Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:35])[CH:7]=[C:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[N:26]([CH3:33])[CH:25]=2)=[CH:16]3)=[O:12])[CH:9]=1)=[O:4].[OH-].[Na+]>O.CO>[OH:31][C:29]([C:27]1[N:26]([CH3:33])[CH:25]=[C:24]([NH:23][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:11]([NH:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:35])[CH:7]=2)=[O:12])=[CH:21][CH:20]=3)=[O:34])[CH:28]=1)=[O:30]
Reactant: COC(=O)c1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)OC)n(C)c4)cc3c2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)O)n(C)c4)cc3c2)cc1C(=O)O
Yield: 86.8 %

Procedure:
A solution of 4-({1-[2-(5-methoxycarbonyl-1 methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 (1.04 g, 2.18 mmole) and NaOH (10 mmole) in a mixture of water/MeOH (1/4) (25 ml) was stirred at 50C for 6 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (50 ml) and acidified with 1M HCl up to pH=3. The precipitate was collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give 0.85 g (87%) of 4-({1-[2-(5-hydroxycarbonyl-1-methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2-carboxylic acid 9 as white crystalline material. MS: 448.08 (M−H). 1H-NMR (DMSO-d6): 11.96 (s, 1H, H-1, indole); 10.45&10.25 (s&s, 1H&1H, —C(═O)NH); 8.30 (m, 1H, H-6, indole); 7.48 (m, 3H with *, H-7, indole); 7.49&7.46 (d&d, *, H-3 or H-5, Py1&Py2); 7.39 (s, 1H, H-3, indole); 6.91 (m, 2H, H-3 or H-5, Py1&Py2); 3.84&3.83 (s&s, 6H, NCH3, Py1&Py2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 200 parts of methanol, 1.2 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 5 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[OH:20][C@@H:21]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=1)[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[OH:20][C@@H:21]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8]2)[CH:37]=1)[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CS(=O)(=O)OCC1CCCC(=O)N1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCC(=O)N2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of (6-oxopiperidin-2-yl)methyl methanesulfonate (0.44 g, 2.2 mmol) in DMF (15 ml) was added Cs2CO3 (3.5 g, 11 mmol) and phenol (Intermediate I) (0.88 g, 3.3 mmol). The reaction mixture was stirred at room temperature for 40 hours and partitioned between water and ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20% MeOH-EtOAc) gave tert-butyl ((3R)-3-hydroxy-3-(3-((6-oxopiperidin-2-yl)methoxy)phenyl)propyl)carbamate as a yellow oil. Yield (0.17 g, 20%); 1H NMR (400 MHz, CD3OD) δ 7.24 (t, J=8.0 Hz, 1H), 6.97-6.93 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 4.64 (t, J=7.2 Hz, 1H), 4.06-4.02 (m, 1H), 3.94-3.90 (m, 1H), 3.86-3.76 (m, 1H), 3.15-3.06 (m, 2H), 2.37-2.30 (m, 2H), 2.05-1.92 (m, 3H), 1.86-1.75 (m, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:4][CH2:3][CH2:2]1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:18])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)CCc1cc(F)ccc1OCC1CCC1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cc(F)ccc1OCC1CCC1
Yield: 17 %

Procedure:
A solution of 3-(2-cyclobutylmethoxy-5-fluoro-phenyl)-propionic acid (195 mg, 0.77 mmoles) and benzoic acid N′-isopropyl-hydrazide (115 mg, 0.64 mmoles) in DMF (5 mL) was treated with diisopropylethylamine (0.28 mL, 1.61 mmoles), and PyBroP (450 mg, 0.97 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (45 mg, 14%). LC-MS m/e 413.32(M+H+)
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]([F:19])([F:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:6][C:7]([F:19])([F:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:1])=[CH:12][N:11]=1
Reactant: O=Cc1ccc(OCC(F)(F)F)nc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
n-Butyllithium (5.14 mL, 13.4 mmol) is added to a suspension of methyltriphenylphosphonium bromide (4.41 g, 12.34 mmol) in tetrahydrofuran (51 mL) at −78° C. under nitrogen atmosphere. The reaction mixture is warmed to room temperature to yield deep red ylide solution. To ylide solution, cooling in ice, is introduced 6-(2,2,2-trifluoroethoxy)nicotinaldehyde (2.11 g, 10.3 mmol, Step-1) in tetrahydrofuran (10 mL) and stirred at room temperature for 3 hours. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (10:1) to give 1.56 g (75% yield) of the title compound as colorless oil.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]([OH:25])[CH3:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:26])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)C>[C:23]([C:22]1[C:13]([O:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:14][C:15]([F:26])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:25])[CH3:24]
Reactant: COC(=O)c1cc(C(C)O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(C(C)=O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a mixture of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate (0.76 g, 2.10 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (1.34 g, 3.20 mmol). The reaction mixture was stirred for 1 hour at ambient temperature and then quenched by addition of saturated sodium bicarbonate solution (5 mL) and saturated sodium thiosulfate solution (5 mL). Dichloromethane (30 mL) was added and the mixture was stirred for 16 hours at ambient temperature. The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue, which re-dissolved in a mixture of diethyl ether and dichloromethane (30 mL, 1:1). Insoluble material was filtered off, and the filtrate was concentrated in vacuo to yield the title compound as a colorless oil (0.75 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 1H), 6.62 (d, J=12.8 Hz, 1H), 3.78 (s, 3H), 3.55 (s, 2H), 2.55 (s, 3H), 1.97-1.90 (m, 3H), 1.72-1.53 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1([CH2:19][C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:16]2[CH2:17][CH2:18][N:13]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:15]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: O=C(CN1CCNCC1)Nc1cccnc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (10 ml) was added 2-(piperazin-1-yl)-N-(pyridin-3-yl)acetamide×3HCl salt (0.180 g, 0.55 mmol) followed by diisopropylethylamine (0.41 ml, 2.36 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 2.5% methanol in ethyl acetate. The title compound was obtained as a yellow solid (0.180 g, 82%); 1H-NMR (500 MHz, DMSO-d6) 2.68 (br s, 4H, piperazine N(CH2)2), 3.14 (br s, 4H, piperazine N(CH2)2), 3.24 (s, 2H, NCH2CO), 6.98 (br s, 2H, NH2), 7.34 (dd, J=8.10, 4.75 Hz, 1H, pyridyl 5-H), 8.06 (d, J=7.50 Hz, 1H, pyridyl 4-H), 8.16 (s, 1H, 6-H), 8.27 (dd, J=4.80, 1.96 Hz, 1H, pyridyl 6-H), 8.78 (d, J=2.30 Hz, 1H, pyridyl 2-H), 9.95 (s, 1H, CONH);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(CNc2cc(Cl)nc3ccnn23)cc1

Procedure:
5.7 g (30.3 mmol) 5,7-dichloropyrazolo[1,5-a]pyrimidine (prepared according to T. Novinson, B. Bhooshan, T. Okabe, G. R. Revankar, R. K. Robins, K. Senga, H. R. Wilson, J. Med. Chem. 1976, 19, 512) and 6.3 g (30.25 mmol) 4-aminomethyl-2'-cyanobiphenyl were dissolved in 150 ml dry ethanol and heated with reflux for 10 h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with 10% aqueous sodium carbonate solution, and dried over sodium sulfate. After evaporation in vacuo the title compound crystallized from ethyl acetate/ether in colorless crystals,
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=1>C1COCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:3][C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2ccccn2)s1

Procedure:
A flame dried round-bottom flask under Ar was charged with NaH (60% dispersion 0.037 g, 0.91 mmol). Anhydrous THF, 2 mL, was added followed by the addition of 2-aminopyridine (0.032 g, 0.033 mmol). 2-Chloro-thiazole-5-carbonitrile (9-2, 0.044 g, 0.30 mmol) was added and the reaction was heated to reflux. After 2 h the reaction was cooled and quenched by the addition of water. The THF was removed in vacuo and the precipitate which formed was filtered and washed with water. The solid was recrystallized from DMSO to provide a pure sample of the desired product. 1H NMR (DMSO-d6) d 12.23 (s, 1H), 8.40 (m, 1H), 8.27 (s, 1h), 7.82 (m, 1H), 7.15 (d, 1H, J=8.3 Hz), 7.08 (m, 1H). MS [M+H]+=203.0.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24](O)=[O:25])=[N:12][CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH2:62]>CN(C=O)C>[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH:62][C:24]([C:11]1[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1)=[O:25]
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid HCl, 2, (8.06 g, 21.7 mmol) in DMF (100 mL) at 0° C. under N2 is added diisopropylethylamine (11.35 mL, 65.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (6.23 g, 32.6 mmol) and 1-hydroxybenzotriazole (HOBt) (0.294 g, 2.2 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (4.09 g, 32.6 mmol) is added. The reaction is allowed to warm slowly to room temperature and stirred 3 days. The reaction volume is partially concentrated under reduced pressure then diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow oil that is purified over silica (EtOAc:heptane gradient 1:1 to 1:0) to afford 3.5 g (40% yield) of the desired product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (1H, t, J=4.9 Hz), 7.95 (1H, d, J=1.8 Hz), 7.38-7.44 (2H, m), 7.22-7.35 (8H, m), 6.85 (1H, d, J=2.6 Hz), 5.14 (2H, s), 5.03 (2H, s), 4.18 (2H, d, J=5.5 Hz), 3.69 (3H, s). HPLC-MS: m/z 407 [M+H]+.
Reaction SMILES: [CH2:1]1[C@@H:6]([OH:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].O>CO>[CH2:1]1[C:2]([OH:10])([C:11]([OH:13])=[O:12])[CH2:3][C@@H:4]([OH:9])[CH:5]([OH:8])[C@@H:6]1[OH:7]
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Solvent: CO
Solvent: O
Product: O=C(O)C1(O)C[C@@H](O)C(O)[C@H](O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Fifteen grams of the hydrochloride salt is neutralized to the free base form as described in Synthesis Example 1. The free base (11.12 g, 0.025 mol) is isolated and dissolved in approximately 200 ml of methanol. Quinic acid (4.91 g, 0.025 mol) is dissolved in 200 ml of a hot solution consisting of 90% methanol and 10% water and added to the solution containing free base. The mixture is stirred for 2 hours at a temperature up to 100° C. The solvent is evaporated under reduced pressure and the resultant solid is collected, dried, and recrystallized from ethanol. The quinate salt obtained (12.4 g, 0.19 mol, 76%) melted with a three degree range between the limits of 136°-139° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17]1[N:22]=[C:21]([OH:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc([N+](=O)[O-])c(=O)[nH]2)o1
Yield: 78.9 %

Procedure:
A mixture containing 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (4.72 g; 22.0 mmoles) and 2-methylthio-5-nitro-4-hydroxypyrimidine (4.0 g; 21.37 mmoles) in 20 ml of ethanol was heated at reflux temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, and the residue was recrystallized from 2-methoxyethanol to give 5.96 g of the title compound, mp 201°-204° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[C:29]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:32]([C:30]1[C:29]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=1)=[O:34]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. MS (ESI) 314 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24].O>O1CCOCC1>[C:25]([C:23]1[CH2:24][O:16][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:15][C:12]=2[CH:13]=1)(=[O:26])[CH3:27]
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)C1=Cc2cc(Oc3ccccc3)ccc2OC1

Procedure:
The starting material is prepared as follows: 5-Phenoxysalicylaldehyde (6.17 g, 28.8 mmol) is dissolved in 100 ml of 1,4-dioxane and treated with potassium carbonate (7.96 g, 57.6 mmol) and methyl vinyl ketone (3.03 g, 43.2 mmol) under nitrogen. The mixture is heated at reflux for 3 hours. Water is added and three extractions with dichloromethane are carried out. The organic extracts are combined, dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yields 3-acetyl-6-phenoxy-2H-1-benzopyran as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH:9]=[N:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:61][C:62]([F:66])([F:65])[CH2:63][NH2:64]>CN(C=O)C>[CH3:22][CH:20]([CH3:21])[CH2:19][C@H:15]([NH:14][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:23]2[CH2:26][C:25]([F:27])([F:28])[CH2:24]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])[C:16](=[O:17])[NH:64][CH2:63][C:62]([F:66])([F:65])[F:61]
Reactant: NCC(F)(F)F
Reactant: CC(C)C[C@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
(S)-2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-4-methyl-pentanoic acid (40 mg, 100 μmol) was suspended in DMF (2 mL). TBTU (35.5 mg, 110 μmol), DIEA (85.9 μl, 0.5 mmol) and 2,2,2-trifluoro-ethanamine hydrochloride (1:1) (CAN 373-88-6, 15 mg, 135 μmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo; ethyl acetate (3 mL) and 2N NaOH solution (2 mL) were added before eluting with ethyl acetate through ChemElut (10 g). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 100% ethyl acetate in n-heptane) to give the desired product (36 mg, 75%) as white solid; LC-MS (UV peak area, ESI) 100%, 480.2035 (M+H).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[F:5][C:6]([F:10])([F:9])[CH:7]=[O:8]>O1CCCC1.[Zn]>[F:5][C:6]([F:10])([F:9])[CH:7]([OH:8])[CH2:3][C:2]#[CH:1]
Reactant: C#CCBr
Reactant: O=CC(F)(F)F
Agent: [Zn]
Solvent: C1CCOC1
Product: C#CCC(O)C(F)(F)F
Yield: 65 %

Procedure:
In a mixture of propargyl bromide (3.46 g, 29 mmol), zinc powder (2.3 g, 0.035 gram-atom) in tetrahydrofuran (60 ml), trifluoroacetaldehyde (1.9 g, 19 mmol) was added under bubbling. An hour later, the reaction mixture was poured into aqueous 2% HCl solution for a similar treatment to the one used in the above Examples. Distillation gave 1,1,1-trifluoro-4-pentyne-2-ol (b.p.: 95°-96° C.) at a yield of 65%. The above product gave the following analytical data:
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[CH:33]=[O:34])=[CH:30][C:29]([O:35][CH3:36])=[CH:28][CH:27]=2.C(OCC)(=O)C>C(#N)C>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[CH:33]=[O:34])=[C:30]([F:21])[C:29]([O:35][CH3:36])=[CH:28][CH:27]=2
Reactant: COc1ccc2ncc(Cl)c(C=O)c2c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc2ncc(Cl)c(C=O)c2c1F
Temperature: 10 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
Selectfluor (2.4 g, 6.77 mmol, 1.5 eq) is added at 10° C. to a stirred solution of 3-chloro-6-methoxy-quinoline-4-carbaldehyde (1.0 g, 4.5 mmol, 1.0 eq) in acetonitrile (50 mL). After 24 hours stirring at 10° C., the reaction mixture is extracted with ethyl acetate (3×100 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 5:1, v/v) to afford 3-chloro-5-fluoro-6-methoxy-quinoline-4-carbaldehyde as a yellow solid (620 mg, 57% yield).
Reaction SMILES: Cl[CH:2]([C:7]1[S:11][C:10]([C:12]2[S:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C)C=O>[N:28]([CH:2]([C:7]1[S:11][C:10]([C:12]2[S:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4])=[N+:29]=[N-:30]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(Cl)C(F)(F)F)s3)s2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(N=[N+]=[N-])C(F)(F)F)s3)s2)cc1
Yield: 71.6 %

Procedure:
A mixture of Example 5C (0.6 g, 0.0013 mol) and sodium azide (1.0 g, 0.013 mol) in N,N-dimethylformamide was heated at 80° C. under nitrogen for 4 hours. Water was added and the solution was extracted with ether. The organic layer was then washed with brine, dried and filtered. The filtrate was concentrated to give 0.5 g of crude as a yellow oil, which was purified on silica gel (10˜30% ethyl acetate in hexane) to give 0.41 g of pure product as a light yellow oil (72% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 4.44-4.61 (m, 1H) 5.10 (q, J=6.62 Hz, 1H) 6.87-6.96 (m, 2H) 6.97 (d, J=3.68 Hz, 1H) 7.08-7.14 (m, 1H) 7.16-7.24 (m, 2H) 7.32 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([CH:14]=O)=[CH:12][N:13]=2)[CH:3]=1.[NH2:16][C:17]1[C:18]([F:30])=[CH:19][C:20]([F:29])=[C:21]([CH:28]=1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]>>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[C:17]([NH:16][CH2:14][C:11]3[S:10][C:9]([NH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)=[N:13][CH:12]=3)[C:18]([F:30])=[CH:19][C:20]=2[F:29])[CH2:26][CH2:27]1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Reactant: Cc1ccnc(Nc2ncc(C=O)s2)c1
Product: Cc1ccnc(Nc2ncc(CNc3cc(C(=O)NC4CC4)c(F)cc3F)s2)c1

Procedure:
2-(4-Methylpyridin-2-ylamino)-thiazole-5-carbaldehyde was treated with 5-amino-N-cyclopropyl-2,4-difluorobenzamide (for preparation see Example 18) in a manner similar to Example 1 to afford the title compound. LC/MS; (M+H)+=416.