Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2ccc(OC)nc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
To a solution of 2-methoxyquinolin-8-ol (500 mg, 2.86 mmol) in MeCN (10 mL) was added ethyl 2-bromoacetate (501 mg, 3.0 mmol) and K2CO3 (789 mg, 5.72 mmol). The mixture was stirred at 80° C. for 5 h. The mixture was filtered and the filtrate evaporated to give the desired compound (700 mg, yield 94%). LCMS (m/z): 262.1 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:36])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M6) (390 mg, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (168 mg).
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH3:24])([CH3:23])[CH2:17][NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][C:16]1([CH3:24])[C:15]2[C:20](=[CH:21][C:12]([NH:11][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[F:1])=[CH:13][CH:14]=2)[C:19](=[O:22])[NH:18][CH2:17]1
Reactant: O=C(Cl)c1cccnc1F
Reactant: CC1(C)CNC(=O)c2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CNC(=O)c2cc(NC(=O)c3cccnc3F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-fluoro-nicotinoyl chloride (283 mg, 1.79 mmol) and 7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (340 mg, 1.79 mmol) in CH2Cl2 (10 mL) was added NaHCO3 (573 mg, 7.16 mmol). The resulting mixture was stirred for 30 min at RT and filtered. The filtrate was concentrated and purified on silica gel column to yield the title compound as white solid. MS (ES+): 314 (M+H)+. Calc'd for C17H16FN3O2—313.12
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@@H:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:7])[CH2:3][OH:4].[N:16]#[C:17]Br>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C@@H:6]([CH3:7])[CH2:5][C@H:2]2[CH2:3][O:4][C:17]([NH2:16])=[N:1]2)=[CH:14][CH:13]=1
Reactant: C[C@@H](C[C@H](N)CO)Oc1ccc(Cl)cc1
Reactant: N#CBr
Product: C[C@@H](C[C@H]1COC(N)=N1)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 1d (2S,4S)-2-amino-4-(4-chloro-phenoxy)-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow solid. MS (ISP): 257.2 ([{37Cl}M+H]+), 255.2 ([{35Cl}M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:24][CH3:22])=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 4 h
Yield: 77.9 %

Procedure:
4-(4-Bromo-1-oxo-1H-phthalazin-2-yl)benzoic acid (0.15 g, 0.43 mmol) and 1,1′-carbonyldiimidazol (0.10 g, 0.65 mmol) were dissolved in DMF (10 ml) at RT. Methyl amine (0.33 ml of a 2M solution in THF, 0.65 mmol) were added and stirring was continued for 4 h. Evaporation of the solvent under reduced pressure, dilution with DCM, extraction with a saturated aqueous NaHCO3 solution and evaporation of the solvent in vacuum gave the title compound (0.12 g, 77% yield) 1H-NMR: (400 MHz, D6-DMSO) 8.55 (1H, d), 8.38 (1H, d), 8.10 (1H, t), 8.03 (2H, d), 8.02 (2H, d), 7.73 (2H, d), 2.82 (3H, d).
Reaction SMILES: C([CH:3]([C:28]([OH:30])=[O:29])[N:4]([CH2:15][P:16]([S:23][CH2:24][CH2:25][CH2:26][CH3:27])([S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[C:32](O)(=O)C>>[CH2:5]([N:4]([CH2:15][P:16]([S:23][CH2:24][CH2:25][CH2:26][CH3:27])([S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[S:17])[CH2:3][C:28]([OH:30])=[O:29])[CH3:32]
Reactant: CCCCSP(=S)(CN(C(=O)OCc1ccccc1)C(CC)C(=O)O)SCCCC
Reactant: CC(=O)O
Agent: Br
Product: CCCCSP(=S)(CN(CC)CC(=O)O)SCCCC

Procedure:
Ethyl-N-[bis(n-butylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (3.1 g.) was dissolved in 15 ml. of 35% hydrobromic acid in acetic acid and stirred for two hours. The solvent was then removed under reduced pressure and the residue triturated four times with diethyl ether. The residue was then dissolved in benzene, treated with excess propylene oxide and concentrated to a viscous oil. The viscous oil was chromatographed on silica gel employing dichloromethane to yield ethyl-N-[bis(n-butylthio)phosphinothioylmethyl]glycine as an oil, ND25 =1.4835.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C@@H:9]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10])=[C:4]([F:18])[CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[NH4+].[Cl-].CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.CCCCCCC.COCCOC>[F:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)[C:7]([F:8])=[CH:6][C:5]=1[C@@H:9]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10]
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(Br)cc1F
Reactant: Cn1cc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(-c2cnn(C)c2)cc1F
Temperature: 100 °C
Yield: 73.7 %

Procedure:
To two microwave vials with stir bars were added (R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.47 mmol), 1-Methyl-4-1H-pyrazoleboronic acid, pinacol ester (917 mg, 4.41 mmol), DME (6 ml), Na2CO3 (3.67 ml, 7.35 mmol) (2.0 M aq) and PdCl2(dppf).CH2Cl2 adduct (60.0 mg, 0.07 mmol) divided evenly between the two vessels. Vessels were capped and heated by microwave irradiation for 20 min at 100° C. Reaction mixtures were combined, diluted with a saturated solution of NH4Cl and EtOAc. Phases partitioned. Aqueous phase extracted with EtOAc and organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 60 to 100%) provided (R)—N—((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (370 mg, 1.08 mmol, 73.7% yield). 1H NMR (400 MHz, CDCL3) δ ppm 1.23 (s, 9H) 1.57-1.60 (m, 3H) 3.33 (d, J=4.06 Hz, 1H) 3.97 (s, 3H) 4.79-4.88 (m, 1H) 7.10 (dd, J=11.20, 6.06 Hz, 1H) 7.20 (dd, J=10.78, 6.19 Hz, 1H) 7.76 (d, J=2.20 Hz, 1H) 7.82 (s, 1H). LCMS m/z 342.1 (M+H)+, Rt 0.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4].[Br:25]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([Br:25])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1nc(Br)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (0.62 g, 1.9 mmol) and N-bromosuccinimide (0.36 g, 2.01 mmol) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 493 mg of the title compound as a pale yellow solid. MS: (+) m/z 402.98, 404.86 (M+1, 79/81Br)
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:29][CH2:28][N:27]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=[N:22][CH:23]=1)(C1C=CC(C)=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:54]>C1COCC1>[F:54][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:29][CH2:28][N:27]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=[N:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#CCCCCF)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
A mixture of 5-(6-tosyloxy-1-hexynyl)-3-(1-tert-butoxycarbonyl -2(S)-azetidinylmethoxy)pyridine (35 mg, 68 μmol) in 1 mL of 1.0 M solution of TBAF in THF was stirred at room temperature for 10 h. The reaction mixture concentrated. The residue was purified by chromatography with hexane-EtOAc (3:1) to give a viscous oil (25 mg, 100%), [α]D−40.6 (c 1.4, CHCl3). 1H NMR (CDCl3) δ 8.24 (s, 2H), 7.24 (m, 1H), 4.52 (dt, 2H, J=47.3, 6.0 Hz), 4.56-4.47 (m, 1H), 4.38-4.26 (m, 1H), 4.12 (dd, 1H, J=10.2, 2.7 Hz), 3.89 (t, 2H, J=7.8 Hz), 2.50 (t, 2H, J=6.9 Hz), 2.42-2.21 (m, 2H), 2.04-1.69 (m, 4H), 1.42 (s, 9H); 13C NMR (CDCl3) δ 156.13, 154.40, 144.85, 137.26, 123.22, 121.05, 92.94, 83.54 (d, J=164.7 Hz), 79.74, 77.69, 68.69, 60.00, 53.62, 47.09, 29.53 (d, J=20.2 Hz), 28.38, 24.31 (d, J=5.0 Hz), 19.03; 19F NMR (CDCl3, CFCl3) δ 135.4 (tt, J=47.3, 24.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (1.00 g, 4.65 mmol, 1.0 eq.) in degassed toluene (20 mL) was added ethyl diazoacetate (0.98 mL, 9.30 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 2 h the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-40% EtOAc/hexanes) to afford racemic ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate as a white solid. Further purification by chiral SFC provided the active isomer (1-4) as the second eluting peak that was used in subsequent reactions. Analytical separation conditions are as follows: Chiralcel OJ-H, 4.6 mm×25 cm, 90/10 CO2/MeOH+0.1% diethylamine, flow rate=2.4 mL/min; peak 1=2.0 min, peak 2=2.6 min. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.64-2.55 (m, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 2.36 (ddd, 1H, J=8.6, 5.7, 3.8 Hz), 1.74-1.61 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). MS: m/z=302 (M+H).
Reaction SMILES: BrCC([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=O.SCCS(O)(=O)=O.[Na:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1.O.C(OCC)(=O)C>[Na:26].[CH3:17][C:8]1([CH3:18])[C:7]2[C:12](=[CH:13][CH:14]=[CH:5][CH:6]=2)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9]1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)CCS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-(bromoacetyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (12) (15.5 mg, 0.050 mmol) in DMF (0.13 mL) and THF (0.13 mL) was added a freshly prepared solution of 2-mercapto-1-ethanesulfonic acid, sodium salt (2) (25 mg, 0.15 mmol) and potassium carbonate (21 mg, 0.15 mmol) in water (0.15 mL) at room temperature. The resulting biphasic mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate (2.5 mL), and the organic layer was separated, washed with water (2×1 mL) and brine (1×1 mL), dried and concentrated to afford 6-[2'-mercapto-1'-ethanesulfonic acid, sodium salt)acetyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (20) as a solid. 1H NMR (pyr-d5): δ 8.19, 7.90, 7.40 (m, 3H), 4.11 (s, 2H), 3.5 (m, 4H), 1.55 (s, 4H), 1.20 (d, 12H).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3]1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(N(CC)CC)C.[BH4-].[Na+]>C(O)C.CC(C)=O>[ClH:1].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)=[CH:14][CH:13]=1
Reactant: NCCc1ccsc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNCCc2ccsc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 2-(3-thienyl)ethanamine hydrochloride (1.0 g, 6.1 mmol), 4-methoxybenzaldehyde (0.74 mL, 6.1 mmol), and triethylamine (1.7 mL, 12.2 mmol) in ethanol (60 mL) was stirred at 25° C. for 5 h. The reaction mixture was cooled to 0° C. and sodium borohydride (289 mg, 7.6 mmol) was added portionwise over 30 min. The reaction mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was diluted with acetone (5 mL) dropwise and concentrated to a residue that was dissolved in CH2Cl2 (10 mL) and 1.0 N NaOH (10 mL). The aqueous layer was separated and extracted with CH2Cl2 (10 mL). The combined organic extracts were washed with brine (10 mL), dried with Na2SO4, filtered, and concentrated to give a crude oil which was purified using flash column chromatography (30% ethyl acetate/hexane →90% EtOAc/hexane). The fractions containing the amine were acidified with 2 N HCl in 1,4-dioxane to yield 4.11-A as a white solid (1.3 g, 78%). 1H NMR (500 MHz, CD3OD): δ 7.46–7.43 (m, 3H), 7.26–7.25 (m, 1H), 7.07–7.06 (m, 1H), 7.05–7.02 (m, 2H), 4.18 (s, 2H), 3.85 (s, 3H), 3.31–3.28 (m, 2H), 3.08 (dd, J=8.3, 7.8 Hz, 2H); LCMS found for C14H 18NOS (M+H)+: m/z=248.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][NH:15][CH3:16].C1COCC1.CCN(CC)CC>>[CH3:14][N:15]([CH3:16])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1)=[O:13]
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 84 %

Procedure:
was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67 mmol) with 2.0 M N,N-dimethylamine in THF (1.60 mL, 3.20 mmol) and Et3N (0.447 mL, 3.20 mmol) in a manner as described in Method A to give the desired amide as brown solid (0.54 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J=4.85 Hz), 7.74 (s, 1H), 7.35 (d, 1H, J=5.02 Hz), 3.28 (s, 3H), 3.22 (s, 3H); ESIMS (MH+): 240.95.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH:53]1([CH2:56][NH2:57])[CH2:55][CH2:54]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[CH:53]1([CH2:56][NH:57][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:44])[CH2:55][CH2:54]1
Reactant: NCC1CC1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC1CC1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 67 h
Yield: 52.8 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.431 g, 0.667 mmol) in a tetrahydrofuran/water mixture (2.70 mL/1.62 mL) was added lithium hydroxide monohydrate (0.0840 g, 2.00 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), cyclopropylmethyl amine (0.161 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This reaction mixture was stirred for 67 h at ambient temperature. The mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with an aqueous saturated solution of sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40-100% ethyl acetate/hexanes gave the title compound (0.241 g, 53% yield). ES-MS (m/z) 443 [M+1(−Tr)]+.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([C:14](=[O:21])[NH:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[OH-].[K+]>C(O)C>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:5]([C:14](=[O:21])[NH:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]([OH:22])=[O:3])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)NOC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)ONC(=O)C(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To 2-tert-butoxycarbamoyl-succinic acid 4-tert-butyl ester 1-ethyl ester (5.92 g, 18.6 mmol) in ethanol (224 mL) was added 20.91 mL of a 10% aqueous solution of potassium hydroxide. The resulting mixture was then stirred at room temperature for 3 hours and then worked up. The crude product was purified by flash chromatography (SiO2, 90% dichloromethane-10% methanol) to afford 3.06 g (57.0% yield) of the desired mono acid: 1H NMR (CDCl3, 400 MHz) 3.65 (t, 1H), 2.78 (dd, 3H), 1.45 (s, 9H), 1.25 s, 9H); 13C NMR (CDCl3, 400 MHz) 171.2, 169.7, 84.0, 82.0, 46.8, 34.5, 28.5, 26.5.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Sodium hydride (554 mg, 13.84 mmol) is added to a solution of 4-fluorophenol (1.60 g, 14.20 mmol) in DMF (20 ml) and the mixture is stirred at room temperature for 2 minutes. 3-Methanesulphonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester is added and the mixture heated at 60° C. for 18 hours. Water (50 ml) is then added and the resulting product is extracted using diethyl ether (3×30 ml). The organic extracts are dried (using MgSO4), filtered and evaporated to give a white solid, which is purified using column chromatography over silica gel (ethyl acetate/isohexane 1:9 v/v) to give the title compound.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][NH:6][CH2:5][CH:4]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:3]1.C(N(CC)CC)C.[NH2:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1>CS(C)=O>[NH2:21][C:22]1[N:23]=[C:24]([N:6]2[CH2:7][C:2]([F:1])([F:13])[CH2:3][CH:4]([C:8]([N:10]([CH3:11])[CH3:12])=[O:9])[CH2:5]2)[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: CN(C)C(=O)C1CNCC(F)(F)C1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C)C(=O)C1CN(c2ccc([N+](=O)[O-])c(N)n2)CC(F)(F)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a solution of 5,5-difluoro-N,N-dimethylpiperidine-3-carboxamide (700 mg, 3.05 mmol) in dimethylsulfoxide (30 mL) were added triethylamine (619.2 mg, 6.11 mmol) and 2-amino-6-chloro-3-nitropyridine (531.1 mg, 3.059 mmol). The reaction mixture was heated to 100° C. After 16 h, the mixture was cooled to room temperature and was partitioned between ethyl acetate and water (2×). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was triturated with pentane to afford 1-(6-amino-5-nitropyridin-2-yl)-5,5-difluoro-N,N-dimethylpiperidine-3-carboxamide (0.9 g) as a yellow solid. MS (ES+APCI) (M+H) 330.2; LCMS retention time: 3.066 min (Method U1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[N:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: OCc1ccc2snnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2snnc2c1

Procedure:
This was prepared by oxidation of benzo[1,2,3]thiadiazol-5-yl-methanol (6a) with manganese dioxide in dichloromethane by the method of Example (4c).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:24])=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([CH:14]3[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]3)[N:13]=2)[CH:8]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:23][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([CH:14]3[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([F:24])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CCC(n2nc(-c3cc(CN)c(F)cc3Cl)[nH]c2=O)CC1
Solvent: C1CCOC1
Product: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)[nH]c2=O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-77, 0.200 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.033 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.36 (s, 6H), 1.37 (s, 9H), 1.62 (m, 2H), 1.79 (m, 1H), 1.82 (m, 2H), 1.89 (m, 2H), 3.46-3.94 (m, 1H), 4.28 (s, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.59 (d, J=9.72 Hz, 1H), 8.15 (m, 1H), 11.95 (s, 1H); MS (m/z): 436.55 (M+H)+.