Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O:3][C:4]([CH2:6][CH2:7][N:8]=[C:9]=[S:10])=[O:5].[CH3:11][C:12]([CH3:32])=[CH:13][CH2:14][CH2:15]/[C:16](/[CH3:31])=[CH:17]/[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][S:23][CH2:24][C@H:25]([NH2:29])[C:26]([OH:28])=[O:27].C(N(CC)C(C)C)(C)C.O[Li].O>C1COCC1.C(OCC)(=O)C.O>[C:4]([CH2:6][CH2:7][NH:8][C:9](=[S:10])[NH:29][C@@H:25]([CH2:24][S:23][CH2:22]/[CH:21]=[C:20](\[CH3:30])/[CH2:19][CH2:18]/[CH:17]=[C:16](\[CH3:31])/[CH2:15][CH2:14][CH:13]=[C:12]([CH3:32])[CH3:11])[C:26]([OH:28])=[O:27])([OH:3])=[O:5]
Reactant: CCOC(=O)CCN=C=S
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=S)NCCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, to a suspension of ethyl-3-isothiocynato propionate (1 mmol) and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol) dropwise. The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (60 mL) and washed by 0.5 N HCl (10 mL×1), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude Compound N-74. The crude Compound N-74 obtained above was dissolved in THF (3 mL) and a solution of LiOH.H2O (126 mg, 3 mmol) in H2O (2 mL) was added slowly at 0° C. The reaction was left for 4 h. The solution was then diluted with ethyl acetate (60 mL) and washed by 0.5 N HCl (10 mL×1), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was then further purified by preparative HPLC (230 mg, 50%) to yield Compound N-74. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-2.04 (m, 8H), 2.53 (t, J=6.0 Hz, 2H), 2.77 (dd, J=6.5, 14.0 Hz, 1H), 2.94-2.95 (m, 1H), 3.05-3.06 (m, 1H), 3.15-3.17 (m, 1H), 3.67 (broad, 2H), 5.00-5.01 (m, 2H), 5.09-5.14 (m, 2H). 13C-NMR (125 MHz, CD3OD): δ 16.17, 16.30, 17.81, 25.96, 27.39, 27.79, 30.68, 31.57, 32.81, 33.20, 33.90, 34.56, 37.55, 40.80, 40.89, 57.93, 61.05, 121.34, 121.70, 125.48, 132.11, 136.24, 140.52, 173.76, 174.55, 175.68; ES-MS: mass calcd for Chemical Formula: C22H36N2O4S2 456.66. Found (M+) m/z 457.2, (M+Na) m/z 479.2.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1>CN(C)C=O>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 15 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil and 0.41 g of triethylamine hydrochloride. To this solution were added 3 ml of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 16 hours at 150° C. After the reaction, dimethylformamide was removed from the reaction liquid by distillation and the residue was treated in the same manner as described in Example 7 to obtain 0.8 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. From the chloroform insoluble matter 0.6 g of the starting 5-fluorouracil was recovered. The yield of the end product was 74% based on the consumed 5-fluorouracil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7](C)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2CC1CCN(C(OC(C)(C)C)=O)CC1)=[O:5])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O.[OH-].[K+]>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2cccc(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2[nH]1
Temperature: 60 °C

Procedure:
The above indole-2-carboxylic acid ethyl ester intermediate was dissolved in THF/MeOH/H2O (3:1:1) and 1 mL of 1N KOH solution. The mixture was heated at 60° C. for 4 h. The mixture was then cooled to 0° C. and acidified with 10% citric acid to about pH 4. The mixture was extracted with EtOAc, dried and concentrated to afford 0.32 g of the indole-2-carboxylic acid intermediate.
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:20])([F:19])[C:6]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:12])[O:7][Si:8]([CH3:11])([CH3:10])[CH3:9].C[Si](C#N)(C)C>C(N(CC)CC)C>[F:20][C:5]([F:19])([F:4])[C:6]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:1]#[N:3])[CH:14]=1)([CH3:12])[O:7][Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(O[Si](C)(C)C)(c1ccncc1)C(F)(F)F
Reactant: CC#N
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CC(O[Si](C)(C)C)(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To 30 ml of acetonitrile were added 4 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine=N-oxide, 4.45 ml of triethylamine, and 4.75 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.3 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine-2-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Product: Nc1nc(NCCN2CCOCC2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 4-(2-aminoethyl)morpholine in dioxane. ES-MS m/e (%): 370 (M{81Br}+H+, 100), 368 (M{79Br}+H+, 97).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=[O:19])[CH2:13]1.C(N(C(C)C)CC)(C)C>>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine (0.175 M, 35 mL, 6.125 mmol) was added to (R)-piperidine-3-carboxylic acid, prepared during the previous step, followed by diisopropylethyl amine (2.275 mL, 12.25 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to afford (R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid which was used for the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][NH2:13]>O>[CH3:12][NH:13][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: ClCc1cc2ccccc2o1
Reactant: CN
Solvent: O
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
2-(Chloromethyl) benzofuran (2.77 g, 16.63 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a nitrogen atmosphere. After 10 minutes, the reaction mixture was warmed to room temperature and stirring was continued for 72 hours. The mixture was diluted with water and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (10% MeOH/CH2Cl2) to afford 1.00 g (37%) of pure product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:18][C:19](=[O:20])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-amino4-nitrophenol (7.7 g, 50 mmol) was prepared in 125 mL chloroform. To this suspension was added benzyltriethylammonium chloride (11.4 g, 50 mmol) and sodium bicarbonate (16.80 g, 200 mmol) and the suspension cooled in an ice bath. A solution of chloroacetyl chloride (4.8 mL, 60 mmol) in chloroform (10 mL) was added. The solution was stirred overnight at room temperature, then refluxed for 3 hours and again let sit overnight at room temperature. The solvent was removed under vacuum and water was added to the residue. The solid was filtered, washed with water, and recrystallized from ethanol. The recrystallized solid was filtered and washed with cold ethanol and then dried, to yield 6-nitro-4-H-benzo[1,4]oxazin-3-one as a solid product. Some additional product precipitated from the ethanol filtrate as a second crop and was recovered by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10][NH2:11])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:11][CH2:10][C:9]([CH3:12])=[CH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=Cc1ccc(F)cc1)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(F)cc1)CNC(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a vigorously stirred mixture of 19.8 g (0.12 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-amine and 30.2 g (0.36 mole) of sodium bicarbonate in 500 ml water at 5° C. was added dropwise 22.2 g (0.14 mole) of 4-fluorobenzoyl chloride. The mixture was stirred another 3 hours at 5° C. then at room temperature overnight. The white solid which had formed was collected, washed with saturated sodium bicarbonate solution, then with water, then with hexane, then air dried to give 33.4 g (97%) of product, m.p. 107°-109° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:10][C:3]1[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=[C:5]([CH3:8])[C:4]=1[NH2:9]
Reactant: C1CCNC1
Reactant: Cc1ccc(Br)c(C)c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCCC2)c(C)c1N
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 3-bromo-2,6-dimethylphenylamine (0.27 g, 1.35 mmol) dissolved in toluene (5.4 mL) and pyrrolidine (0.56 mL, 6.8 mmol) was added sodium t-butoxide (0.39 g, 4.0 mmol). The suspension was deoxygenated for approximately 10 minutes by passing a stream of nitrogen through the solvent. Solid tris(dibenzilideneacetone)dipalladium(0) (10 mg) and rac-2,2′Bis(diphenylphosphino)-1,1′binaphthyl (25 mg) were combined and added in one portion. Nitrogen bubbling continued for an additional 2 minutes before heat was applied (100° C. overnight). The reaction mixture was cooled to room temperature and diluted with ethyl acetate and HClaq (2N). The aqueous layer was adjusted basic with sodium bicarbonate solution and re-extracted with ethyl acetate. The organic layer was dried over sodium sulfate, decanted and concentrated under reduced pressure to give to give the desired 2,6-dimethyl-3-pyrrolidin-1-ylphenylamine as an amber oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.C(=O)(OC(C)(C)C)[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(N(CC)CC)C>C1COCC1>[C:23]([O:22][C:20]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
Combine ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (17.849 mmol, 4.760 g), THF (180 mL) and tert-butoxycarbonyl tert-butyl carbonate (21.419 mmol, 4.675 mL). Stir the mixture at room temperature for about 10 minutes. Add triethylamine (5.225 mL, 37.484 mmol), and stir at room temperature 16 hours. Remove the solids by vacuum filtration, and rinse with EtOAc. Concentrate the filtrate under reduced pressure. Purify the resulting yellow oil by silica gel chromatography (220 g RediSep® silica gel column) eluting with a gradient of 5-45% EtOAc gradient in hexane to give the title compound (3.62 g, 68% yield) as a light yellow crystalline solid. 1H NMR (399.80 MHz, d6-DMSO) δ 8.71 (d, J=2.1 Hz, 1H), 8.15-8.13 (m, 1H), 7.56-7.24 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.24-4.21 (m, 2H), 1.36 (s, 9H), 1.30 (t, J=7.1 Hz, 3H). LCMS (m/z) 331 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:6]=3[C:5]([C:23]([F:26])([F:25])[F:24])([CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:4]=2[CH:3]=1.CCOC(C)=O.CCCCCC.[CH3:39][N:40](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:39]([C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:6]=3[C:5]([C:23]([F:26])([F:24])[F:25])([CH2:18][O:19][CH:20]([CH3:21])[CH3:22])[C:4]=2[CH:3]=1)#[N:40]
Reactant: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(Br)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(C#N)cc21
Temperature: 100 °C
Yield: 60 %

Procedure:
A degassed mix of 3-bromo-7-cyano-5-trifluoromethyl-5-isopropoxymethyl-5,10-dihydrobenzo[b][1,8]naphthyridine (15) (73 mg, 0.171 mmol), Zn(CN)2 (20 mg, 0.171 mmol) and Pd(PPh3)4 (10 mg, 0.00855 mmol) in anhydrous DMF (2 mL) was heated at 100° C. for 16 h 30 min. The reaction mixture was cooled to room temperature, quenched 2 N NH4OH (20 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-30% EtOAc-Hexane) provided 17 (38 mg, 60% yield) as a white solid: m.p. 226-227° C.; low resolution mass spectrum (ESI) m/z 371.2 [(M−H)— calcd for C19H14F3N4O: 371.11].
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](O)=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:16])[N:2]([NH:1][C:26](=[O:27])[CH2:25][C:20]3[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=3)[N:11]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(C2CCC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CCC2)c2ccccc2c1=O

Procedure:
The product of Example 67A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.35-8.28 (m, 1H), 8.01-7.94 (m, 1H), 7.94-7.85 (m, 2H), 7.20-7.10 (m, 3H), 4.12-3.99 (m, 1H), 3.76 (s, 2H), 2.42-2.22 (m, 4H), 2.14-2.00 (m, 1H), 1.89-1.76 (m, 1H); MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:34][C:35]1[N:40]=[C:39]([CH:41]=O)[CH:38]=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(O)C.CCCCCC.CC(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([CH2:41][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:34])[N:40]=2)[CH2:13][CH2:12]1
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Reactant: Cc1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCN(Cc4cccc(C)n4)CCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To the solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) and 6-methylpyridine-2-carbaldehyde (49.2 mg) in ethanol (5 ml) was added sodium triacetoxyborohydride (81.6 mg) and a drop of acetic acid. The resulting mixture was stirred for 1 hour at room temperature. The solvent was evaporated and the residue was partitioned into ethyl acetate (20 ml)/water (20 ml). The organic layer was washed with brine (20 ml), dried over magnesium sulfate, and evaporated to give a yellow gum. Silica gel column chromatography (eluent: acetone hexane (2:3)] was performed to give N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-[(6-methylpyridin-2-yl)methyl]-1,4-thiazepin-7-yl]acetamide (85.9 mg) as a yellowish solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[S:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=3[CH:30]=2)=[O:19])[CH2:13][CH2:12]1)=O>O1CCCC1>[OH:8][CH2:9][C@H:11]1[CH2:12][CH2:13][C@H:14]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[S:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=3[CH:30]=2)=[O:19])[CH2:15][CH2:16]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](CO)CC3)cc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 0.66 mL, 0.66 mmol, 2.0 eq) is added at 0° C. to a stirred solution of trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester (127 mg, 0.33 mmol, 1.0 eq) in tetrahydrofuran (2 mL). After 1 hour stirring at 0° C., the reaction mixture is cautiously quenched with ice-water (3 mL). Tetrahydrofuran is evaporated and the crude is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (trans-4-hydroxymethyl-cyclohexyl)-amide as a yellow solid (47 mg, 40% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:4][N:3]=1.[CH3:32][NH:33][CH3:34]>C(O)C>[CH3:32][N:33]([C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:4][N:3]=1)[CH3:34]
Reactant: CNC
Reactant: O=C(Nc1cnc(Cl)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Solvent: CCO
Product: CN(C)c1ncc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)cn1

Procedure:
In a sealed tube, a mixture of 0.2 g (0.44 mmol) of N-(2-chloropyrimidin-5-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared in the preceding stage, and 1.3 mL (8.89 mmol) of an aqueous solution of dimethylamine at 40%, the whole in solution in 15 mL of ethanol, is heated at 110° C. for 20 h. After this time, the reaction mixture is allowed to return to room temperature, then a white precipitate is collected by filtration, washed with water and dried at reduced pressure to obtain 0.14 g of the expected product.
Reaction SMILES: OO.[CH3:3][C:4]1([CH3:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][S:17][CH3:18])[C:5]1=[O:19].O.C(=O)([O-])[O-:23]>C(O)(=O)C>[CH3:3][C:4]1([CH3:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][S:17]([CH3:18])=[O:23])[C:5]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CSCCN1C(=O)c2ccccc2C(C)(C)C1=O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)CCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
6.9 ml of 30% hydrogen peroxide were added to a solution of 16 gm of 4,4-dimethyl-2-(2-methylmercapto-ethyl)-2H,4H-isoquinoline-1,3-dione in 30 ml of glacial acetic acid, while maintaining the temperature between 20° and 40° C. After 15 minutes the reaction mixture was poured into water, and the resulting mixture was neutralized with ptoassium carbonate and extracted with chloroform. The chloroform phase was evaporated, the residue was purified on a silicagel column (eluant: chloroform/acetone 19:1), and after evaporation of the eluate the residue was recrystallized from cyclohexane by addition of seed crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:39][C@H:40]([CH2:49][O:50][CH3:51])[C:41]([N:43]1[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]1)=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[C:47]([CH:45]1[CH2:44][N:43]([C:41](=[O:42])[C@H:40]([NH:39][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:22])[CH2:49][O:50][CH3:51])[CH2:46]1)#[N:48]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: COC[C@@H](N)C(=O)N1CC(C#N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 10 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), 1-((R)-2-amino-3-methoxy-propionyl)-azetidine-3-carbonitrile trifluoroacetate (42 mg, 0.14 mmol), and HATU (42 mg, 0.11 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.19 mL, 1.1 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with dichloromethane. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 44 mg (63%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=623.