Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.BrC1C=C2C(=CC=1F)NN=C2.C([Li])(C)(C)C.[C:28](=[O:30])=[O:29]>>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: Cc1cc2[nH]ncc2cc1Br
Agent: Fc1cc2[nH]ncc2cc1Br
Agent: [Li]C(C)(C)C
Product: Cc1cc2[nH]ncc2cc1C(=O)O

Procedure:
This compound was prepared in a manner similar to that shown in Scheme 3, using 5-bromo-6-methyl-1H-indazole as the starting material, which was prepared in a manner similar to that of 5-bromo-6-fluoro-1H-indazole. The starting material was treated with t-butyl lithium and carbon dioxide to yield 6-methyl-1H-indazole-5-carboxylic acid, which was in turn treated with thiosemicarbazide and polyphosphoric acid to form 94.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@H:10]1[N:20]2[C@@H:14]([S:15][CH2:16][CH2:17][C@H:18]([NH:22]C(=O)OC(C)(C)C)[C:19]2=[O:21])[CH2:13][CH2:12][CH2:11]1)#[N:9]>C(Cl)Cl>[NH2:22][C@H:18]1[CH2:17][CH2:16][S:15][C@H:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:8]#[N:9])[N:20]2[C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C#N)N2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.9 %

Procedure:
Trifluoroacetic acid (0.15 mL) was added to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (36 mg, 0.11 mmol) in DCM (0.35 mL). The reaction mixture was then stirred at rt for 45 min. The reaction mixture was concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc was isolated, dried over MgSO4, filtered and concentrated give (4S,7S,10aS)-4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carbonitrile (15 mg, 0.067 mmol, 60% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2C1CCCCO1.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([NH2:33])[C:27]=2[CH:26]=[N:25]1.Cl>C(O)C.C([O-])(O)=O.[Na+]>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:33][C:28]2[C:27]3[CH:26]=[N:25][NH:24][C:32]=3[CH:31]=[CH:30][CH:29]=2)[N:16]=1
Reactant: Cc1nc(-c2cnccc2Cl)c2ncn(C3CCCCO3)c2n1
Reactant: Nc1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cnccc2Nc2cccc3[nH]ncc23)c2nc[nH]c2n1
Temperature: 160 °C
Yield: 67.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-(4-chloropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (33 mg, 0.100 mmol) and 1H-indazol-4-amine (26.6 mg, 0.200 mmol, Bionet Research, Cornwall, UK) in Ethanol (1 mL) and a drop of 5 N HCl. The reaction mixture was stirred and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with saturated NaCl (3 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column, eluting with 10% MeOH/CH2Cl2 to provide N-(3-(2-methyl-9H-purin-6-yl)pyridin-4-yl)-1H-indazol-4-amine (23 mg, 67% yield) as yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 13.27 (s, 1H); 12.54 (s, 1H); 10.22 (s, 1H); 8.64 (s, 1H); 8.30 (d, J=5.85 Hz, 1H); 8.16 (s, 1H); 7.30-7.43 (m, 3H); 7.18 (d, J=6.87 Hz, 1H); 2.82 (s, 3H). m/z (ESI, +ve ion) 343 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.[NH4+].[Cl-]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccccc2F)cc1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Into a 250 ml, 3-necked round-bottom flask, was placed a solution of 1-fluoro-2-(4-nitrophenoxy)benzene (5 g, 21.44 mmol, 1.00 equiv) in methanol/H2O (2/1=V/V) (100 mL), and NH4Cl (1 g, 18.70 mmol, 0.87 equiv). This was followed by the addition of Fe (7 g, 5.83 equiv), in portions at 80° C. in 20 min. The resulting solution was stirred for 1 h at reflux in an oil bath. The reaction mixture was cooled in a water bath. The solids were filtered out and the filtrate was concentrated under vacuum. The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.2 g (73%) of 4-(2-fluorophenoxy)aniline as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[S:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:30][C:31]1[S:32][CH:33]=[C:34]([C:36]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:37])[N:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1csc(Br)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2csc(Br)n2)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 60 h

Procedure:
A solution containing 1 eq each of tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, 2-bromothiazole-4-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl (3R,4R)-1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, LCMS (m/z): 612.2/614.2 (MH+); LC Rt=4.26 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23].C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:22](=[S:23])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cnccc1-c1cc2[nH]c(=S)[nH]c2nc1-c1cccnc1
Reaction time: 6 h
Yield: 88.3 %

Procedure:
A solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 2 g, 7.11 mmol), 1,1′-thiocarbonyldiimidazole (2.54 g, 14.22 mmol) and triethylamine (2 mL, 14.22 mmol) in THF (30 mL) was heated at 80° C. in a sealed tube. After 6 hours, the mixture was cooled and the solid was filtered, washed with NH4Cl aq. and water and dried to give the title compound (2.03 g, 88%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([O:28]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][C@H:39]1[O:44][C@@H:43]([CH3:45])[CH2:42][NH:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:45][CH:43]1[O:44][CH:39]([CH3:38])[CH2:40][N:41]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:42]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC(C)O1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 53 mg (0.47 mmol) of (2R,6S)-2,6-dimethylmorpholine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 49 mg (64% of theory)
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[C:8]([N:15]=1)=[N:9][C:10]([CH3:14])=[CH:11][C:12]=2[CH3:13])[CH3:4].[Br:16][C:17]1[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:35]=[N:36][N:37]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:38]=2)[N:19]=[C:20]2[C:25]=1[CH:24]=[C:23]([CH2:26]Br)[CH:22]=[CH:21]2>CN(C=O)C>[Br:16][C:17]1[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:35]=[N:36][N:37]([C:39]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:38]=2)[N:19]=[C:20]2[C:25]=1[CH:24]=[C:23]([CH2:26][N:15]1[C:8]3=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]3[N:6]=[C:5]1[CH2:3][CH3:4])[CH:22]=[CH:21]2
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: BrCc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution obtained by adding sodium hydride (15 mg, 0.366 mmol) to 2-ethyl-5,7-dimethyl-1H-imidazo[4,5-b]pyridine (58 mg, 0.333 mmol) in DMF (2 ml) and stirring for 30 minutes was added 5-[2-(3-bromo-5-(bromomethyl)-2H-indazol-2-yl)phenyl]-2-(triphenylmethyl)-2H-tetrazol (0.250 g, 0.370 mmol) as obtained in Reference Example 9. The mixture was stirred at room temperature for 16 hours. After concentration, it was partitioned by ethyl acetate (10 ml) and water (5 ml). The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of dichloromethane/methanol (100:1), whereby 0.134 g of 3-{[3 -bromo-2-[2-(2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]-2H-indazol-5-yl]methyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine was obtained.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:16])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=CC(=O)O
Reactant: CCCCCCCCC(C)=O
Agent: O=P(O)(O)O
Product: CCCCCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (5.10 g, 6.7 mmol), 2-decanone (15.0 g, 9.6 mmol) and orthophosphoric acid (20 ml). νmax 2925, 2820, 1690, 1460, 1380, 1240, 1120, 880, 720 cm−1. 1H n.m.r. δ (CDCl3) 0.87, t J 7.2 Hz, 3H, CH3; 1.29, m, 10H, CH2; 2.39, s, 3H, CH3; 2.77, t J 6.8 Hz, 2H, CH2; 6.50, s, CH. 13C n.m.r. δ (CDCl3): 13.9, CH3; 22.5, 26.6, 26.9, 29.1, 29.6, 31.6 CH2; 28.8, CH3; 124.3, C2; 157.9, C3; 170.9, COOH; 199.9 C2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[O:29]1[CH2:34][CH:33]=[C:32](B(O)O)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[O:29]1[CH2:30][CH:31]=[C:32]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@:15]5([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:22]2[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][CH:10]=4)[CH2:33][CH2:34]1
Reactant: OB(O)C1=CCOCC1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3=CCOCC3)cc12
Temperature: 110 °C
Yield: 92.9 %

Procedure:
A vial was charged with and (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (79.05 mg, 0.199 mmol), 3,6-dihydro-2H-pyran-4-ylboronic acid (76 mg, 0.598 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.05 mg, 9.96 μmol), and potassium phosphate (127 mg, 0.598 mmol). Dioxane (747 μL) and water (249 μL) were added, and the vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (82.18 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:13][CH2:14][NH:15][CH2:16][CH:8]1[C:7](=[O:17])[NH:6]2.[CH:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[CH2:21].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.CO.C(O)(=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH2:20][CH2:21][N:15]2[CH2:14][CH2:13][N:9]3[C:10]4[C:5]([NH:6][C:7](=[O:17])[CH:8]3[CH2:16]2)=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:12][CH:11]=4)=[CH:23][CH:24]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCNCC12
Reactant: C=Cc1ccncc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccncc3)CC12

Procedure:
A solution of 9.0 g. of 2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 18 ml. of 4-vinylpyridine and 7 ml. of acetic acid was refluxed in 250 ml. of methanol overnight. The solvent was removed and the residue was precipitated with water. The precipitate was filtered and recrystallized from ethanol-water to yield 9.2 g. of the free base, m.p. 204°-206° C. 4 G. of this free base was dissolved in ethanol and treated with dry hydrogen chloride saturated ethanol. The product hydrogen chloride salt was filtered and recrystallized once from i-propanol and once from ethanol to yield 3.4 g. of the dihydrochloride salt of the title compound, m.p. 218°-221° C.
Reaction SMILES: C([NH:4][CH:5]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]2[CH2:15][CH:16]=[CH:17][CH:18]=[C:7]2[S:6]1)(=O)C.CC(C1C=CC=CC=1)=C.N1CCCC1>C1(C)C(C)=CC=CC=1>[NH2:4][C:5]1[S:6][C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1C(NC(C)=O)SC2=CC=CCC21
Agent: C=C(C)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: C1CCNC1
Product: CCOC(=O)c1c(N)sc2ccccc12
Temperature: 102 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
14.4 g of hydrogenation catalyst (Degussa-Hüls; E 101 R/W 5%) are added to a solution of 36 g of ethyl 2-acetylaminotetrahydrobenzothiophene-3-carboxylate in 250 ml of xylene (isomeric mixture) and the mixture is heated to a constant temperature of 139° C. to 141° C. 47 g of α-methylstyrene are metered in over a period of 5 h. The mixture is then refluxed for a further 36 h. It is cooled to 102° C., 32 g of pyrrolidine are added and the mixture is brought back to the reflux point (127° C.); it is stirred for 20 h at this temperature. After cooling to 20° C., the Pd/carbon is filtered off, the filtrate is concentrated to a residue, and the residue is taken up in 75 ml of ethyl acetate and washed with three times 12 ml of 10% hydrochloric acid. The organic phase is washed with twice 5 ml of water and then concentrated to a residue. This is recrystallized from 50 ml of isopropanol to give 21 g of ethyl 2-aminobenzothiophene-3-carboxylate in the form of slightly yellowish crystals (70.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:62]=[O:63]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:62]=[O:63])=[CH:10][CH:9]=2)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cnc2ccc(I)cc2c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2ccc(C=O)cc2c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1d) (1.37 g, 4 mmol), triethylamine (1.4 mL, 10 mmol), diphenylpropylphosphine (dpp, 45 uL, 0.2 mmol) and palladium(II) acetate (45 mg, 0.2 mmol) in dry N,N-dimethylformamide (30 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (2.8 mL, 8 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 3 h. The reaction was allowed to cool to 25° C. and then extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-40% ethyl acetate in hexanes in 30 min) afforded 6-formyl-4-methoxy-quinoline-3-carboxylic acid methyl ester (0.48 g, 50%) as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11]/[C:12](=[C:18](/[C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:34])([CH3:33])[CH2:25][CH:26]=[C:27]2[CH:30]([CH3:32])[CH3:31])=[CH:22][C:21]=1[O:35][CH2:36][CH3:37])\[CH3:19])/[C:13](OCC)=[O:14]>C1COCC1>[F:11]/[C:12](=[C:18](/[C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:34])([CH3:33])[CH2:25][CH:26]=[C:27]2[CH:30]([CH3:32])[CH3:31])=[CH:22][C:21]=1[O:35][CH2:36][CH3:37])\[CH3:19])/[CH2:13][OH:14]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CCC2(C)C

Procedure:
Following General Procedure G-1, diisobutylaluminum hydride (1.0 M in hexanes, 2.2 mL, 2.2 mmol) and ethyl (2E)-2-fluoro-3-(4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)-2-butenoate (Compound A-43, 0.205 g, 0.55 mmol) in THF (6 mL) were reacted to give the title compound.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:45]>ClCCl.C(#N)C>[ClH:45].[ClH:45].[F:44][C:2]([F:1])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COCCCOc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: COCCCOc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 169.1 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-(3-methoxypropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.12 g, 0.19 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 6.5 mL, 0.19 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.095 g, 80%). FIA-MS APCI (+) m/z 519 (M+H).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[N:5][C:6]([NH+:9]2[C:17]3[CH2:16][C@H:15]([CH3:18])[NH:14][CH2:13][C:12]=3[N:11]=[N:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[F:26][C:27]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:17]3[CH2:16][C@H:15]([CH3:18])[N:14]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:27]=4[F:26])=[O:30])[CH2:13][C:12]=3[N:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: C[C@H]1CC2=C(CN1)N=N[NH+]2c1ncc(F)cn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1Cc2c(nnn2-c2ncc(F)cn2)CN1C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of (S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridinium chloride (0.575 g, 2.12 mmol) in CH2Cl2 (10 mL) was added triethylamine (1.18 mL, 8.50 mmol) followed by 2-fluoro-3-(trifluoromethyl)benzoyl chloride (0.625 g, 2.76 mmol). After stirring for 30 min at rt, sat NaHCO3 (20 mL) was added. The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a white solid (0.837 g, 93%). MS (ESI) mass calcd. C18H13F5N6O, 424.11. m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 2H), 7.81-7.49 (m, 2H), 7.46-7.30 (m, 1H), 5.92-5.66 (m, 0.5H), 5.68-5.55 (m, 0.5H), 4.81-4.54 (m, 1H), 4.37 (d, J=16.9 Hz, 0.5H), 4.30-4.18 (m, 0.5H), 3.58-3.40 (m, 0.8H), 3.34-3.12 (m, 1.2H), 1.43-1.12 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C@H:18]([CH2:23][NH:24]C(=O)C(F)(F)F)[CH2:19][C:20]([O-:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17].C(N(C(C)C)CC)(C)C>ClCCl>[NH2:24][CH2:23][C@@H:18]([C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([NH:10][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:12]=1)[CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([C@H](CNC(=O)C(F)(F)F)CC(=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 0.65 mmol of benzoyl chloride was slowly added to (3R)-3-(3-amino-4-chlorophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate (200 mg, 0.59 mmol) (65b), the diisopropylethylamine (1.13 mL, 0.65 mmol) of (3R)-3-(3-amino-4-chlorophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate, and 113 mL (0.65 mmol) of diisopropylethyl amine in 15 mL of dichloromethane. The reaction solution was stirred for 3 h at room temperature. The reaction mixture was then washed with 1N HCl and saturated sodium bicarbonate solution. The solvent was removed under reduced pressure. The residue, methyl (3R)-3-[3-(acetylamino)-4-chlorophenyl]-4-(2,2,2-trifluoroacetylamino)butanoate, was dissolved in 2.5 mL of methanol and 0.2 mL 2N sodium hydroxide. The solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to provide the title compound (65). 1H NMR (400 MHz, CD3OD): δ7.97 (d, J=8.0 Hz, 2H), 7.69 (s, 1H), 7.63-7.59 (m, 1H), 7.55-7.50 (m, 2H), 7.27 (d, J=8.0 Hz, 1H), 3.47-3.18 (m, 3H), 2.81 (dd, J=16.0, 8.0 Hz, 1H), 2.70 (dd, J=16.0, 8.0 Hz, 1H); MS (ESI) m/z 333.1 (M+H)+.