Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]1([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:64][CH3:65])[C:48]([N:50]([CH3:63])[C@@H:51]([C:59](=[O:62])[NH:60][CH3:61])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:64]([C@@H:47]([C:48](=[O:49])[N:50]([CH3:63])[C@@H:51]([C:59](=[O:62])[NH:60][CH3:61])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:46][C:43]1[CH:42]=[CH:41][C:40]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:45][CH:44]=1)[CH3:65])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.24 g; 0.98 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2 g; 1.02 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-(1,1′-Biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (4×20 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.46 g of ((3E)-4-(((1R)-2-(1,1′-biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)-carbamic acid tert-butylester.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[C:8]([CH:9]=[CH2:1])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cccnc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccnc1Br
Temperature: 0 °C

Procedure:
See Spivey, A. C.; Shukla, L.; Hayler, J. F. Org. Lett. 2007, 9, 891-894. Butyllithium (22.75 mL, 59.1 mmol) was added to the THF (450 mL) suspension of methyltriphenylphosphonium bromide (21.13 g, 59.1 mmol) at 0° C. The solution turned to orange and the reaction was lift to room temperature for 30 min before cooled it back to 0° C. 2-bromonicotinaldehyde (10 g, 53.8 mmol) in 50 mL THF was added through canula to the reaction solution. The precipitate was formed and the reaction was lift to room temperature. The color of the reaction turned to green, gray. After a while, the color of to reaction became orange again. The reaction was stirred at room temperature over weekend. The solvent was removed mostly via vacuum and the crude was partitioned between water and diethyl ether. The organic layer was separated and the aqueous layer was extract twice with diethyl ether. The diethyl ether layer was combined, dried (Na2SO4), filtered and concentrated. The product was obtained by flash column eluted with ethyl acetate in hexane (10%) as yellow oil (8.78 g, 89%). MS (ESI)[M+H+]=184.04; 1H NMR δ ppm (400 MHz, CHLOROFORM-d) 8.21-8.29 (m, 1H) 7.78 (dd, J=7.68, 1.89 Hz, 1H) 7.20-7.28 (m, 1H) 6.96 (dd, J=17.37, 11.08 Hz, 1H) 5.72 (d, J=17.37 Hz, 1H) 5.46 (d, J=11.08 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[OH:22][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A solution of 17β-methoxy-5β-androstan-3-one (130 mg, 0.42 mmol) in dry THF (15 mL) was treated with lithium tri(tert-butoxy)aluminum hydride (1 mL, 1M in THF, 1 mmol) at -73° C. After stirring the mixture at -75° C. for 3 hr and then at -10° C. for 1.5 hr, the mixture was quenched with NaOH solution (1N, 2 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (9:1) gave 3α-hydroxy-17β-methoxy-5β-androstane (107 mg); mp 151-156° C.; TLC Rf (hexane:acetone 7:3)=0.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([O-])(O)=O.[Na+].[C:33](Cl)(Cl)=[S:34]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)([N:16]=[C:33]=[S:34])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(N=C=S)c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (0.132 g, 0.335 mmol) in chloroform (1 mL) was added H2O (1 mL) and NaHCO3 (84 mg, 1.01 mmol). To this vigorously stirred mixture was added thiophosgene (38.3 μl, 0.502 mmol) dropwise. The reaction was stirred at room temperature for 2 hours and diluted with CHCl3 and H2O. The organic layer was separated and washed with brine, dried over MgSO4 and concentrated. The crude mixture was purified by silica gel ISCO chromatography (12 g column) using hexanes/EtOAc (0-30% over 20 min) to give 5-chloro-2-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-isothiocyanato-2-phenylethyl)pyridine as a yellow oil (73 mg, 50% yield). LCMS: 4.3 min [M+1] 437.1 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (d, J=13.69 Hz, 2H), 4.07 (d, J=13.45 Hz, 2H), 6.89 (dd, J=7.83, 1.47 Hz, 3H), 7.16-7.22 (m, 5H), 7.24 (d, J=1.47 Hz, 1H), 7.37 (dt, J=4.22, 2.17 Hz, 2H), 7.40 (t, J=1.96 Hz, 1H), 7.52 (s, 2H), 7.66 (dd, J=8.31, 2.45 Hz, 2H), 8.65 (d, J=1.96 Hz, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Reaction time: 16 h

Procedure:
Methanesulphonyl chloride (27 ul) was added to 1-(3-aminophenyl)-3-quinolin-4-ylurea (0.08 g) in dichloromethane (25 ml) containing triethylamine (48 ul) and stirred for 16 h. The precipitate that formed was separated by filtration, washed with tetrahydrofuran and diethyl ether and dried to give the title compound (0.081 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[F:23][C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[CH:26]=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:26]\[C:25]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:24]=1[F:23])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(F)ccc1F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (6.1 g) and 2,5-difluorobenzaldehyde (2.0 g) in dry dichloromethane (60 mL), was treated dropwise with a solution of DBU (2.5 mL) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 h, then was concentrated to approximately 20 mL and partitioned between ethyl acetate (150 mL) and 1N hydrochloric acid (50 mL). The organic extract was collected, consecutively washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (sodium sulfate), filtered and evaporated. The crude product (6.5 g) was purified by flash chromatography (20% ethyl acetate/hexanes) to yield the title compound (4.0 g, 82%). 1H NMR (300 MHz, CDCl3) δ 3.85 (s, 3H), 5.10, (s, 2H), 6.60 (bs, 1H), 6.9-7.1 (m, 2H), 7.21 (m, 1H), 7.2-7.3 (m, 6H). MS APCI, m/z=348 (M+1). LC/MS: 2.53 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[O:3]1.N1CCCCC1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O>C(O)C>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1/[CH:31]=[C:12]1/[C:13](=[O:18])[NH:14][C:15]2[C:11]/1=[CH:10][C:9]([B:4]1[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1)=[CH:17][CH:16]=2
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: O=Cc1ccco1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(C)OB(c2ccc3c(c2)/C(=C\c2ccco2)C(=O)N3)OC1(C)C
Temperature: 80 °C
Yield: 39.3 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2.00 g, 7.7 mmol), ethyl alcohol (77 mL), piperidine (0.15 mL, 1.5 mmol), and 2-furaldehyde (0.77 mL, 9.3 mmol) were added to a 250 mL round-bottomed flask. The flask was sealed under a septum and heated to 80° C. for 5 hours. The mixture was cooled and filtered through a medium glass frit. The filtrate was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 70% EtOAc in hexane. The combined fractions were evaporated, and the product was crystallized out of EtOAc and hexanes at −20° C. to give (E)-3-(furan-2-ylmethylene)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.02 g, 39%) as an orange solid. LCMS (M+H) 338.1 calc. for C19H21BNO4 338.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.[CH3:23][C:24]1([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26](=O)[CH2:25]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:26]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]([CH3:33])([CH3:23])[CH2:25]2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCOCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a stirred suspension of Zn (0.59 g, 9.00 mmol) in THF (10 mL) was added TiCl4 (0.50 mL, 4.50 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. After cooling to room temperature, a solution of 61 (0.34 g, 1.12 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.53 g, 3.37 mmol) in THF (15 mL) was added and the reaction mixture refluxed for an additional 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (20 mL). The quenched reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 55% EtOAc:hexanes to give 62 as a white solid (0.36 g, 75%). mp 122-124° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.60-3.65 (m, 2H), 3.65-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.05-4.15 (m, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H). LRMS (APCI): m/z 425 (M+H)+, 423 (M−H)−. Anal. Calcd for C27H36O4: C, 76.38; H, 8.55; Found: C, 76.17; H, 8.65.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[Br:26][C:11]1[C:10](=[O:27])[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:35](=[O:36])[O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)[C:14]([CH3:15])=[CH:13][C:12]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CN)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.08 g, 2.48 mmol) was suspended in dichloromethane (7.5 mL). Pyridine was added (0.222 mL, 2.74 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (5.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded a yellow solid (0.85 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of thiophene-2-carbonyl chloride (40 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 7.8 mg of the title compound.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[N:50]=[CH:51][C:52]([CH2:55][NH2:56])=[N:53][CH:54]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:56][CH2:55][C:52]4[CH:51]=[N:50][C:49]([CH3:48])=[CH:54][N:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)cn1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 8.40 (s, 1H), 7.31-7.23 (m, 2H), 7.08-6.99 (m, 2H), 6.72 (t, J=4.6 Hz, 1H), 6.12 (s, 1H), 4.70 (d, J=4.6 Hz, 2H), 4.44 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.39 (m, 2H), 2.57 (s, 3H), 2.50 (s, 3H): MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[OH:11][C@@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]>ClCCl>[OH:11][C@@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([CH:8]=[O:9])=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]
Reactant: Cc1c[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Phosphorus oxychloride (500 μL, 1.3 mmol) and N,N-dimethylformamide (704 μL, 9 mmol) were dissolved in 15 mL of anhydrous dichloromethane under stirring at room temperature, and the reaction solution was stirring for 15 minutes while maintaining the temperature at −10° C. in an ice-water bath. (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5e (586 mg, 2 mmol) was dissolved in 8 mL of dichloromethane under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the ice-water bath was removed. The reaction system was allowed to warm up to room temperature and stirred for another 2 hours. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was quenched with iced water and stirred for 15 minutes. The mixture was adjusted to pH about 12 with 10N sodium hydroxide solution. The mixture was extracted with the solvent mixture of dichloromethane and methanol (V:V=20:1, 100 mL ×5). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (490 mg, yield 78.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Cl
Solvent: c1ccncc1
Product: COc1ccc(CNc2ncccc2C(=O)O)cc1
Yield: 77.2 %

Procedure:
p-Methoxybenzylamine (8.24 mL, 63.5 mmol) was added to a solution of 2-chloronicotinic acid (5 g, 31.7 mmol) in pyridine and refluxed overnight. The pyridine was distilled and the residue was dissolved in 1N NaOH. The solution was diluted with water to adjust the pH to 10 to 11 and washed by dichloromethane. The aqueous phase was neutralized with cold aqueous 10% HCl solution to adjust the pH to 4 to 5. The solids formed were filtered, washed with cold water, and dried in a vacuum oven to yield 6.32 g (77%) of 2-(4-methoxy-benzylamino)-nicotinic acid (11) as white solids. MP: 229° C.; 1H-NMR (DMSO-d6): δ 3.72 (s, 3H), 4.60 (d, J=3.6 Hz, 2H), 6.40 (dd, J=4.9, 7.7 Hz, 1H), 6.62 (d, J=7.6 Hz, 2H), 7.25 (d, J=7.6 Hz, 2H), 8.09 (dd, J=1.8, 7.0 Hz, 1H), 8.26 (dd, J=1.8, 7.0 Hz, 1H), 8.48 (br. s, 1H), 13.11 (s, 1H); EIMS: 259 (M+1), 281 (M+23).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:32]1[N:40]=[C:39]([CH3:41])[N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1.[NH2:48][C:49]1[CH:50]=[N:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1.O1CCCC1>>[CH3:56][O:55][C:52]1[N:51]=[CH:50][C:49]([NH:48][C:12]2[N:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:14][C:13]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[CH:54][CH:53]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 75 %

Procedure:
LiHMDS (1.0 M in THF, 3.75 mL, 3.75 mmol) was slowly added to a stirred mixture of tert-butyl 4-((6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.6397 g, 1.250 mmol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, Mo.; 186 mg, 1.50 mmol) in tetrahydrofuran (10 mL, 1.250 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h before being quenched with NH4Cl(aq) (10 mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc(3×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatograph (hexanes to 50% ethyl acetate/hexanes) to give tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.577 g, 0.937 mmol, 74.9% yield) as a yellow foam. LCMS (API-ES) m/z 616 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CO.ClCCl>[CH2:23]([NH:27][C:3](=[O:22])[C@H:4]([CH:19]([CH3:20])[CH3:21])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CN
Reactant: COC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)CNC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Following General Procedure H above and using N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-L-valine methyl ester (from Example 1 above) and isobutylamine (Aldrich), the title compound was prepared as a oil. The reaction was monitored by tlc (Rf=0.3 in 10% methanol/dichloromethane).