered to separate picolinamide from the catalyst bed. The catalyst bed is washed with de-mineralized water to make catalyst free from hydrolyzed mass of 2-cyanopyridine. The wet catalyst is recycled back for next batch of hydrolysis. The colorless mother liquor is concentrated and dried to get pure picolinamide. The recovered water layer containing 2-cyanopyridine and alcohol is recycled back for next hydrolysis batch.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][O:27][CH3:28])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][O:27][CH3:28])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COCc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 19.4 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (411 mg, 1.09) and 10% palladium on activated carbon (100 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature before The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 19.4%) as a white solid: LC/MS m/e calcd for C23H28N2O3S [M+H]+ 413.56, observed 413.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.30 (s, 1H), 8.20 (s, 1H), 7.89-7.93 (m, J=8.3 Hz, 2H), 7.55-7.66 (m, 2H), 6.67 (s, 1H), 4.61 (s, 2H), 4.37 (t, J=8.0 Hz, 1H), 3.33-3.48 (m, 3H), 3.08-3.13 (m, 3H), 2.25-2.33 (m, 1H), 2.12-2.20 (m, 1H), 1.61-1.88 (m, 5H), 1.45-1.56 (m, 2H), 1.18-1.31 (m, 2H).