Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:29][CH2:30][C:31]([N:33]=[C:34]=[O:35])=[O:32]>C1(C)C=CC=CC=1>[Cl:29][CH2:30][C:31]([NH:33][C:34]([N:20]([C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:24])[CH3:21])=[O:35])=[O:32]
Reactant: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: O=C=NC(=O)CCl
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C(=O)NC(=O)CCl
Temperature: 50 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
In a solution of 0.86 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-methyl benzoic acid amide in 10 mL of toluene, 0.36 g of chloroacetyl isocyanate was added, and stirred at 50° C. for 24 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 0:1 to 3:2) to obtain 0.93 g of the aimed product as colorless oily substance.
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH3:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=1>O>[CH3:22][C:23]1[C:28]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1cncc(C)n1
Solvent: CCOCC
Solvent: O
Solvent: CCCCOCCCC
Product: Cc1cnc(-c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
First, in a nitrogen atmosphere, 50 mL of a dibutylether solution containing phenyl lithium (produced by Wako Pure Chemical Industries, Ltd, 2.1 mol/L) and 250 mL of diethyl ether were mixed. Then, 10.33 g of 2,6-dimethylpyrazine was added into this solution while the solution was being cooled with ice, and stirred at a room temperature for 24 hours. Water was added into this mixture and an organic layer was extracted with diethylether. The obtained organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtrated. After the solvent of the filtrate was distilled off, the obtained residue was purified by silicagel column chromatography using dichloromethane as a developing solvent, thereby obtaining an objective pyrazine derivative Hmppr-Me (reddish brown liquid, yield: 16%). A synthesis scheme of Step 1 is shown by the following (a-2).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:14](=[O:15])[CH2:13][C:12]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][C:8]2=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[C:25]([C:35](O)=[O:36])[CH:24]=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:14](=[O:15])[CH2:13][C:12]3([CH2:16][CH2:17][N:18]([C:35]([C:25]4[CH:24]=[C:23]([O:22][CH3:21])[C:32]5[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=5)[N:26]=4)=[O:36])[CH2:19][CH2:20]3)[O:11][C:8]2=[CH:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cn1)OC1(CCNCC1)CC2=O
Reactant: COc1cc(C(=O)O)nc2c(OC)cccc12
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(C)(C)C)ncc2O3)nc2c(OC)cccc12

Procedure:
The compound was prepared according to the procedure described in Example 1, using 6′-tert-butylspiro[piperidine-4,2′-pyrano[2,3-c]pyridin]-4′(3′H)-one instead of N-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)acetamide and using 4,8-dimethoxyquinoline-2-carboxylic acid in place of 4-methoxyquinoline-2-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 8.49 (1H, d, J=1.0 Hz), 7.77 (1H, dd, J=8.0, 1.1 Hz), 7.64 (1H, d, J=1.0 Hz), 7.47 (1H, t, J=8.0 Hz), 7.19 (1H, s), 7.08 (1H, dd, J=8.0, 1.1 Hz), 4.65-4.57 (1H, m), 4.23-4.15 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.66-3.33 (2H, m), 2.90-2.76 (2H, m), 2.24-1.83 (4H, m), 1.36 (9H, s). MS (M+H)+=490.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH3:16].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-alanyl-L-tryptophan in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-tryptophan.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][NH:14][CH2:13]3)=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][N:14]([CH3:20])[CH2:13]3)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(C23CNCC2C3)c2ccccc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C23CC2CN(C)C3)c2ccccc12

Procedure:
A stirred solution/suspension of 1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (85 mg, 0.38 mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde (0.23 mL, 3.0 mmol), then with sodium triacetoxyborohydride (318 mg, 1.5 mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride containing 2-propanol (2×10 mL). The combined organic solution was dried (MgSO4) and concentrated in vacuo to afford 1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (76 mg, 84%, essentially pure without chromatography). This was dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with ether, collected, and dried in vacuo to afford 1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane, hydrochloride (72 mg, 82%) as a white solid. MS (M+1) 238.1. 1H NMR (CDCl3) δ□ 12.70 (br s, 1H), 8.16 (m, 1H), 8.04 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 7.26 (m, 1H), 4.20 (m, 1H), 4.06 (m, 1H), 3.50 (m, 1H), 3.14 (m, 1H), 2.90 (d, 3H, J=5 Hz), 2.68 (s, 311), 2.40 (m, 1H), 2.13 (m, 1H), 1.22 (m, 1H). 13C NMR (CDCl3) δ 135.73, 133.21, 131.70, 126.81, 126.35, 126.33, 125.41, 124.54, 61.65, 57.62, 41.52, 30.97, 22.37, 19.75.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(N(CC)CC)C>ClCCl>[Cl:28][CH2:29][C:30]([N:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)[CH3:1])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (200 mg) is dissolved in dichloromethane (5 ml) and thereto is added α-chloroacetyl chloride (55 μl) under ice cooling. Continually thereto is added triethylamine (0.23 ml) and the mixture is stirred at room temperature overnight. After the solvent is concentrated, the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane/ethanol to give 1-{1-[4-(N-α-chloroacetyl-N-methylamino)benzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.18 g) as white powder, m.p.: 220°-222° C. (decomposed).
Reaction SMILES: [CH3:1][C:2](=[CH2:27])[CH:3]([N:8]1[C:11](=[O:12])[CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:9]1[S:24]([OH:26])=O)[C:4]([O:6][CH3:7])=[O:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCCl.C(OCC)(=O)C>[Cl-].[Na+].O>[C:17]1(=[O:18])[N:13]([CH:10]2[C:11](=[O:12])[N:8]3[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:2](=[CH2:1])[CH2:27][S:24](=[O:26])[C@H:9]23)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC
Temperature: 25 °C

Procedure:
A solution of 0.10 g. of methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate and 0.04 g. of phosphorous pentoxide in 20 ml. of 1,2-dichloroethane was stirred at room temperature for 1 hour. A tlc of the reaction mixture indicated only trace amounts of the methylenecepham sulfoxide. The mixture was then refluxed for 30 minutes, cooled to room temperature, and combined with 25 ml. of ethyl acetate and 50 ml. of brine. The organic layer was separated, washed with aqueous sodium bicarbonate and brine and dried (MgSO4). Evaporation in vacuo to dryness provided 0.04 g. of the title product as a white froth.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[C:22]([F:31])[CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:33])([CH3:32])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[C:22]([F:31])[CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:33])([CH3:32])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)S3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-2-fluorobenzoate (Compound 236, 100.0 mg, 0.219 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 40° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 78.0 mg (83%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.94 (1H, d, J=7.8 Hz), 7.43-7.17 (9H, m), 5.93 (1H, s), 2.38 (3H, s), 1.47 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[N:5]([CH3:7])[CH3:6].CCCCCC.C([Li])CCC.C(OC([N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1)=O)(C)(C)C.[Cl-].[NH4+].[OH-].[Na+]>O1CCCC1>[CH3:6][N:5]([CH3:7])[C:4]1[CH:3]=[C:2]([C:32]2[CH2:33][CH2:34][NH:29][CH2:30][CH:31]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1cccc(C2=CCNCC2)c1
Temperature: -78 °C
Yield: 11.7 %

Procedure:
3-Bromo-N,N-dimethylaniline (Aldrich Co., 1.24 g) was dissolved in tetrahydrofuran (18 ml) and the mixture was cooled to −78° C. An n-butyllithium hexane solution (2.6 M, 3.0 ml) was added to the solution and the mixture was stirred for min. 1-(tert-Butoxycarbonyl)-4-piperidone (1.0 g) was added thereto, and the mixture was gradually warmed to room temperature. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate (5:1-2:1)). 10% Aqueous sulfuric acid (5 ml) and 1,4-dioxane (5 ml) were added to the intermediate, and the mixture was stirred with heating at 70° C. for 3 hr. After completion of the reaction, the mixture was cooled to 0° C. A 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[3-(dimethylamino)phenyl]-1,2,3,6-tetrahydropyridine (119 mg, yield 10%).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:26]=[CH:27][C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[N:29]=3)=[N:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][CH:12]=1.CO.[OH-].[K+]>C1COCC1.O>[CH3:34][C:32]1[CH:31]=[C:30]([CH3:35])[N:29]=[C:28]([CH:27]=[CH:26][C:15]2[C:14]3[C:18](=[CH:19][C:11]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:36])=[O:2])=[CH:12][CH:13]=3)[N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)[CH:33]=1
Reactant: COC(=O)c1ccccc1Nc1ccc2c(C=Cc3cc(C)cc(C)n3)nn(C3CCCCO3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Temperature: 70 °C

Procedure:
To a stirred solution of 2-[3-[2-(4,6-Dimethyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid methyl ester (1.98 g, 4.11 mmol) in THF:MeOH (12 ml, 3:1) was added Potassium hydroxide (1.15 g, 20.5 mmol) dissolved in H2O (3 ml). The reaction was heated at 70° C. for 2 hr, cooled, concentrated under reduced pressure to about 5 ml and diluted with more water. The solution was neutralized with 2N HCl and the precipitate was collected by filtration and washed with water to give 2.00 g (quantitative) of a bright yellow solid. 1H NMR (DSMO-d6) δ 513.12 (1H, broad s), 9.82 (1H, s), 8.13 (1H, d, J=8.7 Hz), 7.95 (1H, dd, J=1.5, 8.0 Hz), 7.89 (1H, d, J=16.4 Hz), 7.60 (1H, s), 7.50 (1H, d, J=16.4 Hz), 7.46 (1H, d, J=6.9 Hz), 7.37 (1H, d, J=7.7 Hz), 7.20 (1H, d, J=8.7 Hz), 7.06 (1 H, s), 6.86 (1H, t, J=6.9 Hz), 5.85 (1H, d, J=7.3 Hz), 3.82 (2H, m), 2.50 (3H, s, obscured by dmso), 2.48 (2H, m), 2.34 (3H, s), 2.03 (2H, m), 1.76 (1H, m), 1.59 (2H, m). Anal. Calcd for C28H28N4O3.0.5 KOH: C, 67.72; H, 5.79; N, 11.28.
Reaction SMILES: I[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:9]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([F:27])[C:23]([I:26])=[C:24]([F:25])[C:19]=3[NH:18][C:17]2=[S:28])=[CH:11][CH:10]=1>C1COCC1>[C:9]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([F:27])[C:23]([I:26])=[C:24]([F:25])[C:19]=3[N:18]=[C:17]2[S:28][CH3:2])=[CH:11][CH:10]=1
Reactant: Fc1cc2c([nH]c(=S)n2Cc2ccc(-c3ccccc3)cc2)c(F)c1I
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CSc1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Iodomethane (2 M in methyl-text-butyl ether, 22.87 mL, 45.7 mmol) was added to a solution of cesium carbonate (14.9 g, 45.7 mmol) and 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1,3-dihydro-2H-benzimidazole-2-thione (10.94 g, 22.87 mmol) in THF (100 mL). After stirring at rt. overnight, volatiles were removed. Chromatography over silica eluting with 15-60% EtOAc/hexanes afforded the desired product as a beige solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(O)(=O)C.[O:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=[C:24]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=23)[N:23]=1>O1CCCC1>[N+:28]([C:27]1[C:22]([NH:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[N:23][C:24]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=23)=[N:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1Cl
Reactant: NC1CCOCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
Diisopropylethylamine (2.30 mL, 13.20 mmol) and tetrahydro-2H-pyran-4-amine acetate (526 mg, 3.28 mmol) were added to a stirred suspension of 3-(4-chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 24e, 0.91 g, 3.29 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and water was added. The mixture was filtered to give the title compound (0.785 g, 70%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][Si](C)(C)C>>[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: C[Si](C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 115 °C

Procedure:
A glass reactor equipped with a stirrer, reflux condenser and gas inlet was charged with solid 4-fluorobenzenesulfonyl chloride (0.250 mol, 49.65 g). Hexamethyldisilazane (0.263 mol, 56.6 ml) was added to the reactor and the mixture was gradually heated with stirring to a temperature of 115° C., at which time it became clear. The mixture was then heated at the boiling point for 21 hours. Analysis of the mixture by 1H NMR indicated that the reaction was about 50% complete. Volatile materials were then removed by heating at a temperature of 65° C. under reduced pressure to yield a brown liquid which was distilled to remove unreacted sulfonyl chloride. The residue was redistilled under a pressure of 0.03 mm. Hg. The fraction collected from 40° to 97° C. was analyzed by 1H NMR and was found to contain the N-mono- and N,N-bis(trimethylsilyl)sulfonamides in a 1:1 molar ratio. Using the same analytical technique a second fraction collected within the range from 97° and 122° C. was found to contain the N-mono- and N,N-bis(trimethylsilyl)sulfonamides in a 8.5:1 molar ratio. The second fraction was used as the starting material (3c) for the subsequent reaction.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[C:6](=[O:18])[N:7]([CH3:17])[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][N:7]([CH3:17])[C:6](=[O:18])[C:5]3[S:19][C:2]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:3][C:4]2=3)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: CN1CC(c2ccc(Cl)cc2)c2cc(Br)sc2C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc2C1=O
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 19.7 %

Procedure:
To a 2.0-5.0 mL microwave vial was added a solution of 2-bromo-4-(4-chlorophenyl)-6-methyl-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.0400 g, 0.112 mmol) and morpholine (0.02934 mL, 0.3364 mmol) in anhydrous 1,4-dioxane (1.500 mL, 19.22 mmol) and degassed under nitrogen for 10 min. Cesium carbonate (0.1700 g, 0.5216 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0195 g, 0.0336 mmol) were added followed by tris(dibenzylideneacetone)dipalladium(0) (0.0103 g, 0.0112 mmol). The reaction mixture was sealed and heated via microwave to 140° C. and allowed to stir for 40 minutes. The reaction was cooled to ambient temperature and quenched by the addition of a solution of saturated aqueous solution of sodium bicarbonate (10.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was submitted for HPLC purification to afford the product (0.0080 g, 19.0%) as a white solid. LC/MS (AA) ES+ 361, 363, 365. 1H NMR (dmso-d6, 400 MHz): d 7.51 (1H, s), 7.41-7.39 (2H, m), 7.25-7.23 (2H, m), 5.03 (1H, J=4.80, Hz, t), 3.80-3.66 (5H, m), 3.46-3.40 (1H, m), 3.11-3.09 (4H, m), 2.84 (3H, s).
Reaction SMILES: [OH-].[K+].Cl.CN.[C:6]([N:11]1[CH2:16][CH:15]([CH3:17])[C:14](=O)[CH:13]([CH3:19])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].[C:20]([BH3-])#[N:21].[Na+]>CO>[CH3:20][NH:21][CH:14]1[CH:15]([CH3:17])[CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:19]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CC(C)C(=O)C(C)C1
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCOC(=O)N1CC(C)C(NC)C(C)C1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
Powdered KOH (0.92 g, 16.44 mmol) was added in portions to the stirred solution of methylamine hydrochloride (1.11 g, 16.44 mmol) in methanol (20 ml) at 0-5° C. and 1-carbethoxy-3,5-dimethyl-4-piperidinone (2.2 g, 1.1 mmol),obtained by a procedure as described in Example 25 (Step-1), was added in portions to it. The resulting reaction mixture was stirred for 45 min at 10° C. and a solution of sodium cyanoboro-hydride (0.7 g, 1.1 mmol) in methanol (5 ml) was added dropwise to it. Cooling was removed and stirring was for 24 hr at 30° C. The reaction mixture was basified with 20% KOH solution, filtered (to remove insoluble impurities) and filtrate was concentrated to dryness. The obtained residue was dissolved in water and extracted with chloroform. Chloroform layer was extracted with 50% HCl and acid layer was basified with 20% KOH solution. The separated oil was extracted with chloroform, dried (Na2SO4) and concentrated to give a Mixtures A+B of 4-methylamino-1-carbethoxy-3,5-dimethylpiperidine. Yield 1.34 g (60%), C11H22N2O2, m/z 214 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[Cl:9])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)n1
Yield: 39.5 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 12 mmol), dioxane (80 mL), and 2,4,6-trichlorobenzoyl chloride (1.95 g, 8 mmol) (stir at 0-25° C. for 16 hr.) gives the title intermediate (1.0 g, 39% yield): mass spectrum (ion spray): m/z=316.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[S:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: c1cn[nH]c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 13.1 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 15.2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to afford a yellow resin. UPLC-MS (Condition 3) tR=1.33 min, m/z=598.4 [M+H]+, m/z=596.5 [M−H]−.