Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:33])([F:20])[F:34])[CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-[3-(trifluoromethoxy)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.95-8.02 (m, 2H), 7.73-7.75 (m, 1H), 7.63-7.64 (m, 4H), 7.50 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.38-7.40 (bs, 1H), 7.27-7.30 (m, 1H), 3.79 (s, 2H); MS (ESI−) M/Z 472 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:32])[C:26]=3[N:25]([CH:33]([CH3:36])[CH2:34][OH:35])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1>>[F:32][C:31]1[C:26]2[N:25]([CH:33]([CH3:36])[CH2:34][OH:35])[CH:24]=[C:23]([C:21]([C:17]3[CH:16]=[C:15]([NH:14][C:9](=[O:11])[CH2:8][N:6]4[CH:7]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=[N:5]4)[CH:20]=[N:19][CH:18]=3)=[O:22])[C:27]=2[CH:28]=[N:29][CH:30]=1
Reactant: O=C(O)Cn1cc(C(F)(F)F)cn1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using [4-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Preparation 74) and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc. LCMS (5 minute run) Rt=2.85 minutes MS m/z 491 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH:22]C(OCC1C=CC=CC=1)=O)[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH2:22])[C:9]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)N(OCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=N)N(OCCN)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)-ethoxyguanidine (730 mg, 1.5 mmol), as prepared in the preceding step, and 10% Pd/C (70 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (290 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 9.08 (br s, 1H), 4.08 (t, J=5.2 Hz, 2H), 2.99 (q, J=5.1 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: CC(=O)CCC(=O)C.CN1CC=C([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](N)[CH:23]=3)[N:18](S(C3C=CC=CC=3)(=O)=O)[CH:17]=2)CC1.C(O)(=O)C>C(O)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(N)cc23)CC1
Agent: CC(=O)CCC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hexane-2,5-dione (2 mL) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-5-amine (300 mg, 0.82 mmol) in ethanol (50 mL). Acetic acid (2 mL) was added, and the resulting solution was stirred at room temperature overnight. The solvent was concentrated, followed by column chromatography purification using a 1:10 methanol/dichloromethane solvent system provided 30 mg (8%) of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-phenylsulfonyl)-1H-indole as a yellow solid. 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.95 (d, 2H), 7.62 (s, 1H), 7.50 (d, 2H), 7.26 (2H), 6.84 (d, 2H), 6.11 (s, 1H), 5.90 (s, 2H), 3.46 (d, 2H), 3.07 (t, 2H), 2.74 (s, 2H), 2.62 (s, 2H), 1.98 (s, 6H). LC/MS (EI) tR 2.46, m/z 446.0 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:15]([O:19][C:20]([N:22]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12](=[O:14])[CH2:11][CH2:10][S:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(SCCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SCCC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of the compound prepared in Example 8(11) (106 mg) in DMF (5 ml), N-t-butoxycarbonyl-N-t-butoxycarbonyloxyamine (120 mg), EDC hydrochloride (106 mg) and 4-(dimethylamino)pyridine (6 mg) were added at 0° C. The mixture was stirred for 16 hours at room temperature. To the reaction solution, water was added and it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (211 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=1)[NH2:1]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C#N)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nnn[nH]2)c(N)c1
Temperature: 100 °C
Yield: 42.2 %

Procedure:
To a mixture of 2-amino-4-methylbenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 244 mg of 5-methyl-2-(1H-tetrazol-5-yl)aniline. MS (EI) for C8H9N5: 176 (M+H). Step 2: N-[5-Methyl-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 5-methyl-2-(1H-tetrazol-5-yl)aniline (240 mg, 1.4 mmol) in 6 mL of DCM was added DIPEA (7.5 mmol, 5.5 eq.) followed by thiophene-2-carbonyl chloride (6.8 mmol, 5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. This crude material was further purified by redissolving the material into minimum volume of aqueous NaOH (0.1 M), and then reacidified with concentrated HCl. The solid was collected by filtration, washed with EtOAc, and dried under vacuum to afford 26.8 mg of the desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.35 (s, 1H), 7.98-7.94 (m, 2H), 7.90 (d, 1H), 7.33 (t, 1H), 7.20 (d, 1H), 2.42 (s, 3H). MS (EI) for C13H11N5OS: 286 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH3:24])=O)(C)(C)C.[N+:25]([O-])([OH:27])=[O:26].C(Cl)(Cl)Cl>O>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:23][CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCN)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
The ester 198 (4.0 g, 11.8 mmol) was added in small portions to a stirred solution of 70% HNO3 (2 mL acid/g of substrate) at room temperature and the reaction mixture was allowed to stir overnight. After 16 hours TLC (CHCl3) revealed the complete loss of starting material. The reaction mixture was cooled in an ice bath, and 15 g of iced water was added, precipitating the product. The precipitate was collected by vacuum filtration and washed with small amount of iced water. The filtrate was cooled and a second crop of precipitate was collected by vacuum filtration and washed with iced water. The combined precipitate was dried in vacuo to provide compound 199 as a yellow solid, which was not purified further, but used directly in the subsequent reaction (2.3 g, 70%). mp=101-103° C.; 1H-NMR (CDCl3/DMSO-d6, 270 MHz): δ2.31 (m, 2H, H2′), 3.20 (br, 2H, H3′), 3.95 (s, 3H, OCH3ether), 3.98 (s, 3H, OCH3ester), 4.24 (t, 2H, J=5.95 Hz, H1′), 7.11 (s, 1H, H6), 7.49 (s, 1H, H3), 8.21 (s, 3H, NH); 13C-NMR (CDCl3, 68.7 MHz): δ26.5 (C2′), 37.0 (C3′), 53.0 (OCH3ester), 56.0 (OCH3ether), 66.7 (C1′), 108.3 (C3), 111.0 (C6), 121.6 (Carom), 140.9 (C2), 149.3 (Carom), 152.6 (Carom), 166.8 (C═O); MS (E/I) m/z (relative intensity): 284 (M+., 90), 237 (70), 227 (93), 196 (47), 181 (38), 137 (100), 122 (81), 93 (52), 79 (44); HRMS (E/I) exact mass calcd for C12H17N2O6: m/e 284.1008, obsd m/e 284.1018; IR (Nujolò) n: (cm−1) 3472, 2937, 2911, 2855, 1733, 1532, 1516, 1462, 1377, 1292, 1224, 1143, 1052, 884, 812, 792, 773, 756, 724, 646.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:3]=1[O:4]C1CCCCO1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1>[OH:4][C:3]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:2]=1[B:26]([OH:27])[OH:25]
Reactant: COc1ccc(OC2CCCCO2)c(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(O)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
2-(2-Bromo-4-methoxyphenoxy)tetrahydropyran (1.9g, 6.62 mmol) was dissolved in dry THF (25 ml) and the solution cooled to -78° C. under nitrogen. n-Butyl lithium (1.6M in hexanes, 4.6 ml, 7.36 mmol) was added dropwise with stirring over 10 minutes. The reaction was stirred at −78° C. for 1 hour. Triisopropoxy borane (1.6 ml, 6.9 mmol) was added dropwise and the mixture allowed to warm to room temperature overnight. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with DCM (2×200 ml). The combined organic extracts were washed with 2N hydrochloric acid (50 ml), dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane to give the title compound as a pale brown solid (660 mg, 59%); MS 166/167 (M−H)−; HPLC retention time (system 2) 3.53 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.O=[S:10](Cl)Cl.S(=NS(C)(=O)=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[S:10][CH:8]=[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1N
Agent: CS(=O)(=O)N=S=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: c1ccc2nscc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of o-toluidine (10 g, 93.4 mmol) in 50 mL toluene was added SOCl2 (12.1 g, 102 mmol) dropwise at 0° C. After the addition was complete, the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in toluene (100 mL), then a solution of N-sulfinylmethanesulfonamide (20.6 g, 146 mmol) was added dropwise, followed by pyridine (7.3 g, 93.4 mmol). The mixture was heated to reflux and stirred at that temperature overnight. Toluene was then removed under reduced pressure, the residue was dissolved in EtOAc (200 mL) and washed with water (2×200 mL). The organic layer was washed with brine, dried and evaporated to give the crude product. The crude product was purified by column chromatography (3% EtOAc/PE) to afford 6.2 g title compound as colorless oil. 1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.9, 6.5, 1.2 Hz, 1H), 7.26 (dd, J=7.9, 6.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[N:11][NH2:12].[N:22]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[N:11][N:12]=[N:22]1
Reactant: O=N[O-]
Reactant: NN=C(Nc1cccc(F)c1F)c1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-n2nnnc2-c2c[nH]c3ncccc23)c1F
Yield: 57.1 %

Procedure:
N-(2,3-Difluoro-phenyl)-N′-amino-1H-pyrrolo[2,3-b]pyridine-3-carboxamidine (prepared by using procedures described in Method G) (20 mg, 0.07 mmol) was dissolved in 2N HCl (2 mL)). A solution of NaNO2 (6 mg) in water (1 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min and neutralized with 6N NaOH. The precipitate was collected by filtration and the crude product was purified by HPLC to afford a white solid (12 mg, 0.04 mmol).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1.[C:20](OCC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][S:18][C:14]1[N:13]=[C:12]([CH2:11][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:17]=[CH:16][N:15]=1
Reactant: CSc1nccc(C)n1
Reactant: CCOC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2ccccc2)n1
Yield: 99.5 %

Procedure:
86 ml (86 mmoles) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran was added drop-wise by addition funnel to a solution of 6.03 g (43 mmoles) 4-methyl-2-(methylthio)pyrimidine and 6.46 g (43 mmoles) ethyl benzoate in 86 ml tetrahydrofuran under a nitrogen atmosphere. After 2 hours the reaction was quenched with saturated ammonium chloride solution. Most of the tetrahydrofuran was removed in vacuo. The residue was diluted with 400 ml ethyl acetate and 200 ml water. The organic layer was separated and washed 2×100 ml saturated sodium chloride solution, separated, dried over Na2SO4, filtered, and concentrated in vacuo to give 10.45 g (42.77 mmoles) of 2-[2-(methyl thio)pyrimidin-4-yl]-1-phenyle thanone as a viscous red-brown oil that solidified upon standing. MH+=244.9.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH3:19])=[CH:13][CH:12]=1>O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH3:19])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: Fc1cccc(F)n1
Solvent: O
Product: COc1ccc(CN(C)c2cccc(F)n2)cc1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.183 mL, 2.00 mmol) and (4-methoxyphenyl)-N-methylmethanamine (0.604 g, 4.00 mmol) in 2 mL of water. The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer were dried over anhydrous sodium sulfate, filtered and concentrated to give 470 mg of a crude yellow oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate) to give 400 mg of N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine as a clear, colorless oil. To a solution of diisopropylamine (1.92 mL, 13.6 mmol) in 25 mL of THF at 0° C. was added butyllithium (1.6 M in hexanes, 8.93 mL, 14.3 mmol). The mixture stirred for 30 minutes and was then cooled to −60° C. and N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine (1.760 g, 7.15 mmol) was added dropwise in 10 mL of THF. The reaction stirred for 1 h at −60° C. and then triisopropyl borate (2.88 mL, 12.5 mmol) was added and the reaction allowed to warm up to RT and stirred for 1 h. Ammonium chloride (sat.) was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2.13 g of a crude yellow foam, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 750 mg of a off-white solid. ES+=291.2 (M+H)
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30].[C:31]([O:36][CH2:37][CH3:38])(=[O:35])[C:32]#[C:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:37]([O:36][C:31]([C:32]1[C:33]([CH3:34])=[N:14][N:15]2[C:16]([O:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[CH:17][CH:18]=[CH:19][C:20]=12)=[O:35])[CH3:38]
Reactant: N[n+]1ccccc1OCc1c(F)cccc1F
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 540 mg (1.00 mmol, 81% pure) of 1-amino-2-[(2,6-difluorobenzyl)oxy]pyridinium-2,4,6-trimethylbenzenesulphonate from Example 128A in DMF (10 ml) at 0° C. was admixed with 0.35 ml (3.06 mmol) of ethyl 2-butynoate and 623 mg (4.51 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature overnight and added dropwise to 20 ml of water while stirring. The resulting suspension was extracted with ethyl acetate (2×20 ml). The combined organic phases were dried with a phase separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 200 mg (25% of theory, 43% pure) of the target compound.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].Cl[C:59]1[N:66]=[CH:65][CH:64]=[CH:63][C:60]=1[C:61]#[N:62]>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:59]1[N:66]=[CH:65][CH:64]=[CH:63][C:60]=1[C:61]#[N:62]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1cccnc1Cl
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C#N)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloronicotinonitrile. ESI-MS (m/z): 416 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:20][C:13]3=[N:14][CH:15]=[C:16]([S:18][CH3:19])[CH:17]=[C:12]3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:20][C:13]3=[N:14][CH:15]=[C:16]([S:18]([CH3:19])=[O:26])[CH:17]=[C:12]3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -5 °C

Procedure:
To a stirred solution of 1.0 g of 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylthio)-2H-pyrano[2,3-b]pyridine in 25 ml of methylene chloride at -25° C. there was added dropwise a solution of 0.55 g of 80-85% m-chloroperoxybenzoic acid in 20 ml of methylene chloride over 5-10 minutes while keeping the temperature between -20° and -30° C. A precipitate formed. The mixture was then allowed to warm to -5° C. over 2 hours and then extracted with aqueous saturated sodium bicarbonate solution, aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to leave a pale yellow solid. This was recrystallized from a mixture of ethyl acetate and hexane to give 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylsulfinyl)-2H-pyrano[2,3-b]pyridine as a cream-colored solid melting at about 159°-162° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:19][CH2:18]1.C([Mg]Br)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:18][CH3:19])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Reactant: CN1CCCC1=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a red solution of 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (2.95 g, 13.0 mmol), Fe(acac)3 (512 mg, 1.45 mmol) and NMP (1.58 g, 16.0 mmol) in THF (400 mL), a solution of ethylmagnesium bromide (1.81 g, 13.6 mmol) in THF is slowly added at −77° C. The brown solution turns green-grey. The suspension is warmed to rt, stirred for 30 min before the yellow solution is again cooled to −70° C. and another portion of the Grignard reagent (1.38 g, 10.4 mmol) is added. The reaction mixture is warmed to rt, stirred for 16 h and then carefully quenched with 1 N aq. HCl (100 mL) and diluted with ether. The org. layer is separated and the aq. phase is extracted with ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-ethyl-6-methyl-isonicotinic acid tert.-butyl ester as a yellow oil which is dissolved in 4 N HCl in dioxane (50 mL). The solution is stirred at 50° C. for 16 h before the solvent is evaporated to give 2-ethyl-6-methylisonicotinic acid hydrochloride as a beige powder; LC-MS: tR=0.28 min, [M+1]+=166.25; 1H NMR (CDCl3): δ 8.19 (s, 2H), 3.12 (q; J=7.6 Hz, 2H), 2.84 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).