Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[CH2:15]([OH:18])[C:16]#[CH:17]>>[C:1]1([N:7]2[CH:17]=[C:16]([CH2:15][OH:18])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CCO
Solvent: CCOCC
Product: OCc1cn(-c2ccccc2)nn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Phenyl azide (2.02 g, 17.0 mmol) was dissolved in neat propargyl alcohol (3 mL) and the mixture was heated to 90° C. for 2 h. The reaction mixture was cooled to room temperature and the reaction mixture was diluted into diethyl ether and left overnight during which time 7 precipitated as a crystalline solid to afford 1.03 g (35%) of the desired product 7 while the mother liquor contained primarily the regioisomer 9: 1H NMR (400 MHz, CDCl3) δ 7.97, (s, 1H), 7.70, (d, J=8.40 Hz, 2H), 7.50, (m, 2H), 7.41 (m, 1H), 4.88, (d, J=6.00 Hz, 2H), 2.70, (bs, 1H). Step b: Preparation of 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (9). To a solution of (1-phenyl-1H-1,2,3-triazol-4-yl)methanol, 7, (1.03 g, 5.87 mmol) in CH2Cl2 (50 mL) was added MnO2 (2.05 g, 23.5 mmol). The reaction mixture was stirred for 3 days at room temperature. The reaction mixture was then filtered through Celite© and the resulting filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 0.83 g (82%) of 9: 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.51 (s, 1H), 7.53, (d, J=9.6 Hz, 2H), 7.58-7.49, (m, 3H). Step c: Preparation of N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (Y). To a solution of 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde, 9, (0.23 g, 1.35 mmol) in 1,2-dichloroethane (2 mL) was added N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.20 g, 1.23 mmol), sodium triacetoxyborohydride (0.10 g, 1.60 mmol), and 3 drops of acetic acid. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then poured into aqueous saturated NaCl (10 mL) and was extracted with ethyl acetate (10 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 35 mg (9%) of Y: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.78, (d, J=8.4 Hz, 2H), 7.50-7.39, (m, 4H), 7.20, (m, 1H), 4.72, (d, J=13.6 Hz, 1H), 4.63-4.58 (m, 2H), 2.90-2.60 (m, 6H), 2.22-2.17 (m, 1H), 2.10-1.95, (m, 1H), 1.90-1.78, (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].Br[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([CH:16]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:21])=[O:18]
Reactant: Cc1cccc(C)c1N
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C(C)Nc1c(C)cccc1C
Yield: 79.6 %

Procedure:
Furthermore, the reaction of 2,6-dimethylaniline at 120° to 125° C., in the presence of sodium bicarbonate as an acid-binding agent, with a three-fold molar excess of methyl 2-bromopropionate has been disclosed in U.S. Pat. No. 4,008,066. With this process, N-(1'-methoxycarbonylethyl)-2,6-dimethylaniline is obtained in a yield of 79.6% of theory.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH:29]1[C:38]2[N:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:32][CH2:31][CH2:30]1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:10]2[NH:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:29]2[C:38]3[N:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)cc1
Yield: 25.9 %

Procedure:
Benzaldehyde (0.5 mL, 4.92 mmol) was condensed with N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (170 mg, 0.428 mmol) in dry MeOH (3 mL) for 17 h at room temperature and the resultant imine was reduced with sodium borohydride (329 mg, 8.70 mmol) for 1 h (see General Procedures A and B). Purification of the crude product by flash chromatography (14 g silica, 30:1:1 EtOAc/CH3OH/NH4OH) followed by radial chromatography (2 mm TLC plate, 100:1:1 CH2Cl2/CH3OH/NH4OH) gave the N-alkylated product (54 mg, 26%) as a foam.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl:12][C:13]1[C:22]([NH2:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:24]([C:28]1[CH:37]=[CH:36][C:31]([C:32](OC)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>ClCCCl.CO>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:23][C:22]2[C:13]([Cl:12])=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:33])=[CH:36][CH:37]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1
Reactant: Nc1cc2ccccc2nc1Cl
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cc3ccccc3nc2Cl)cc1
Temperature: 25 °C

Procedure:
A solution of trimethylaluminum in toluene (2.0 M, 0.56 mL, 1.12 mmol) was added to a solution of 2-chloro-quinolin-3-ylamine (0.2 g, 1.12 mmol) and methyl 4-tert-butylbenzoate (0.227 mL, 1.18 mmol) in 1,2-dichloroethane (10 mL). The solution was heated at reflux for 6 hours, cooled to room temperature and treated with methanol (˜1 mL). The product was preabsorbed onto silica gel, and purified by flash chromatography, using 10% ethyl acetate in hexane as the eluant to give the product as a colorless solid, 0.32 g (84%). MS: m/z 339 (MH+). 1H NMR (DMSO-d6): δ 1.34 (s, 9 H), 7.60 (d, 2 H), 7.69 (d of d, 1 H), 7.82 (d of d, 1 H), 7.99 (d, 3 H), 8.09 (d, 1 H), 8.67 (s, 1 H) and 10.31 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:5]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:1][O:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:5]1
Reactant: COCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of tert-butyl 4-[1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (270 mg; compound B24) in DCM (1.69 ml) is slowly added trifluoroacetic acid (0.56 ml) at 0° C. The reaction mixture is stirred for 10 min at 0° C. and for 50 min at RT. All volatiles are removed in vacuo to give the title compound as a solid, which is used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1C2C(=NC=CC=2)N(OC(N(C)C)=[N+](C)C)N=1.Cl.[NH:66]1[CH:70]=[C:69]([CH2:71][NH2:72])[CH:68]=[N:67]1>CN(C=O)C.C(OCC)(=O)C>[NH:66]1[CH:70]=[C:69]([CH2:71][NH:72][C:18]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[O:19])[CH:68]=[N:67]1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: NCc1cn[nH]c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn[nH]c1)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
To solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 200 mg, 0.44 mmol) in DMF was added DIPEA (0.46 mL, 2.65 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (201 mg, 0.53 mmol). The reaction was stirred at room temperature for 10 minutes before the addition of (1H-pyrazol-4-yl)methanamine hydrochloride (64 mg, 0.49 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with water (3×5 mL) and brine (25 mL). The organic layer was collected, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2% MeOH in DCM to afford the title compound (68 mg, 29%).
Reaction SMILES: C(C1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=C.S([O-])([O-])=O.[Na+].[Na+].[C:22]([OH:26])(C)([CH3:24])[CH3:23].[OH2:27]>>[F:15][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:23]=1[CH:22]([OH:26])[CH2:24][OH:27])=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2
Reactant: O
Reactant: CC(C)(C)O
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: COc1ccc2ncc(F)c(C(O)CO)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a solution of AD-mixβ (50 g) in tert-butanol/water (200 mL/200 mL), cooled in an ice-bath for 30 minutes, 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (Preparation 6) (8 g, 39.2 mmol) was added and the reaction mixture was stirred at room temperature for 48 hours. Sodium sulfite (75 g) was added and the mixture was stirred for a further 30 minutes. It was extracted with diethyl ether then several times with 10% methanol in chloroform. The organic extract was evaporated under vacuum to afford the desired product as an oil (8.93 g, 96%). MS (+ve ion electrospray) m/z 239 (MH+); enantiomeric excess=44%, as determined by chiral analytical HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:37])[CH2:18][NH:19]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[NH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of #B118 (7.0 g, 14.0 mmol, 1.0 eq) in DMF (70 mL) was added piperidine (4.7 mL, 47.5 mmol, 3.4 eq.) at room temperature. The mixture was stirred at room temperature for 30 min, evaporated in vacuo. The residue was washed with petroleum ether (100 mL×2) and re-crystallized from EtOAc (50 mL) and petroleum ether (200 mL) to gave #B119 (3.3 g, 84.6%) as a white solid. 1H NMR (400 Hz, CDCl3): δ 9.37 (s, 1H), 7.57 (d, 2H), 7.25 (d, 2H), 4.80 (br, 1H), 4.27 (d, 2H), 3.47 (s, 2H), 1.45 (s, 9H)
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][C:10](=[O:42])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([F:41])[CH:12]=1)C>C(O)C>[F:41][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:43])=[O:5])=[O:42]
Reactant: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)O)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 91.6 %

Procedure:
Add sodium hydroxide (5.0N, 0.03 mL, 0.15 mmol) to 3-{3-fluoro-4-[1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyloxy]-benzoylamino}-propionic acid ethyl ester (0.0172 g, 0.03 mmol) in ethanol (0.5 mL) and stir for three hours. Acidify with 1.0 N HCl and extract desired compound with ethyl acetate three times. Dry organic fractions with Na2SO4, filter and concentrate under reduced pressure to provide 0.015 g (92%) of title compound. MS (ESI) m/z 546.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH3:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>N1C=CC=CC=1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([NH:1][C:15](=[O:18])[CH2:16][CH3:17])[O:3][N:4]=[C:5]2[N:6]([CH3:14])[C:7]1=[O:13]
Reactant: Cn1c(=O)c2c(N)onc2n(C)c1=O
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1onc2c1c(=O)n(C)c(=O)n2C
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
0.588 g of 3-amino-5,7-dimethyl-isoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was dissolved in 15 ml of pyridine under heating. Then, 1.5 g of propionyl chloride was added to the solution, and the mixture was stirred at 80° C. for 4 hours. The solvent was removed from the reaction solution under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The chloroform layer was taken and dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on a column of silica gel, and the column was eluted with chloroform:acetone:formic acid (20:1:0.1). The intended compound was recovered from the resultant eluate and recrystallized from isopropyl ether-acetone to give 0.345 g of colorless prisms, melting point: 150°-152° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)[C:15]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[C:12]32)=[CH:7][C:6]=1[O:36][CH3:37])([CH3:3])[CH3:2].[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39].O>CN1CCCC1=O>[C:38]([NH:42][CH2:25][CH2:24][CH2:23][C:16]1[C:15]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[C:12]2[C:13]3[C:8](=[CH:7][C:6]([O:36][CH3:37])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:14]=3)[CH2:9][CH2:10][N:11]2[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1c(CCCNC(C)(C)C)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Yield: 87 %

Procedure:
A solution of 30 mg of 6c and 20 mg of tert-butyl amine in 1 ml of N-methylpyrolidone was heated in a microwave oven at 120° C. for 30 min. The reaction mixture was cooled, poured into 5 ml of water and extracted with ethyl acetate. The product was purified by chromatography over silica gel, using a gradient of CH2Cl2/methanol as eluent, to provide 25 mg of 6d;
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:19]([F:21])[F:20])=[N:8][N:9]([CH3:18])[C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:18][N:9]1[C:10]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:19]([F:21])[F:20])=[N:8]1
Reactant: CCOC(=O)c1c(C(F)F)nn(C)c1C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(F)F)c(C(=O)O)c1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
N-Methyl-3-difluoromethyl-5-pentafluoroethyl-4-pyrazolecarboxylic acid ethyl ester (0.5 g, 1.55 mmol) in ethanol (3 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (0.6 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (10 ml) and extracted with diethyl ether (10 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×10 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Methyl-3-difluoromethyl-5-pentafluoroethyl-4-pyrazolecarboxylic acid (0.44 g, 1.50 mmol, 97%) was isolated as a colourless solid.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]2)=O)(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]2
Reactant: CC(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-acetyl-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.20 g, 4.49 mmol) in DCM (25 mL) is added 4M HCl in 1,4-dioxane (20.0 mL, 80.0 mmol) and the reaction stirred at about 25° C. for 18 hours. The reaction is concentrated, suspended in Et2O, and filtered to afford the title compound (U) as a hydroscopic solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([Br:11])=[CH:9][S:8][C:7]=1[CH:12]=O)=O)C.[NH2:14][NH2:15].O>CCO>[Br:11][C:10]1[C:6]2[C:4](=[O:3])[NH:15][N:14]=[CH:12][C:7]=2[S:8][CH:9]=1
Reactant: CCOC(=O)c1c(Br)csc1C=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]ncc2scc(Br)c12
Yield: 22.8 %

Procedure:
4-Bromo-2-formyl-thiophene-3-carboxylic acid ethyl ester (1.0 g, 3.8 mmol), NH2NH2.H2O (0.27 g, 4.58 mmol) and 20 mL of EtOH were refluxed under nitrogen for 5 h. The reaction mixture was cooled and precipitate formed, then filtered to give the title compound (0.2 g, yield: 23%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)[C@H](N)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](CO)C(C)C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (S)-2-amino-3-methylbutan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=461.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:22][CH:23]([F:25])[F:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:68][C:69]1[S:70][C:71]([NH:77][C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])=[C:72]([C:74](O)=[O:75])[N:73]=1>C(Cl)Cl.O>[Br:68][C:69]1[S:70][C:71]([NH:77][C:78](=[O:79])[O:80][C:81]([CH3:83])([CH3:82])[CH3:84])=[C:72]([C:74](=[O:75])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH2:22][CH:23]([F:25])[F:24])[C:6]=2[N:7]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:9][CH2:8]2)[N:73]=1
Reactant: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(N)cnn2CC(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2CC(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.6 %

Procedure:
To a solution of (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide (248 mg, 0.67 mmol) in DCM (20 mL) was added DIPEA (1.0 mL, 5.7 mmol), PyBOP (700 mg, 1.34 mmol) and 2-bromo-5-(tert-butoxycarbonylamino)-thiazole-4-carboxylic acid (282 mg, 0.87 mmol) and the mixture was stirred at room temperature for 20 hr. Water (50 mL) was added and stirring continued for 1 hr. The mixture was extracted with DCM (50 mL), the combined organic layers were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a pale yellow gum (405 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 10.27 and 10.26 (2s, 1H), 8.32 and 8.27 (2s, 1H), 7.88 and 7.85 (2s, 1H), 6.36-6.02 (m, 1H), 4.67-4.11 (m, 2H), 3.41-3.08 (m, 5H), 3.08 and 2.95 (2s, 3H), 2.22-1.71 (m, 4H), 1.31-1.18 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=1>>[CH3:27][C:28]1[S:29][C:30]([C:34]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: Cc1nc(C)c(C(=O)O)s1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5sc(C)nc5C)c4)CC3)cccc2n1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O-:9].[Na+].[I-].[K+].Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16]>CO.C1C=CC=CC=1>[C:3]12([C:26]3[CH:31]=[CH:30][C:8]([O:9][CH:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[C:15]([O:17][CH3:18])=[O:16])=[CH:28][CH:27]=3)[CH2:4][CH:5]3[CH2:14][CH:19]([CH2:24][CH:1]([CH2:6]3)[CH2:2]1)[CH2:20]2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C[O-]
Reactant: Oc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 5.7 g of p-(1-adamantyl))phenol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. After 20 minutes, a white solid separates. The mixture is refluxed overnight, cooled and filtered to remove the white solid. The solid is heated in 50 ml of hot chloroform and filtered to remove a small amount of insoluble residue. The filtrate is diluted with 50 ml of hexane and filtered to give the product as white crystals, mp 148.4°-150.5° C.