Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:18]2[NH:26][C:25]3[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=3[CH:19]=2)[N:3]=1.CCN(CC)CC.[CH3:35][C:36](OC(C)=O)=[O:37]>C(Cl)Cl>[C:36]([N:15]1[CH2:16][CH2:17][C@@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:37])[CH3:35]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Yield: 47.9 %

Procedure:
Prepared according to Example 50, using (R)-2-(2-methyl-3-(pyrrolidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 61, 135 mg, 0.372 mmol), Et3N (57.0 μl, 0.410 mmol), and Ac2O (70.3 μl, 0.745 mmol) in DCM (3.7 mL). Purification by trituration with Et2O provided 2-(3-(((3R)-1-acetyl-3-pyrrolidinyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (72 mg, 47.8%). 1H NMR (DMSO-d6) δ: 7.84-7.91 (m, 1H), 7.57-7.62 (m, 1H), 7.32-7.40 (m, 1H), 7.12-7.21 (m, 2H), 6.91-6.98 (m, 1H), 4.61-4.75 (m, 1H), 3.45-3.98 (m, 3H), 3.38-3.45 (m, 2H), 2.82-2.90 (m, 2H), 2.57 (s, 3H), 2.04-2.44 (m, 2H), 1.98 (s, 3H), 1.12-1.21 (m, 2H). m/z (ESI, +ve) 405.1 (M−H)+.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:12]C(=O)OC(C)(C)C)[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.O>Cl>[CH:1]1([CH2:4][C@H:5]([NH2:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc([C@H](CC2CC2)NC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: O
Product: Cc1nc([C@@H](N)CC2CC2)no1
Yield: 74.8 %

Procedure:
A solution of (S)-tert-butyl 2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethylcarbamate (0.5 g, 2 mmol) in sat. hydrochloric acid (10 mL) was stirred at room temperature for 1 h. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2×20 mL) and adjusted with 2 M sodium hydroxide solution to pH=9˜10. It was then extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give crude product as a white solid (0.25 g, 80%); MS (EI): m/e 168.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:26])[C:10]([O:24][CH3:25])=[C:11]([C:20]([O:22][CH3:23])=[O:21])[N:12]([CH2:14][CH:15]([O:18]C)[O:16]C)[CH:13]=1)=[O:7].CS(O)(=O)=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:26])[C:10]([O:24][CH3:25])=[C:11]([C:20]([O:22][CH3:23])=[O:21])[N:12]([CH2:14][CH:15]([OH:18])[OH:16])[CH:13]=1)=[O:7]
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)NCc2ccc(F)cc2F)cn1CC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1c(OC)c(=O)c(C(=O)NCc2ccc(F)cc2F)cn1CC(O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-B, 0.106 g, 0.24 mmol) in acetonitrile (0.9 mL) and acetic acid (0.1 mL) was treated with methanesulfonic acid (0.005 mL, 0.072 mmol), sealed with a yellow cap, and heated to 70° C. After 16 hours, the mixture was cooled to afford a crude solution of methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxy late, 1-C. LCMS-ESI+ (m/z): [M+H]+ calculated for C18H19F2N2O7: 413.12; found: 413.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([I:25])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:31][CH3:30])=[O:19])=[CH:20][C:21]([I:25])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:26]([F:27])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(I)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 3 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 1, Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (15 mL) was added dropwise methylamine (2.0 M solution in THF, 1.4 mL, 2.8 mmol) and the reaction mixture was stirred for 3 hours, at which point thin layer chromatography on silica: gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH3:18])=[O:16]>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: Nc1nnn[nH]1
Reactant: COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Amino tetrazole (10.00 g, 117.56 mmol)/Triethyl amine (16.48 ml, 118.739 mmol) in acetonitrile was added Methyl chloroformate (9.1375 ml, 118.739 mmol) at 0° C. The reaction mixture was slowly brought to room temperature and stirred for about 30 minutes. After about 30 minutes the reaction warmed and was refluxed for about 2 hrs. The reaction was then cooled to room temperature and the solvent was removed under reduced pressure, leaving a residue. The residue was washed with dilyte HCl to yield a white-colored solid. The solid was then dried at 105 C for about 6 hrs, resulting in a 92% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.CN(C)C(N(C)C)=N.[F:39][C:40]([F:47])([F:46])[C:41](OCC)=[O:42]>CO>[F:39][C:40]([F:47])([F:46])[C:41]([NH:22][C@@H:20]([CH3:21])[C@H:19]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=1)[N:10]=[CH:11]2)[C:23]1[CH:24]=[CH:25][C:26]([S:29][CH3:30])=[CH:27][CH:28]=1)=[O:42]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine hydrochloride (9a) (150 mg, 0.34 mmol) was dissolved in MeOH (2 mL). 1,1,3,3-tetramethylguanidine (128 μL, 1.02 mmol) was added and the mixture was stirred for 5 min, ethyl trifluoroacetate (83 μL, 0.7 mmol) was added and the reaction mixture was stirred at r.t. for 2.5 h. The reaction mixture was evaporated and the residual material was purified by semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 20 min gradient of 20%-90% MeCN in water followed by isocratic final concentration until product had eluted. UV=254 nm was used for detection. Fractions with product was combined and lyophilized to afford the title compound as a colourless solid. Yield 128 mg (74%)
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][C@@H]1NCCN(C(OC(C)(C)C)=O)C1.BrC1C=CC([N+]([O-])=O)=NC=1>>[CH3:23][C@@H:15]1[N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=[N+]([O-])c1ccc(Br)cn1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 50 %

Procedure:
Following the procedure described for compound 101g and starting with (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) and 5-bromo-2-nitropyridine (10.5 g, 50 mmol) afforded 191e as a yellow solid (8.05 g, 50%). MS-ESI: [M+H]+ 323
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].C(Cl)Cl.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.O>[Si:21]([O:5][CH2:4][CH2:3][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[NH2:1])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A round-bottom flask was charged with (R)-3-amino-3-(3,4-dichlorophenyl)propan-1-ol (9.25 g, 42.0 mmol, CASRN 147611-61-8), DMAP (0.513 g, 4.20 mmol) and DCM (84.1 mL) then a solution of TBDMS-Cl (6.65 g, 44.1 mmol) and DCM (10 mL) was added. The reaction was stirred at RT for 2 d. The reaction mixture was poured into water and extracted with DCM. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:8 to 500:10) to afford 10.2 g (72%) of (R)-3-(tert-butyl dimethylsilyloxy)-1-(3,4-dichlorophenyl)propan-1-amine (186): m/z (APCI-pos) M+1=334.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[CH2:4][CH2:3]1.C[O-].[Na+].Cl[C:18]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=2[N:19]=1.[OH-].[Na+]>CO.C(Cl)Cl>[CH2:11]([O:10][C:9](=[O:13])[NH:8][CH:5]1[CH2:4][CH2:3][N:2]([C:18]2[N:22]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:7][CH2:6]1)[CH3:12]
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: CCOC(=O)NC1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)NC1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 140 °C

Procedure:
19 g (0.09 mole) of ethyl 4-piperidylcarbamate hydrochloride is solubilized in 120 ml of methanol and neutralized with 17.2 ml of 5.3N sodium methylate. The mixture is filtered and the filtrate evaporated to dryness. The evaporation residue is then mixed with 21.6 g (0.083 mole) of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole and heated to 140° C. for 5 hours. The reaction mass is taken up with methylene chloride and alkalinized with 2N sodium hydroxide. The organic phase is washed with water, dried, filtered and evaporated. The oil obtained is chromatographed on silica (eluent: methylene chloride/methanol, 97.5:2.5). Ethyl[1-{1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl}-4-piperidyl]carbamate is obtained.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[N:8]([CH2:22][CH2:23][CH3:24])[C:9](=[O:21])[C:10]2[NH:11][C:12]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:13][C:14]=2[N:15]=1)C.C1COCC1.[OH-].[Na+].Cl>O.C(O)C>[CH:16]1([C:12]2[NH:11][C:10]3[C:9](=[O:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]([NH:6][CH2:5][C:4]([OH:25])=[O:3])=[N:15][C:14]=3[N:13]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCCn1c(NCC(=O)OCC)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCn1c(NCC(=O)O)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 55 °C
Yield: 13 %

Procedure:
To a solution of (8-cyclopentyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-ylamino)-acetic acid ethyl ester (0.05 g, 0.144 mmol) prepared in the previous step in a mixture of water (5 ml), THF (5 ml) and ethanol (5 ml) was added sodium hydroxide (0.017 g, 0.425 mmol) and the resulting reaction mixture was heated at 50-60° C. overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in 2 ml of water. The solution obtained was neutralized with 1N HCl. The solid formed was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by crystallization with dichloromethane/ether/methanol mixture to give the product (0.006 g, 13%) as a pale yellow solid.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C@H:24]1[CH:23]=[CH:22][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[C:2](=[O:1])[C@H:3]1[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccco2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccco1
Yield: 71 %

Procedure:
The title compound was prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-(furan-2-yl)prop-2-en-1-imine using 10 mol % 9 as the catalyst in 71% yield as a yellow solid. [α]D20 (c 1.58, CHCl3)=+125.7; mp=98-100° C.; 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 2H, J=7.0, 1.9 Hz), 7.12 (d, 2H, J=8.0 Hz), 7.00 (dd, 21-1, J=7.0, 1.9 Hz), 6.87 (d, 1H, J=1.8 Hz), 6.11 (dd, 1H, J=3.2, 1.8 Hz), 5.82 (d, 1H, J=3.2 Hz), 5.51 (dd, 1H, J=8.0, 6.8 Hz), 4.15-4.10 (m, 2H), 3.90 (s, 3H), 3.75 (t, 1H, J=6.7 Hz), 3.45-3.40 (m, 1H), 2.72 (dd, 1H, J=17.3, 6.0 Hz), 2.52 (s, 3H), 2.04 (dd, 1H, J=17.3, 7.7 Hz), 1.22 (t, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.7, 168.7, 164.2, 142.6, 131.4, 129.6, 125.7, 114.1, 110.4, 108.0, 61.0, 56.0, 43.2, 35.1, 31.5, 14.3; IR (thin film) ν 3114, 2982, 2843, 1724, 1595, 1498, 1363, 1263, 1167, 1133, 1092, 1025 cm−1; HRMS (ESI) calcd for C20H21NO7S [M+Na]+ 494.1243, found 494.1265; >99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=43.7 min, tr (3R,4R)=37.4 min.
Reaction SMILES: C([Cl:4])(=O)C.C(O)C.[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:23]=1>C(OCC)C>[ClH:4].[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH:23]=1
Reactant: CC(=O)Cl
Agent: Fc1cccc2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c12
Solvent: CCOCC
Solvent: CCO
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add dropwise acetyl chloride (2.3 ml, 32.4 mmol) to anhydrous ethanol (50 mL) and stir the solution for 10 min at ambient temperature and add to a solution N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine (10.7 g, 29.2 mmol) in diethyl ether. Concentrate the resulting solution under reduced pressure to give a yellow solid. Recrystallize the yellow solid from ethyl acetate/methanol to give the title compound: mp 163-164° C.; MS (m/e): 367 (M−1), 365 (M−1); Calculated for C19H18F4N2O HCl: Calcd: C, 56.65; H, 4.75; N, 6.95. Found: C, 56.45; H, 4.54; N, 6.90.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.[OH-].[Na+]>C1COCC1.CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CSc1ccc2nnc(-c3cccs3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetate (50 mg, 0.156 mmol) dissolved in a 2/1 mixture of THF and MeOH was added 100 uL of 2N NaOH, and the whole was stirred at room temperature for 3 h. The reaction mixture was then evaporated to dryness, the residue dissolved in water (5 mL), and the solution acidified with 6M HCl. The resulting precipitate was filtered, washed twice with cold water, and dried to give acid 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetic acid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([CH3:15])[CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([CH3:15])[CH:14]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ncc(C2(O)CCC(=O)CC2)cc1C
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1C

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methoxy-5-methyl-pyridin-3-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: C(NC1CC2C(=CC=C(NC(C3C(C4C=CC(F)=CC=4)=CC=CC=3)=O)C=2)C1)(=O)C.[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1Cl.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:46]1[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccnc1Cl
Agent: CC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(F)cc3)cc2C1
Product: COC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester is prepared similarly to the title compound of Example 3 using 2-chloronicotinic acid methyl ester (1.45 g, 8.45 mmol) and 4-trifluoromethylbenzeneboronic acid (2.41 g, 12.68 mmol) to give the product as an oil: 1H NMR (CDCl3, 300 MHz): δ 8.80 (1H, dd), 8.19 (1H, dd), 7.67 (4H, q), 7.40 (1H, dd), 3.70 (3H, s). MS (ES+) m/z 282 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13](=[O:14])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a slurry of the product of Example 100A (3.6 g, 8.1 mmol) in dichloromethane (100 mL) and pyridine (1.3 g, 16.2 mmol) was added 2,2,2-Trichloroethyl chloroformate (2.16 g, 10.2 mmol). The solution was stirred for 16 hours, washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was triturated in 9:1 hexane/ethyl acetate to give the title compound as an orange powder (4.15 g, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Na].C(N(C(C)C)CC)(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]#[CH:43])=[CH:37][CH:36]=1>CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I>[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]#[C:43][C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[N:10][N:11]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:12]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:37][CH:36]=1
Reactant: O=S(=O)(O)c1ccc(Cn2nnc(-c3cccc(Br)c3)n2)cc1
Reactant: C#CCc1ccc(F)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(O)c1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1
Temperature: 100 °C
Yield: 8.26 %

Procedure:
A suspension of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]benzenesulfonic acid, sodium salt (0.50 g, 1.27 mmol) in DMF (3 mL) was treated with diisopropylethylamine (0.88 mL, 5.1 mmol), palladium tetrakis(triphenylphosphine) (“Pd(PPh3)4”, 0.29 g, 0.25 mmol), CuI (cat), and 1-fluoro-4-prop-2-ynyl-benzene (0.42 g, 3.1 mmol), and the mixture degassed with nitrogen. The reaction mixture was heated in the microwave for 15 minutes at 100° C., cooled to room temperature, poured into 1N HCl, extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated onto silica gel. The mesh was purified on a 3.5×15 cm silica gel column eluted with ethyl acetate (“EtOAc”)-methanol (“MeOH”) 4:1 with 1% acetic acid (“AcOH”). Evaporation and trituration with ether afforded 0.052 g of orange solid (8.26% yield) NMR (DMSO-d6); 8.03–7.99 (m, 1H), 7.61–7.51 (m, 6H), 7.46–7.42 (dd, 1H), 7.36–7.33 (d, 2H), 7.19–7.15 (t, 2H), 5.98 (s, 2H), 3.90 (s, 2H)
Reaction SMILES: [F:1][CH:2]([F:24])[CH2:3][O:4][C@@H:5]1[CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1>CO>[F:24][CH:2]([F:1])[CH2:3][O:4][C@@H:5]1[CH2:9][NH:8][C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1
Reactant: COC(=O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](OCC(F)F)CN1

Procedure:
To nitrogen flushed pressure bottle was added Pd/c (200 mg) under nitrogen. A solution of (2S,4S)-1-benzyl 2-methyl 4-(2,2-difluoroethoxy)pyrrolidine-1,2-dicarboxylate (2.0 g, 5.83 mmol) in MeOH (140 mL) was added to the bottle. The reaction mixture was hydrogenated at 50 psi overnight. The reaction mixture was passed through a pad of celite and washed with MeOH. The filtrate was concentrated and the residue was used for the next step without purification. 1H NMR (CDCl3, 400 MHz) δ ppm 3.56-3.79 (1H, m), 3.96 (1H, br s), 3.60-3.70 (1H, m), 3.62 (3H, s), 3.43-3.50 (2H, m), 3.07-3.09 (1H, m), 2.94-3.03 (1H, m), 2.78-2.87 (1H, m), 2.05-2.15 (2H, m); 13C NMR (126 MHz, CDCl3) δ ppm 174.72 (1C), 114.40 (1C, t, J=241 Hz), 80.41 (1C), 67.96 (1C, t, J=27.6 Hz), 58.78 (1C), 52.40 (1C), 52.29 (1C), 52.19 (1C, s), 35.96 (1C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][N:16]=4)=[CH:30][CH:29]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCc1ccc(-c2ccnc(F)c2)nc1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-fluoro-[2,4′-bipyridin]-5-yl)methanamine 24-2 (15 mg, 0.074 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (18 mg, 0.09 mmol), and HATU (36 mg, 0.095 mmol) were added N,N-diisopropylethylamine (DIEA, 26 μL, 0.15 mmol) and DMF (0.6 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-((2′-fluoro-[2,4′-bipyridin]-5-yl)methyl)-4-(pyrazin-2-yl)benzamide 24 as a solid. MS m/z 386.2 (M+1).