Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].C(OC([N:36]1[C:40]([C:41]#[N:42])=[CH:39][CH:38]=[C:37]1B(O)O)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[C:41]([C:40]1[NH:36][C:37]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=2[N:22]2[CH2:23][C@H:24]([OH:28])[C@@H:25]([OH:27])[CH2:26]2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:38][CH:39]=1)#[N:42]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2C[C@H](O)[C@@H](O)C2)[nH]1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 28.1, 100 mg, 0.217 mmol), (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1, 103 mg, 0.436 mmol), Pd(PPh3)2Cl2 (15.22 mg, 0.022 mmol), Na2CO3 (92 mg, 0.867 mmol), DME (920 μL), water (263 μL) and EtOH (131 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 90 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH-1% NH4OH, from 1% to 10% MeOH-1% NH4OH) followed by preparative SFC (Column NH2, from 26% to 31% in 10 min) to yield the title compound as an off-white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=473.2 [M+H]+, m/z=471.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.76 Hz, 2H) 3.26-3.32 (m, 2H) 3.89 (br. s, 2H) 5.08 (d, J=2.93 Hz, 2H) 6.24 (d, J=3.67 Hz, 1H) 6.84 (d, J=8.93 Hz, 1H) 7.00 (d, J=3.67 Hz, 1H) 7.33 (d, J=8.44 Hz, 2H) 7.84-7.93 (m, 4H) 10.10 (s, 1H) 12.52 (br. s, 1H).
Reaction SMILES: [N+:1]([C:4]1([N+:20]([O-:22])=[O:21])[CH2:11][NH:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][N:6]([N:18]=[O:19])[CH2:5]1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:24].[N+:28]([O-])([OH:30])=[O:29]>>[N+:18]([N:6]1[CH2:7][C:8]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:9][N:10]([N+:28]([O-:30])=[O:29])[CH2:11][C:4]([N+:1]([O-:3])=[O:2])([N+:20]([O-:22])=[O:21])[CH2:5]1)([O-:24])=[O:19]
Reactant: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CNCC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(O)O
Product: O=[N+]([O-])N1CC([N+](=O)[O-])([N+](=O)[O-])CN([N+](=O)[O-])CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
nitrating the 3,3,7,7-tetranitro-1-nitrosoperhydro-1,5-diazocine in a mixture of concentrated sulfuric acid and 90% nitric acid at a temperature of from about 0° C. to about 5° C. to form 1,3,3,5,7,7-hexanitroperhydro-1,5-diazocine; and
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([CH:16]([CH3:18])[CH3:17])([CH2:12][CH2:13][CH2:14]Cl)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:19](CN)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:35][N:36](C)C=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]([CH:16]([CH3:18])[CH3:17])([CH2:12][CH2:13][CH2:14][N:36]([CH3:35])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCCc1ccccc1
Reactant: CC(C)C(C#N)(CCCCl)c1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(C#N)(CCCN(C)Cc1ccccc1)c1ccc(F)c(F)c1

Procedure:
The product of Example 1, Step (b), (0.54 g, 0.0020 mole), N-benzylmethylamine (0.29 g, 0.0024 mole) and potassium carbonate (0.33 g, 0.0024 mole) were stirred in dimethylformamide (25 mL) for 10 days at room temperature. The mixture was concentrated in vacuo. Water (25 mL) and ethyl acetate (25 mL) were added to the residue. The layers were separated and the aqueous layer was washed with ethyl acetate (25 mL). The ethyl acetate layer and washes were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography to give an oil. The structure was supported by NMR, infrared spectroscopy and elemental analysis (M.W.=356.46+0.15 mole H2O). Analysis: Calcd. for C22H26N2F2. 0.15M H2O): C, 73.57; H, 7.38; N, 7.80; Found: C, 73.57; H, 7.33; N, 7.71.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][Si](C)(C)N[Si](C)(C)C.C[Si](Cl)(C)C.CI>C(O)(=O)C>[CH3:10][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CI
Solvent: CC(=O)O
Product: Cc1cn(C)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 17 h

Procedure:
Thymine (2.0 g, 16 mmol), hexamethyl-disilazane (32 mL) and trimethyl silylchloride (4.1 mL) were added in 100 mL mad apple-type flask with a magnetic stirrer and allowed to stir for 17 hr. at 140° C. until the reaction solution became transparent. After the reaction solution was cooled to 60° C., the solution was added with methyl-iodide (10 mL) and was allowed to stir for 29 hr. at 60° C. Then, the reaction solution was added with 6 N aqueous acetic acid solution (6 mL×10) and subjected to evaporation under reduced pressure. The residues were dissolved by the addition of 2-propanol and insolubles were filtered out. The filtrate was added with ethanol-water mixture. The object was recrystallized in ethanol-water mixture to give white solids (1.6 g, yield, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O.[CH:26](N(CC)C(C)C)(C)C.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](Cl)=[O:42]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:26])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:23][C:41](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccn3)c1)N2
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To s solution of 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (150 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.91 mmol) in dichloro methane (10 mL) was added picolinoyl chloride (77 mg, 0.54 mmol) with ice cooling. Upon completion of addition, the resultant mixture was allowed to stir for 20 h. Solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to afford 84 mg of methyl 2-(4-fluoro-3-(picolinamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. Yield: 42.4%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[C:16]([CH3:25])([CH3:24])[CH2:15]1>ClCCl.O>[CH3:24][C:16]1([CH3:25])[CH2:15][CH:14]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18][CH:17]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCC(O)CC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (2.6 g, 22 mmol) and triethylamine (2.4 g, 22 mmol) were added to a solution of methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate (1.38 g, 7.4 mmol) in dichloromethane (30 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. Then the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (400 MHz, CDCl3): δ 5.30-4.78 (m, 1H), 3.65 (s, 3H), 3.05 (s, 3H), 2.25-2.21 (m, 1H), 2.19-2.13 (m, 2H), 1.90-1.88 (m, 1H), 1.79-1.75 (m, 2H), 1.63 (s, 1H), 1.06 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)C.C(OC([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=O)(C)(C)C>>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([CH:6]([N:42]2[C:43]3[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]5[CH2:27][CH2:26][CH2:25][NH:24][C:33]=5[N:32]=4)=[CH:45][CH:44]=3)[CH:40]=[CH:41]2)[CH2:5][C:4]([OH:3])=[O:16])[CH:8]=[N:9][CH:10]=1)[CH3:15]
Reactant: CCOC(=O)C#Cc1cncc(OCC)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOc1cncc(C(CC(=O)O)n2ccc3cc(OCCc4ccc5c(n4)NCCC5)ccc32)c1
Yield: 70 %

Procedure:
The title compound was synthesized from (5-ethoxy-pyridin-3-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 70% yield. Mass Spectrum (LCMS, ESI) calculated for C35H40N4O6: 513.2 (M-Boc+H); found: 513.3 (-Boc).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:9]=[C:10]=[S:11].[NH4+].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][N:26]=[C:25]([CH3:30])[CH:24]=3)[CH:19]=1>CC(C)=O>[CH3:31][N:22]1[C:23]2[C:28](=[CH:27][N:26]=[C:25]([CH3:30])[CH:24]=2)[CH:29]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:10]([NH:9][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])=[S:11])[CH:15]=[CH:16][C:17]=2[CH3:33])[C:21]1=[O:32]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: [N-]=C=S
Reactant: O=C(Cl)C1CCCC1
Agent: [NH4+]
Solvent: CC(C)=O
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NC(=O)C3CCCC3)ccc1C)c(=O)n2C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The mixture of cyclopentanecarbonyl chloride (13 mg, 0.1 mmol) and ammonium isothiocyanate (7.6 mg, 0.1 mmol) in acetone (1.0 mL) was heated at 40° C. for 3 h. To the above reaction mixture, 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (15) (27.5 mg, 0.1 mmol) was added at rt and stirred for 30 min. The solvent was removed under vacuum to yield N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenylcarbamothioyl)cyclopentanecarboxamide 27, which was used without purification. MS m/z 435.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH2:13][CH3:14])[CH2:4][NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:1][O:2][CH:3]([O:12][CH2:13][CH3:14])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:29](=[O:30])[CH2:28][Cl:27]
Reactant: O=C(Cl)CCl
Reactant: CCOC(CNCC1OCCO1)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]([CH3:23])([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:13][OH:14].C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[CH3:11][C:12]([CH3:23])([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH:13]=[O:14]
Reactant: CC(C)(CO)COC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)COC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
DMSO (2.69 mL, 50.97 mmol) was added dropwise to a solution of oxalyl chloride (2.87 mL, 33.98 mmol) in dichloromethane (85.0 mL) at −78° C. After several minutes, neat 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.2 g, 16.99 mmol) was added dropwise and after stirring for 1 h at −78° C., triethylamine (9.5 mL, 68.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 30 min. Sat. NH4Cl was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and washed with brine. The organic layers were combined, dried over Na2SO4 and concentrated to give a pale liquid. The crude liquid was passed through a short silica gel column and eluted with 50% ethyl acetate in hexanes to provide 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (3.09 g, 97%) as a pale liquid after removal of solvents under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[N+:34]([O-])([OH:36])=[O:35]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([N+:34]([O-:36])=[O:35])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc([N+](=O)[O-])c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (1.59 g) was dissolved in THF (4 mL) under N2 then 70% HNO3 (4 mL) was added and the mixture was stirred at 50° C. overnight. The mixture was diluted with AcOEt (150 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous MeOH (100 mL) and dry HCl gas was bubbled through the mixture at 0° C. for a few minutes. The mixture was stirred at room temperature overnight, concentrated, taken up with AcOEt and washed with 1N HCl, satd. NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography (silica gel; eluent: hexanes and AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-nitrophenyl)-L-phenylalanine methyl ester (1.1 g).
Reaction SMILES: [SH:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][S:17]S(C)(=O)=O>O.C(O)C>[CH3:8][C:2]([S:1][S:17][CH3:16])([CH3:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)(S)CCC(=O)O
Reactant: CSS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSSC(C)(C)CCC(=O)O
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of mercaptopentanoic acid 7 (6.0 mL, 40 mmol) was dissolved in 50 mL of deionized water in a 250 mL flask. The solution was magnetically stirred as sodium carbonate (6.4 g, 60 mmol) was added to the acid at a rate that would not cause excessive frothing. The flask was equipped with a 100 mL addition funnel, which was charged with a solution of methyl methanethiolsulfonate (7.5 g, 60 mmol) dissolved in 30 mL of glass-distilled 100% ethanol. The flask was cooled in an ice/water bath and the system was maintained under an argon atmosphere. The methyl methanethiolsulfonate solution was added drop-wise to the flask as rapidly as possible but without causing excessive frothing. The cooling bath was removed and the reaction mixture was allowed to stir for an additional 3 hours. Solvent was removed by rotary evaporation under vacuum, until approximately 20 mL remained. After which 10 mL of saturated sodium bicarbonate and 30 mL of deionized water were added. The mixture was washed three times with 25 mL portions of ethyl acetate in a separatory funnel. The aqueous layer was adjusted to approximately pH 2 with 5 M HCl and was extracted twice with 120 mL portions of ethyl acetate. The organic layers were combined and washed with 20 mL of a solution composed of saturated NaCl and 1M HCl at a ratio of 4:1. The organic layer was then dried over 14 g of anhydrous sodium sulfate and solvent was removed by rotary evaporation under vacuum to give 5.4 g of product 8 (70% yield). The material can be taken to the next step without further purification. 1H NMR (CDCl3): δ1.54 (6H, s), 2.15-2.21 (2H, m), 2.64 (3H, s), 2.69-2.72 (2H, m). MS (M+Na+) calc.: 217.0, found: 217.1
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=O)(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[CH2:23][O:24][C:20]=2[C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.N1CCCCC1>CO>[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])/[C:23](=[CH:14]/[C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)[NH:10][N:9]=3)/[O:24][C:20]=2[C:19]=1[CH2:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: CS(=O)(=O)c1ccc2[nH]nc(C=O)c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A solution of 5-(methylsulfonyl)-1H-indazole-3-carboxaldehyde (0.0392 g, 0.175 mmol) in methanol (0.7 mL) was added with tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0915 g, 0.252 mmol) synthesized in the same manner as that of Example B42, Step 5, and piperidine (0.00149 g, 0.0175 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0470 g, 47%).
Reaction SMILES: [S:1]1[CH2:5][C:4](=O)[NH:3][C:2]1=[O:7].P(Cl)(Cl)([Cl:10])=O.CN(C)[CH:15]=[O:16]>>[Cl:10][C:4]1[NH:3][C:2](=[O:7])[S:1][C:5]=1[CH:15]=[O:16]
Reactant: O=C1CSC(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: O=Cc1sc(=O)[nH]c1Cl
Temperature: 80 °C
Yield: 40 %

Procedure:
The reaction between 2,4-thiazolidinedione (III), dimethylformamide and phosphorus oxychloride is described in Khim. Geterotsikl. Soedin 1975, page 85 (English translation: Chem. Het. Comp. 1975, page 73). In this reaction, the three substances mentioned are, in an optimum molar ratio of 1:1.5:3, heated at 80° C. for 16 hours and at 115° to 130° C. for a short time and then hydrolyzed, whereupon 4-chloro-2,3-dihydro-2-oxo-5-thiazolecarboxaldehyde of the formula (I) ##STR2## is obtained in 40 to 60% yield.
Reaction SMILES: CN1C2C(=CC(NS(C(F)(F)F)(=O)=O)=CC=2)C=C1C(O)=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C([O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42](N)[CH:41]=1)C>CN(C=O)C.C(Cl)Cl>[C:39]([OH:47])(=[O:38])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Cn1c(C(=O)O)cc2cc(NS(=O)(=O)C(F)(F)F)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To 1-Methyl-5-Trifluoromethansulfonylamino-1H-Indole-2-Carboxylic Acid (0.51 g, 1.6 mmol) in 8 ml of DMF was added HOBt (240 mg, 1.8 mmol), EDC (370 mg, 1.9 mmol), TEA (0.445, 3.2 mmol), and 3-aminobenzoic acid ethyl ester (265 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for a day. The reaction was diluted with 200 ml of methylene dichloride and washed with water and brine, then concentrated. The residue was treated with 40 ml of MeOH and 20 ml of 1H NaOH. The reaction mixture was stirred at room temperature for 4 hr and then concentrated via a rotor-evaporator to remove the methanol. The aqueous solution was adjusted pH to 4 with 6N HCl. The solid was filtered, washed with water, and purified by either recrystalization with CH2Cl2/Hexane or flash column using 30% EtOAc/Hexane with 1% AcOH to give 0.19 g of 3-[1-Methyl-5-trifluoromethansulfonylamino-1H-indole-2-carbonyl)-amino]-benzoic acid as a beige solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H, COOH), 11.68 (s, 1H, SNH), 10.65 (s, 1H, NHCO), 7.93 (m, 4H, ArH), 7.64 (m, 2H, H-7 & H-4), 7.38 (s, 1H, H-3), 7.20 (dd, J=1.6, 9 Hz, H-6), 4.01 (s, 3H, CH3), MS, m/z, 440 (M−H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH3:16]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:21]([NH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[S:22])=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)NC(=S)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
In 150 ml of isopropyl ether was dissolved 13.51 g of 4-amino-benzoic acid t-butyl ester. To the solution was added, while stirring at room temperature, 9.83 g of ethoxycarbonyl isothiocyanate. The mixture was stirred for two hours, the resulting crystalline precipitate was collected by filtration and recrystallizated from isopropyl ether to give 21.83 g of the title compound as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:27])[CH:21]=1>CO>[ClH:1].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[N:3]=[C:4]([N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:5]3[CH:10]=[CH:9][S:8][C:6]=3[N:7]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: CN(c1ccccc1)c1nc(Cl)nc2sccc12
Reactant: Cc1cc(F)ccc1N
Solvent: CO
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2ccsc2n1
Product: Cl

Procedure:
2-Chloro-4-(N-methylphenylamino)thieno[2,3-d]-pyrimidine (1.5 g, 0.00544 mol) and 4-fluoro-2-methylphenylamine (1.5 g, 0.0120 mol) were heated at 160° for 2.5 hours. Addition of methanol gave a solid which was collected by filtration and dried, (1.81 g). Recrystallization from ethanolic HCl/methanol gave the title compound as the hydrochloride salt, (1.44 g), m.p.216°-218°.
Reaction SMILES: [F:1][C:2]([N+:29]([O-:31])=[O:30])([N+:26]([O-:28])=[O:27])[CH2:3][O:4][CH:5](OCC([N+]([O-])=O)([N+]([O-])=O)F)[O:6][CH2:7][C:8]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[F:9].[Cl-].[Al+3].[Cl-].[Cl-].C([Cl:39])(=O)C>>[Cl:39][CH:5]([O:6][CH2:7][C:8]([F:9])([N+:13]([O-:15])=[O:14])[N+:10]([O-:12])=[O:11])[O:4][CH2:3][C:2]([N+:29]([O-:31])=[O:30])([N+:26]([O-:28])=[O:27])[F:1]
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=[N+]([O-])C(F)(COC(Cl)OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]

Procedure:
refluxing tris(2-fluoro-2,2-dinitroethoxy)methane with aluminum chloride and acetyl chloride to produce chloro bis(2-fluoro-2,2-dinitroethoxy)methane;