Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[S:3]([CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=1)[CH3:12])([C:5]1[S:6][CH:7]=[C:8](Br)[N:9]=1)=[O:4].[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]=[S:3]([CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=1)[CH3:12])([C:5]1[S:6][CH:7]=[C:8]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[N:9]=1)=[O:4]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CN=S(=O)(c1nc(Br)cs1)C(C)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN=S(=O)(c1nc(-c2ccc(C)cc2)cs1)C(C)c1ccc(C(F)(F)F)nc1
Yield: 68.9 %

Procedure:
A suspension of 5-{1-[methyl(4-bromo-1,3-thiazol-2-yl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (13) (0.055 g, 0.133 mmol), 4-methylphenyl boronic acid (0.027 g, 0.199 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol) in dioxane (0.9 ml) and 2M Na2CO3 (0.070 g, in 0.33 ml of water) was heated at reflux for 2 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in EtOAc, and subsequently washed with water and brine. The combined organic layers were dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by column chromatography (SiO2, with a gradient of 50% EtOAc/hexanes) to give 5-{1-[methyl(4-(4-methylphenyl)-1,3-thiazol-2-yl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (19) as a dark yellow semi-solid (0.039 g, 70%). 1:1 mixture of two diastereomers 1H NMR (300 MHz, CDCl3) δ 8.85 (d, 1H), 8.75 (d, 1H), 8.1 (m, 2H), 7.7 (m, 6H), 7.2 (m, 4H), 6.9 (d, 2H), 5.4 (m, 1H), 5.2 (m, 1H), 3.3 (s, 3H), 3.1 (s, 3H), 2.4 (d, 6H), 2.0 (d, 3H), 1.9 (d, 3H); LC-MS (ESI): Mass calcd for C19H18F3N3OS2 [M+H]+, 426. Found 426.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].Cl.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC(C)(Cc1ccc(F)c(C(F)(F)F)c1)NC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(N)Cc1ccc(F)c(C(F)(F)F)c1

Procedure:
3.30 g (12.5 mmol) N-[2-(4-fluoro-3-trifluoromethyl-phenyl)-1,1-dimethyl-ethyl]-formamide are combined with 25 mL water and 25 mL conc. hydrochloric acid and refluxed for 2 hours. The reaction mixture is diluted with water, made alkaline with potassium carbonate solution and extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and freed from solvent. Brown oil.
Reaction SMILES: CO[C:3]([C:5]1([NH:14][C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].CC(C)([O-])C.[K+].O.Cl>CN(C)C=O>[CH3:13][N:11]([CH3:12])[N:8]1[CH2:7][CH2:6][C:5]2([NH:14][C:15](=[O:26])[CH:16]([C:17]3[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:3]2=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1(NC(=O)Cc2c(C)cc(C)cc2C)CCN(N(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2C(=O)NC3(CCN(N(C)C)CC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
300 mg 1-Dimethylamino-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylic acid methyl ester (from Step 3) is dissolved in 5 ml N,N-dimethylformamide, and 466 mg potassium t-butoxide is added. The mixture is stirred at room temperature for 18 hours. Then water is added, and the pH adjusted to 5.2 by the addition of aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated. The residue is purified by chromatography on silica gel, with toluene/ethanol/dioxane/triethylamine/water (20:8:4:4:1) as a solvent. Thus, 196 mg 8-Dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione is obtained as a solid, mp 237-241° C. 1H-NMR (d4-methanol): 6.94 ppm (s, 2H), 3.09 ppm (m, 2H), 2.79 ppm (m, 2H), 2.53 ppm (s, 6H), 2.28 ppm (m, 5H), 2.16 ppm (s, 6H), 1.64 ppm (m, 2H).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-2-[(4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 1, 435 mg) in dry dichloromethane (6 mL), TFA (2 mL, 26.0 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge to afford the title compound as a yellow gum (320 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1)=[CH2:14].[CH2:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](F)=[O:34])=[CH:31][CH:30]=1)[CH2:27][CH3:28]>C1COCC1>[CH2:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([CH:20]2[C:19](=[O:25])[C:18]3[C:23](=[CH:24][C:15]([CH:13]=[CH2:14])=[CH:16][CH:17]=3)[O:22][CH2:21]2)=[O:34])=[CH:36][CH:37]=1)[CH2:27][CH3:28]
Reactant: C=Cc1ccc2c(c1)OCCC2=O
Reactant: CCCc1ccc(C(=O)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cc1ccc2c(c1)OCC(C(=O)c1ccc(CCC)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
To a flame-dried 10 mL round-bottom flask under nitrogen charged with butyllithium (2.5 M in hexanes) (0.875 mL, 2.19 mmol) in THF (1 mL) at 0° C. was added diisopropylamine (0.312 mL, 2.19 mmol) dropwise. The solution was stirred at 0° C. for 20 min. The solution was then cooled to −78° C., and 7-vinylchroman-4-one (Preparation 2D, 1.79 M in THF) (1.02 mL, 1.82 mmol) was added dropwise via syringe. The mixture was stirred for 20 min. at −78° C. 4-propylbenzoyl fluoride (0.303 g, 1.823 mmol) in 1 mL of THF was then added dropwise via syringe, and the reaction mixture was stirred at −78° C. for 60 min. and then warmed to room temperature. The reaction was quenched with 1N aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The yellow residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12%) to give 3-(4-propylbenzoyl)-7-vinylchroman-4-one (0.179 g, 0.559 mmol, 31% yield). The compound was triturated with methanol with sonication, filtered, washed with methanol, and dried to give 3-(4-propylbenzoyl)-7-vinylchroman-4-one (0.125 g, 0.390 mmol, 21% yield) as a yellow solid. LC/MS M+1=321.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (t, 3H), 1.58-1.68 (m, J=7.42, 7.42, 7.42, 7.42, 7.21 Hz, 2H), 2.65 (t, J=7.63 Hz, 2H) 4.71-4.77 (m, 1H), 4.78-4.83 (m, 1H), 5.20 (dd, J=9.16, 4.99 Hz, 1H), 5.47 (d, J=11.10 Hz, 1H), 6.05 (d, J=17.76 Hz, 1H), 6.73-6.82 (m, 1H), 7.17 (s, 1H) 7.24 (dd, J=8.18, 1.25 Hz, 1H), 7.38 (d, J=8.32 Hz, 2H), 7.73 (d, J=8.05 Hz, 1H), and 7.96 (d, J=8.32 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)=[C:5]([CH3:25])[O:4][N:3]=1.[N:26]1C=CC=CC=1.O=S(Cl)Cl>C1COCC1>[NH2:26][C:10]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:25])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccc(F)cc1)C(=O)N2
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccc(F)cc1)C(=O)N2
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
Under N2, to a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)-3-hydroxyindolin-2-one (52 g, 154 mmol, 1.0 eq) in THF (500 mL) was added pyridine (40 mL, 496 mmol, 3.2 eq) and SOCl2 (16 mL, 219 mmol, 1.4 eq) slowly at −15° C.˜−20° C., the mixture was stirred for 20 min at −15° C.˜−20° C., quenched with brine, washed with brine (300 mL×2), to the THF layer was added NH3/H2O (100 mL), the mixture was stirred for 2 hours at room temperature, washed with brine, dried, concentrated, purified by silicon gel to give a crude product which was recrystallized from i-PrOH/toluene to give 14 g (yield 27%) product as white solid. 1H NMR (DMSO-d6) δH 10.57 (s, 1H), 7.40-7.44 (m, 2H), 7.22-7.24 (dd, 1H, J=8.0 Hz, 1.6 Hz), 7.11-7.16 (m, 3H), 6.98-7.00 (d, 1H, J=8.0 Hz), 2.75 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][O:16][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CCCC(=O)O)nc12
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
To a solution of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.3 g, 1.0 mmol) in tetrahydrofuran(10 ml) was added sodium hydride (50% in oil) (0.054 g, 1.1 mmol) and the mixture was stirred for 10 min. To the mixture was added glutaric anhydride (0.13 g, 1.1 mmol) and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water. The pH was adjusted to 4 with 2M HCl. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (94:6) as eluent gave 0.034 g (8%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1B1OC(C)(C)C(C)(C)O1)[CH:35]=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=2[CH3:31])[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: Cc1cc(C=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (400 mg, 0.84 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (310 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 69.28%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl[C:37]1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.CNC.C1COCC1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([N:29]([CH3:37])[CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(N(C)C)nc2s1
Yield: 9 %

Procedure:
Preparation analogous to 96a (step 11) by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and dimethylamine 2M in THF (1.531 mmol, 765 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(dimethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96b (3 mg, 9%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.25 (s, 3H), 3.20 (s, 6H), 7.28 (d, J=8.6 Hz, 1H), 7.61 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.30 (s, 1H), 8.43 (s, 1H), 10.13 (s, 1H), 10.35 (s, 1H). (m/z)=499 (M+H)+.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([O:14]CC)=[O:13])[C:3]([F:6])([CH3:5])[CH3:4].[OH-].[Na+].[CH3:31]O.O>O1CCCC1>[F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([OH:14])=[O:13])[C:3]([F:6])([CH2:4][CH3:31])[CH3:5]
Reactant: CO
Reactant: CCOC(=O)C(Cc1cccc(C(F)C(C)(C)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(F)C(F)c1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate (2.849 g, 7.223 mmol), sodium hydroxide (0.58 g, 14.4 mmol), methanol (10 ml), water (10 ml) and tetrahydrofuran (10 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-2-[3-(1,2-difluoro-2-ethylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid as a liquid.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.B(Br)(Br)Br>C(Cl)Cl>[N:1]1([CH:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(-c2ccc(C(C)n3ccnc3)nc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1ccc(-c2ccc(O)cc2)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a stirred solution of 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-methoxyphenyl)pyridine (0.075 g, 0.26 mmol; prepared as described for Example 15) in DCM (3 mL) was added BBr3 (0.1 mL 0.4 mmol) at 0° C. The reaction was stirred at rt for about 1 h. The reaction mixture was quenched with saturated NaHCO3 solution (5 mL), diluted with water (100 mL), and extracted with DCM (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120) using 4% methanol in DCM eluent to afford 4-(6-(1-(1H-imidazol-1-yl)ethyl)pyridin-3-yl)phenol as an off-white solid (35 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 8.74 (d, 1H), 7.99 (dd, 1H), 7.85 (s, 1H), 7.50 (d, 2H), 7.28 (s, 1H), 7.20 (d, 1H), 6.91 (s, 1H), 6.84 (d, 2H), 5.64-5.59 (m, 1H), 1.80 (d, 3H), LC-MS m/z calcd for [M+H]+ 266.12. found 266.2.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(CN2CCCC2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CN2CCCC2)n1
Yield: 55.7 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyrrolidin-1-ylmethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-pyrrolidin-1-ylmethyl-thiazole-4-carboxylic acid (0.244 g, 1.151 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The crude product was washed with water. Yield 55.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.23 (d, 3H), 1.72-1.76 (m, 4H), 2.57-2.61 (m, 4H), 3.95 (s, 2H), 4.32 (dd, 1H), 4.41 (dd, 1H), 4.41-4.50 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.09 (dd, 1H), 8.13 (s, 1H), 8.44 (d, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1.F[B-](F)(F)F.[CH3:21][O+](C)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:21])=[N:14]2)=[CH:2]1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(CCc2ccoc2)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCc2ccoc2)CCCC1

Procedure:
The product of Example 170 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl>CC(O)=O>[O:26]=[S:22]1(=[O:25])[CH2:23][CH2:24][N:19]2[CH2:18][CH2:17][CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:20]2=[N:21]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of 9-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (6.97 g) and 6 M HCl aq. (10.0 mL) in AcOH (100 mL) was stirred at 60° C. for 2 hr. After cooling to room temperature, the solvent was removed in vacuo. The residual solid was recrystallized from MeOH-IPE to give the title compound (5.01 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:25]([F:28])([F:27])[F:26])=[O:24].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>ClC(Cl)C>[C:35]([O:22][NH:21][C:19]([C:4]1[C:3]([S:23]([C:25]([F:27])([F:28])[F:26])=[O:24])=[C:2]([NH2:1])[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=1)=[NH:20])(=[O:37])[CH3:36]
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)ONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime (0.50 g, 1.06 mmol) was dissolved in 8 ml of dichloroethane, and then pyridine (0.10 ml, 1.2 mmol) was added and acetyl chloride (99 mg, 1.26 mmol) dissolved in 2 ml of dichloroethane was added dropwise at room temperature. After the completion of adding dropwise, the mixture was stirred at room temperature for 2 hours and the solvent was distilled off. To the resulting mixture, 50 ml of ethyl acetate was added, then 15 ml of water and 15 ml of an aqueous saturated sodium chloride solution was added. The ethyl acetate layer was taken and washed once with 30 ml of 0.5 N hydrochloric acid, then washed three times with 30 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 0.54 g (1.06 mmol) of the title compound as a colorless amorphous. Yield 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:24][S:25]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]3[C:8]=2[NH:7][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]3)[CH2:17][CH2:16]1)(=[O:27])=[O:26]
Reactant: Cc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: CS(=O)(=O)Cl
Product: Cc1cc(NC2CCN(S(C)(=O)=O)CC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
(5-Methyl-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine prepared in Example 90 and methanesulfonylchloride were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][N:32]=1>N1C=CC=CC=1>[F:40][C:30]([F:29])([F:41])[C:31]1[N:32]=[CH:33][C:34]([C:35]([N:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[NH:20][C:19]4[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=4[CH:13]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3][O:2][CH3:1])=[O:36])=[CH:38][CH:39]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCOC)C(=O)c4ccc(C(F)(F)F)nc4)nc3)cc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
9a (40 mg) was dissolved in pyridine (5 mL) at room temperature. 6-(Trifluoromethyl)nicotinoyl chloride (218 mg) was added. The mixture was stirred at room temperature for 24 h. After quenching with ice, the crude product was purified by column (26 g silica gel, RT Scientific) (CH2Cl2:MeOH=100:0 to 98:2) to give the 10a (43 mg).