Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C1N=C2C=CC(N)=CN2N=1)C.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:44])[C:25]=1[C:26](=[O:43])[NH:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([N:37]3[CH2:42][CH2:41]O[CH2:39][CH2:38]3)[N:36]=2)[CH:33]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:44])[C:25]=1[C:26](=[O:43])[NH:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([N:37]([CH2:42][CH3:41])[CH2:38][CH3:39])[N:36]=2)[CH:33]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: CCN(CC)c1nc2ccc(N)cn2n1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N(CC)CC)nn2c1

Procedure:
Using N*2*,N*2*-diethyl-[1,2,4]triazolo[1,5-a]pyridine-2,6-diamine, this compound was prepared following the same method as for the synthesis of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester. Off white solid (1.2 g, 45%). MS: m/z=386 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH2:3]1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1.C(Cl)Cl>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:3]1
Reactant: CCCc1c(OCc2ccccc2)ccc2c1OC(CCC(=O)OC)(CCC(=O)OC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O

Procedure:
The title compound, 102 mg, m.p. 202°-205° C., was prepared by the method of Example 22 substituting the title product of Example 18 (455 mg) for the title product of Example 21, and utilizing methylene chloride as the extraction solvent instead of ethyl acetate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18](C(OC(C)(C)C)=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]3[C:41](=[O:42])[CH:40]4[N:36]([CH2:37][S:38][CH2:39]4)[C:35]3=[O:43])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)[C:46]([OH:48])=[O:47]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[C:15]([C:46]([OH:48])=[O:47])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]3[C:41](=[O:42])[CH:40]4[N:36]([CH2:37][S:38][CH2:39]4)[C:35]3=[O:43])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3C(=O)C4CSCN4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N3C(=O)C4CSCN4C3=O)cc2n1Cc1ccc(-c2ccccc2)c(C(=O)O)c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(5,7-dioxo-1H,3H-imidazo-[1,5-c]thiazol-6-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1
Reactant: CNC
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Dimethylamine (50% solution in water, 20 mL) was added to a stirred solution of 2-chloro-4-methyl-5-nitropyridine (15.0 g, 86.9 mmol) in tetrahydrofuran (150 mL), and the mixture was stirred at 0° C. for 2 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (15.7 g, 86.6 mmol, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13]([OH:29])[CH2:12]1.[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:29][CH:13]2[CH2:12][CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)[C:14]2=[O:28])=[O:38])=[CH:40][CH:41]=1)([O-:32])=[O:31]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) mixture of rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (1.260 g; 3.06 mmol), 4-nitrobenzoic acid (1.023 g; 6.12 mmol), and PPh3 (1.767 g; 6.73 mmol) in anh. THF (50 ml) was treated dropwise with a solution of DEAD (1.173 g; 6.73 mmol) in anh. THF (10 ml). The resulting mixture was further stirred at 0° C., under nitrogen, for 5 min., and then at rt for 4 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (toluene/AcOEt=5/1) afforded rac-(3R*,5S*)-5-(2,6-dimethoxyphenyl)-2-oxo-1-(4-(trifluoromethoxy)benzyl)-pyrrolidin-3-yl 4-nitrobenzoate as a colorless solid. LC-MS (conditions A): tR=1.02 min.; [M+H]+: 561.17 g/mol.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:51])[C@H:7]([CH2:47][CH:48]=[CH:49][CH3:50])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][C:24]([CH3:46])([CH3:45])[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].[F-]>O1CCCC1.C(OCC)C>[CH2:1]([NH:5][C:6](=[O:51])[C@H:7]([CH2:47][CH:48]=[CH:49][CH3:50])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:10]1[CH2:23][C:24]([CH3:46])([CH3:45])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO)C(=O)NCCCC
Reaction time: 4 h

Procedure:
474 mg of 3-[N-tert-butoxycarbonyl-4(S)-(4-tert-butyl-diphenylsilyloxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-but-2-enyl-propionic acid (N-butyl)amide are dissolved in 5 ml of tetrahydrofuran, and 1.2 ml of a 1M tetraburylammonium fluoride solution in tetrahydrofuran are added at room temperature under argon. After 4 h, the reaction mixture is diluted with diethyl ether, washed with water and brine, dried (Na2SO4) and concentrated. Purification over silica gel (mobile phase A) gives the title compound: Rf (A)=0.40; FAB-MS: (M+H)+ =483.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][C:16]=2[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])=[CH:17][C:16]=2[O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:14])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)COc1cc(OCC=C(C)C)ccc1C(=O)C=Cc1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)=CCOc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)c(OCC(=O)O)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 47.3 g of 4-t-butyl-2'-ethoxycarbonylmethoxy-4'-(3-methyl-2-butenyloxy)chalcone in 600 ml of ethanol was added a solution of 29.0 g of potassium carbonate in 100 ml of water, the mixture was stirred at 45° C. for 8 hours. After neutralization with dilute sulfuric acid, the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to give 29.9 g of 4-t-butyl-2'-carboxymethoxy-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow needles.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and (4-fluorophenyl)acetyl chloride (7.20 mg, 0.0420 mmol) in THF (5 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using Hexane:EtOAc (2:1) to give the desired product (13 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=8.4 Hz), 7.59 (s, 1H), 7.31-6.93 (m, 13H), 5.13 (q, 1H, J=6.0 Hz), 3.56 (s, 2H), 3.07 (d, 1H, J=11.7 Hz), 2.91 (d, 1H, J=11.0 Hz), 2.62-2.42 (m, 2H), 2.40-2.30 (m, 1H), 2.12-1.54 (m, 9H), 1.24 (d, 6H, J=6.7 Hz); ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>O1CCCC1.C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:37])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Yield: 70.9 %

Procedure:
The (3-hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (1.67 g, 7.49 mmol) and triphenylphosphine (2.61 g, 9.96 mmol) were combined and dissolved in tetrahydrofuran (40 mL). Carbon tetrabromide (3.23 g, 9.74 mmol) was dissolved in acetonitrile (20 mL) and added dropwise to the reaction while stirring. After stirring for 5 h, the reaction was concentrated in vacuo to give a thick golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes) afforded (3-bromomethyl-phenyl)-carbamic acid tert-butyl ester (1.52 g, 78%) as a white powder: H1-NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 4.46 (2H, s), 6.47 (1H, bs), 7.06 (1H, d, J=7.2 Hz), 7.19-7.27 (2H, m), 7.51 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2ccccc12
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1O
Temperature: 85 °C
Reaction time: 0.83 h

Procedure:
5 g (34 mmol) 4-hydroxyquinoline are added in small portions to nitric acid (66%) heated at 85° C. The reaction mixture is stirred for 50 min at this temperature. 150 ml water are heated to 100° C. and the reaction mixture is added slowly through a dropping funnel to the boiling water. The yellow precipitate which is formed is filtered off and washed with hot and cold water and acetone to become almost colorless. The title compound is dried at 60° C. under vacuum. mp: 357-358° C.; MS: 191 (M++1); HPLC: tret=8.73 min (Grad 3).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.NC1C=CC(O)=CC=1>C(O)(=O)C>[OH:36][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: Nc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(O)cc1
Yield: 41 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (500 mg, 2.14 mmol), triethyl orthoformate (5 ml), 4-aminophenol (444 mg, 4.07 mmol), and acetic acid (0.5 ml) were used to give 283 mg (0.88 mmol, 41% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:15][CH2:16][CH2:17][C:18]1[C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[O:20][N:19]=1.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O>[F:27][C:25]1[CH:24]=[CH:23][C:22]2[C:18]([CH2:17][CH2:16][CH2:15][N:5]3[CH2:6][CH2:7][C:2]([OH:1])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:3][CH2:4]3)=[N:19][O:20][C:21]=2[CH:26]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To 50 ml of dry dimethylformamide was added, 6.0 g of 4-hydroxy-4-phenylpiperidine, 8.0 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 13.0 g of sodium bicarbonate, and a few crystals of potassium iodide. After stirring at 80° C. for one hr, the mixture was cooled, filtered, and the filtrate evaporated to an oil. The oil was stirred with 100 ml water for five mins, and then extracted with ether/ethyl acetate. The organic layer was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvents were evaporated. Trituration with ether gave 3.0 g (25%) of product, mp 133°-137° C. Recrystallization twice from ethyl ether gave the analytical sample, mp 138°-139° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[C:11](=O)[NH:10][C@@H:9]1[C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][NH:10][C@@H:9]1[C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(N2Cc3cn(S(C)(=O)=O)nc3C2)C(=O)N[C@@H]1c1cc(F)ccc1F
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CN[C@@H]1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of the product from Step D (18.43 g, 36.0 mmol) in tetrahydrofuran (250 mL) was added borane dimethyl sulfide complex solution (144 mL, 288 mmol, 2.0 M solution in tetrahydrofuran) over 15 min. The reaction was placed in a preheated 70° C. bath and stirred for 75 min. The mixture was cooled to 0° C. and methanol (100 mL) slowly added over 15 min. The ice bath was removed and the mixture stirred for 30 min and the solvent removed in vacuo. The residue was dissolved in ethanol (150 mL) and heated at 70° C. for 4 h, cooled to ambient temperature and the solvent removed in vacuo. The crude solid was purified by column chromatography (silica gel Biotage 40M) eluting with methanol/ethyl acetate (gradient from 0% to 10%) to give the minor (first eluting) diastereomer tert-butyl {(2R,3S,5S)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate and the major (second eluting) diastereomer, the title compound as colorless solids. LC/MS 498.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[O:5]
Reactant: COC(=O)c1cccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncccc1C=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
A solution of methyl 2-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL) at 0° C. was treated dropwise with lithium aluminum hydride in THF (6.6 mL, 1 M), stirred at 0° C. for 1.5 hours, treated with ethyl acetate (3 mL), warmed to 25° C., and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. A solution of the residue (0.391 g) in dichloromethane (16 mL) was treated with MnO2 (2 g), stirred at 25° C. for 68 hours, filtered through celite®, and the solvent was evaporated to give the title compound (0.303 g, 75% yield), which was used without further purification.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH:10]12[O:16][CH:14]([CH2:15][NH:8][CH2:9]1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2

Procedure:
5.60 g (17.6 mmol) of tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate are dissolved in 100 ml of ethanol, 1.00 g of 10% palladium on activated carbon is added, and hydrogenation is carried out at 100° C. and 100 bar. The catalyst is filtered off with suction, and the filtrate is concentrated, whereupon 3.80 g (94.5% of theory) of pure product crystallize out.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C:10]([CH3:16])([CH3:15])[C@H:9]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10]([CH3:16])([CH3:15])[C@H:9]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC1(C)OCCN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Yield: 85 %

Procedure:
(S)-benzyl 4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylate (163 g, 461 mmol) was reacted with a solution of borane in THF (1 mol/L, 692 mL) according to the procedure as described in Example 34, Step B to give the title compound as colorless oil (133 g, 85%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH2:25])[C:5]=2[NH2:26].[NH:27]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:28]([C:30](O)=[O:31])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C>CCOC(C)=O.CN(C)C=O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH:25][C:30]([C@@H:28]([NH:27][C:33](=[O:34])[O:35][CH2:36][CH:37]1[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:44]3[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:29])=[O:31])[C:5]=2[NH2:26]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(N)c3N)cc(Br)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)[C@H](C)NC(=O)OCC2c4ccccc4-c4ccccc42)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To an oven-dried carousel reaction flask charged with a magnetic stir bar at room temperature under argon was added (R)-2,7,8-triamino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene (0.200 g, 0.479 mmol), Fmoc-Ala-OH (0.179 g, 0.575 mmol), dimethylformamide (2.4 mL), HOBt 0.084 g, 0.62 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) (0.119 g, 0.623 mmol). The black solution was stirred at room temperature overnight. The solution was diluted with EtOAc (50 mL), washed with water (3×30 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to give the crude product as a brown residue. Purification by flash column chromatography (silica gel 12 g pre-packed column, gradient elution with EtOAc:Hexanes, 1:9 to 1:4 to 1:1) gave 0.046 g (13%) of the title compound as a yellow solid: mp: 212-217° C. (dec); 1H-NMR (DMSO-d6): δ 9.37 (br s, 1H), 7.89 (d, J=7.7 Hz, 2H), 7.76-7.69 (m, 3H), 7.44-7.39 (m, 2H), 7.35-7.30 (m, 2H), 6.98 (d, J=1.9 Hz, 1H), 6.88 (br s, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 6.31 (d, J=8.3 Hz, 1H), 4.79 (br s, 2H), 4.69 (s, 1H), 4.31-4.23 (m, 4H), 3.80 (s, 3H), 3.70 (s, 3H), 1.32 (d, J=6.9 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:17])=[N:13][N:12]=1.Cl>CO>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)c1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A mixture of 2M NaOH (2 mL, 4 mmol) and methyl 6-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]piperidin-1-yl}nicotinate (17 mg, 0.04 mmol) (Example 612) in MeOH (10 mL) was stirred for 16 h then taken to pH 7 by addition of 2M HCl. The solution was concentrated by evaporation to give a cloudy aqueous mixture that was cooled on an ice bath. The precipitate was collected by filtration, washed with water and Et2O and dried to give the title compound (13 mg, 88%) as a solid; 1H NMR (CD3OD) δ 8.61 (s, 1H), 8.02-7.88 (m, 2H), 7.16-7.05 (m, 2H), 7.05-6.97 (m, 1H), 6.75 (d, 1H), 4.47-4.37 (m, 2H), 4.17-4.06 (m, 1H), 3.08-2.97 (m, 2H), 1.99-1.89 (m, 2H), 1.63-1.50 (m, 2H); MS m/e MH+ 427.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.Cl.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]Cl)[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][CH2:28][N:30]([CH2:34][CH3:35])[CH2:31][CH3:32])=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCN(CC)CCOc1ccc(C2c3cc(OC)ccc3-c3ccc4ccccc4c32)cc1
Temperature: 0 °C
Yield: 42.5 %

Procedure:
Seven grams of the product of Example 1 was combined with 5.7 g of diethyl-(2-chloroethyl)amine hydrochloride and 12.1 g of potassium carbonate in 75 ml of methyl ethyl ketone, and the mixture was stirred under reflux for 31/2 hours. The mixture was then poured into ice water, extracted twice with 300 ml portions of ethyl acetate, and the organic extract was washed with brine, dried, and evaporated under vacuum to a tan liquid. The impure product was purified by chromatography over a silica gel column, eluting with a gradient solvent beginning with 200 ml of toluene, then proceeding in 200 ml increments to 100% ethyl acetate, and finally eluting with 500 ml of 1:9 methanol:ethyl acetate. The product-containing fractions were evaporated under vacuum to obtain 3.85 g of the desired product, m.p. 109°-115° C.