Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][O:16][C:13](=[O:15])[CH3:14])=[N:7][CH:8]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)Nc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
2-Cloro-N-(5-chloropyridin-2-yl)acetamide (30.68 g) obtained in Reference Example 20(1) is dissolved in N,N-dimethylformamide (500 ml), thereto is added sodium acetate (24.55 g) and the mixture is stirred at 60° C. for 5 hours. The reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine. The solution is dried over magnesium sulfate, treated with activated charcoal, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and the resulting crystals are collected by filtration, washed with n-hexane, and dried to give N-(5-chloropyridin-2-yl)-2-acetoxyacetamide (30.58 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[CH3:17][O:16][C:14](=[O:15])[O:10][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: COC(=O)Cl
Reactant: Cc1ccc(O)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A solution of 2,3-difluoro-4-methyl phenol (3.3 g, 22.89 mmol) in THF (30 ml) was cooled to 0° C. in an ice bath, and 60% NaH (0.916 g, 22.9 mmol) was added. When the gas evolution ceased, methyl chloroformate (1.76 ml, 22.9 mmol) was added. The ice-bath was removed and the mixture was stirred at room temperature for three hours. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 9:1) gave 3.85 g (83%) of carbonic acid 2,3-difluoro-4-methyl-phenyl ester methyl ester as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.[C:37](O)(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].S(=O)(=O)(O)O>>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([CH2:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:2]=1[F:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Yield: 55 %

Procedure:
Substantially the same manner as that in Example 123 was repeated except that 1.06 g (2.10 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4), 24 mL of hexanoic acid and 6 mL of concentrated sulfuric acid were used, and the resulting compound was purified by silica gel column chromatography (chloroform:acetonitrile=30:1-20:1) and recrystallized from ethyl acetate/n-hexane, to give 489 mg of Compound 125 (yield: 55%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1.CS(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3cccc(Cl)c3)cc2)S1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.38 g, 1.30 mmol) in DCM (8 mL) at 0° C. was added a solution of 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.25 g, 0.66 mmol) in DCM (8 mL) followed by dimethyl sulfoxide (0.23 mL, 3.30 mL). After stirring for 15 minutes N,N-diiisopropylethylamine (0.34 mL, 2.00 mmol) was added. After 45 minutes the reaction was poured into cold saturated NaHCO3 and the mixture was extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-15% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 117 mg (47%) of a white solid. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[C:20]2[CH:27]=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14]([C:19]3[C:20]4[CH:27]=[CH:26][NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCCNC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
1,7-Diazaspiro[4.5]decane-1-carboxylic acid tert-butyl ester (51 mg) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (36 mg), potassium carbonate (59 mg) and water (1 ml), and the mixture was stirred for 1.5 hours with refluxing. The mixture was cooled to room temperature, and thereto was added water. The mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, followed by chloroform/methanol=20/1) to give the titled compound (60 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:27](OCC)(=[O:33])[C:28](OCC)=[O:29]>C(OCCO)C>[CH:22]1([N:21]2[C:3]3[N:4]=[C:5]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)=[CH:11][CH:10]=4)[N:6]=[CH:7][C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:33])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NC1CCCC1
Solvent: CCOCCO
Product: O=c1[nH]c2cnc(Nc3ccc(N4CCOCC4)cc3)nc2n(C2CCCC2)c1=O
Yield: 49 %

Procedure:
A mixture of 0.354 g (1 mmol) of 5-amino-4-(cyclopentylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine and 5 mL (32 mmol) of diethyl oxalate in 20 mL of 2-ethoxyethanol is heated under reflux for 3 hours and then cooled to give 0.20 g (49%) of the title compound (Compound 23): mp (EtOH) 283–286° C. 1H NMR [(CD3)2SO]: δ 11.87 (br, 1H, exchangeable with D2O, H-5), 9.29 (br, 1H, exchangeable with D2O, 2NH), 8.12 (s, 1H, H-4), 7.50 (br d, J=9.0 Hz, 2H, H-2′,6′), 6.90 (d, J=9.1 Hz, 2H, H-3′,5′), 5.62 (pentet, J=8.8 Hz, 1H cyclopentyl CH), 3.74 (br t, J=4.7 Hz, 4H, CH2O)), 3.03 (br t, J=4.7 Hz, 4H, CH2N), 2.21–2.11 (m, 2H, cyclopentyl), 1.97–1.84 (m, 2H, cyclopentyl), 1.84–1.74 (m, 2H, cyclopentyl), 1.63–1.52 (m, 2H, cyclopentyl).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>C(O)C.[H][H]>[CH3:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1ncccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Product: Cc1ncccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 47.4 %

Procedure:
tert-Butyl 4-(2-methyl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (209 mg, 0.76 mmol) was dissolved in ethanol (42 ml) and hydrogenated in a H-cube hydrogen generator with a flow of 1 ml/min and at a temperature of 70° C. The mixture was evaporated under reduced pressure, the residue was purified by preparative HPLC (Waters X-Bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 100 mg of a colourless solid (0.36 mmol, yield 47%). MS (ESI) m/z=277.2 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34](=[O:38])[N:35]([CH3:37])[N:36]=2)[N:33]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34](=[O:38])[N:35]([CH3:37])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1nc2ccc(Cl)nn2c1=O
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
0.52 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 3 ml of N,N-dimethylformamide; 0.0704 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. 0.325 g of 6-chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was added, followed by stirring at room temperature for 2 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.502 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([CH:12]([OH:28])[C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:28])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(C#N)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To propane-1-sulfonic acid {3-[(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-amide (14, 313 mg, 0.770 mmol) dissolved in 5 mL of tetrahydrofuran, Dess-Martin periodinane (327 mg, 0.770 mmol) was added as a solid. The reaction was stirred at room temperature for 1 hour, then quenched with water. The aqueous layer was extracted with ethyl acetate, and the organice layers combined, washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes to provide the desired compound (P-0002, 179 mg). MS(ESI) [M−H+]−=403.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].B.C1COCC1>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:13][NH2:14])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCC1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
The mixture of 1-(4-nitro-phenyl)-cyclopropanecarbonitrile (3.0 g, 15.9 mmol) and borane THF complex (1.0 M solution in THF, 32 ml, 32 mmol) in 50 ml of anhydrous THF was heated at reflux overnight. The mixture was cooled to RT, quenched with 2.5 ml of 50% AcOH aqueous solution, then partitioned between EtOAc and NaHCO3 (aq). The combined organic portions were washed with brine, dried with MgSO4, filtered, and condensed. The crude was purified by flash column chromatography (1 to 2% of MeOH in CH2Cl2). The titled compound was obtained as a light brownish solid. MS (ES+): 192.9. Calc'd for C10H12N2O2—192.2.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]([CH2:20][CH2:21][CH3:22])[C:7]=1[C:23]#[N:24])(=[O:3])[NH2:2].Cl.Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH2:30][CH2:29]1.C[O-].[Na+].CO>CN(C=O)C>[NH2:24][C:23]1[C:7]2[C:6](=[N:11][C:10]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]4[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=4)[CH2:30][CH2:29]3)=[CH:9][C:8]=2[CH2:20][CH2:21][CH3:22])[S:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: OC(CNC1CCNCC1)COc1ccncc1
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC(N)=O)c1C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1cc(N2CCC(NCC(O)COc3ccncc3)CC2)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a sealed tube was added trifluoro-methanesulfonic acid 6-carbamoylmethylsulfanyl-5-cyano-4-propyl-pyridin-2-yl ester (66.7 mg, 0.174 mmol) in 4 mL of dry DMF, followed by the addition of 1-(piperidin-4-ylamino)-3-(pyridin-4-yloxy)-propan-2-ol trihydrochloride salt (69 mg, 0.191 mmol) and N-N-diisopropylethylamine (180 mg, 1.39 mmol). The reaction mixture was stirred at 70° C. for 2 h. DMF was removed in vacuo. The residue was dissolved in 5 mL of MeOH, followed by the addition of sodium methoxide, 0.5 M solution in MeOH (1.74 mL, 0.86 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a flash chromatography column. The column was eluted with 0–5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected, concentrated and dried under high vacuum pump to afford 24 mg (28.5%) of the title compound as a light brown solid product. (TLC: Rf=0.4, 5% 2M NH3 in MeOH/CH2Cl2, UV). ES+ 485.29 m/z (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccnc(C#CCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
The residue of step A was dissolved in absolute ethanol (50 ml). The solution was flushed with argon, and a slurry of Pd/C (9.346 g, 0.325 mmol) in absolute ethanol (20 ml) was added. The resulting suspension was stirred in an athmosphere of hydrogen overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica, gradient of 1 to 5% methanol containing 7N ammonia in DCM) to yield 1.22 g (5.4 mmol, 84%, two steps). MS(ESI) m/z=251.2 [M+1]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:53][CH2:52][C:47]3([O:51][CH2:50][CH2:49][O:48]3)[CH2:46][CH2:45]2)=[C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])[CH:33]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:26])[C:10]3([CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH2:37][C:36](=[O:38])[NH:35][CH:34]3[C:32]3[CH:33]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=3[O:43][CH:44]3[CH2:53][CH2:52][C:47]4([O:48][CH2:49][CH2:50][O:51]4)[CH2:46][CH2:45]3)[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(Cl)ccc1OC1CCC2(CC1)OCCO2)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2OC2CCC3(CC2)OCCO3)N1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 1b (0.4 g, 1 mmol) was reacted 1-[5-chloro-2-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (1.5 g, 5 mmol) in toluene to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (Yield 0.23 g, 37%)
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.[Na].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12)[CH3:25]
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Reactant: CCO
Agent: [Na]
Product: CCOc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
6.2 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.02 mol.) are added to a solution of 0.5 g. of sodium (0.022 mol.) in 150 ml. of absolute ethanol. The mixture is heated at 120° (bath temperature) in an autoclave for four hours. After cooling, the crystallized 4-ethoxy-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridin-11(1H)-one is filtered off and washed with water; yield: 3.5 g. An additional crop of 2.1 g. is obtained by work up of the mother liquor, total yield: 5.6 g. (87.5%). m.p. 150°-152° (recrystallized from ethanol).
Reaction SMILES: C[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[CH:2][S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2ncsc2c1
Temperature: 25 °C

Procedure:
See FIG. 3A. Nitration of 2-methylbenzothiazole was performed following the method of Mizuno, J. Pharm. Soc. Japan, 72, 745 (1952). A mixture of fuming nitric acid (1.6 mL) and concentrated sulfuric acid (1.2 mL) was added to an ice-cooled solution of 2-methylbenzothiazole (2 g) in sulfuric acid (8 mL). The solution was allowed to warm to room temperature for one hour, then poured onto 100 mL of ice. The solid was filtered, washed with water, and recrystallized from ethanol (80 mL) to provide 2.5 g of yellowish needles.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[C:11]2[N:12]=[C:13]([S:15][CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[S:14][C:10]=2[C:9]([F:26])=[CH:8][C:7]=1[F:27].Br[CH2:29][C:30]([OH:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]1[C:11]2[N:12]=[C:13]([S:15][CH2:16][C:17]([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:29][C:30]([OH:32])=[O:31])=[O:18])[S:14][C:10]=2[C:9]([F:26])=[CH:8][C:7]=1[F:27]
Reactant: O=C(O)CBr
Reactant: O=C(CSc1nc2c(F)c(F)cc(F)c2s1)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CN(C(=O)CSc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.4 %

Procedure:
To DMSO (5 ml) was added 2-(4,5,7-trifluorobenzothiazol-2-ylthio)-N-phenylacetamide (354 mg, 1 mmol), bromoacetic acid (278 mg, 2 mmol) and potassium carbonate (414 mg, 3 mmol) and the mixture was stirred at room temperature for 5 hours under a nitrogen stream. The resultant reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and then evaporated to yield crude crystals, which were recrystallized from ethyl acetate-hexane to give N-[2-(4,5,7-trifluorobenzothiazol-2-ylthio)acetyl]-N-phenylglycine (80 mg, 19%) as slightly yellow crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]>O1CCCC1>[CH2:8]([O:7][C:5]([CH2:4][NH:1][C:2]([O:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])=[O:3])=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=C=O
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 20 °C
Reaction time: 72 h
Yield: 16.6 %

Procedure:
1.5 g of ethyl isocyanatoacetate was added to a solution containing 0.54 g of the product obtained in Example 8 in 10 ml of tetrahydrofuran and the solution was stirred for 3 days at 20° C. The solvent was evaporated in reduced pressure and the raw product was purified in a silica gel column using toluene-dioxane-acetic acid (8:1:1) as an eluent. Crystallization from acetone-petroleum ether yielded 0.13 g (17%) of the desired product desired, m.p 155°-158° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:23]4[C@H:19]([O:20]C(C)(C)[O:22]4)[C@@H:18]([CH2:26][N:27]([CH3:47])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([CH:43]7[CH2:46][O:45][CH2:44]7)=[CH:42][C:36]=6[N:35]=5)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.FC(F)(F)C(O)=O.O>>[NH2:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@@H:16]3[CH2:17][C@H:18]([CH2:26][N:27]([CH3:47])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([CH:43]7[CH2:44][O:45][CH2:46]7)=[CH:42][C:36]=6[N:35]=5)[CH2:29]4)[C@@H:19]([OH:20])[C@H:23]3[OH:22])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C6COC6)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (115 mg, 0.159 mmol) was dissolved in a mixture of Trifluoroacetic Acid (4.00 ml, 51.9 mmol) and Water (0.40 ml, 22 mmol) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 2 h, the reaction mixture was allowed to warm to RT. After 1 the reaction mixture was concentrated in vacuo. The residue was taken up in 6 ml MeOH, concentrated and the process was repeated twice. The resultant residue was placed on high vacuum. The crude residue was diluted with 2 ml MeOH, treated with 140 mg K2CO3 and 10 drops of H2O and allowed to stir at RT until the solution was basic by pH paper. The solution was filtered through a fine frit and the solids washed with MeOH. The filtrate was concentrated to a solid that was placed on high vacuum overnight. The crude material was purified by prep TLC on two 20 cm×20 cm×1.0 mm prep TLC plate, eluting with 14% 7N NH3 in CH3OH/CH2Cl2 to give the product as a colorless glass (37 mg) 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1 H), 7.52 (br. s., 1 H), 7.48 (d, J=8.29 Hz, 1 H), 7.28 (m, 1 H), 7.20 (t, J=3.42 Hz, 1 H), 6.60 (d, J=3.52 Hz, 1 H), 5.12 (m, 2 H), 4.80 (m, 2 H), 4.38 (m, 1 H), 4.32 (m, 1 H), 3.89 (q, J=5.60 Hz, 1 H), 3.04 (m, 1 H), 2.85 (m, 2 H), 2.70 (m, 1 H), 2.52 (m, 1 H), 2.41 (m. 2 H), 2.27 (dd, J=10.99, 6.63 Hz, 2 H), 2.19 (s, 3 H), 2.17 (s, 3 H), 2.14 (m, 1 H), 2.03 (d, J=7.88 Hz, 1 H), 1.91 (m, 3 H), 1.62 (m, 1 H), 1.51 (m, 1 H).