Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:15])(=[O:19])=[O:18]
Reactant: CCOC(=O)CCCBr
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (10), (Aldrich) (0.060 mole), ethyl 4-bromobutyrate (Aldrich) (0.055 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give ethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (300). See eg., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, p. 228 (1991).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34]>O>[C:22]([O:21][C:19]([N:11]([C:3]1[C:4]([CH3:10])=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=1[NH:1][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(C#N)cc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Di-t-butyl (2-amino-4-cyano-6-methylphenyl)imidodicarbonate (104 mg, 0.3 mmol) obtained in Step 2 was added with pyridine (0.24 mL, 3 mmol, 10 eq) and heptyl chloroformate (0.11 mL, 0.6 mmol, 2 eq), and the mixture thus obtained was stirred at room temperature for 10 minutes, followed by further stirring at 80° C. for 2 hours. Upon completion of the reaction, the resulting product was added with distilled water, and extracted with ethyl acetate. The organic layer thus obtained was dried over MgSO4, and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=1:9) to obtain the title compound in a colorless liquid (146 mg, yield: 99%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][NH:18]1.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:21]=1[CH2:20][CH2:19][NH:18][C:17]2=[O:16])=[O:4]
Reactant: CN(C)C(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide (40.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 eq.) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:3][CH:2]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:18]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][N:9]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:8][CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ccccc2)CC3)cc1
Reaction time: 6 h
Yield: 6.4 %

Procedure:
The (5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(4-trifluoromethylphenyl)amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added phenylboronic acid (83 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under the vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (8.0 mg, 6.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2.C([O-])(O)=O.[Na+].[I:26]Cl>C(Cl)Cl.CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:26])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:5]2
Reactant: ClI
Reactant: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (560 mg, 2.09 mmol) in a mixture of CH2Cl2 (10 mL) and MeOH (2.5 mL), was added NaHCO3 (263 mg, 3.13 mmol) followed by 1M ICl in CH2Cl2 (2.1 mL, 2.1 mmol). The mixture was stirred for 30 min and then quenched with sat. aq. NaHSO3. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-amino-6-iodo-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=395.0; found=394.7 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.58-7.51 (2 s, 1H); 7.45-7.35 (m, 5H); 6.70-6.64 (2 s, 1H); 5.24 (s, 2H); 4.67 (s, 2H); 4.65 (s, 2H); 4.15 (br, s, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18].Br.Br.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[OH:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Yield: 69.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3 g), 4-(4-hydroxyphenyl)piperazine dihydrobromide (3.8 g) and sodium bicarbonate (2.8 g) in a mixture of dimethylformamide (30 cc) and tetrahydrofuran (20 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. After purification by recrystallization from boiling acetone (215 cc), 2-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.1 g) is obtained, m.p. 195° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][C:4]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15].[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[Cl:21][C:10]1[C:9]([O:13][CH3:14])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]([CH2:3][CH2:2][F:1])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1(CCF)Cc2cc(OC)ccc2C1=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCF)Cc2c(ccc(OC)c2Cl)C1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate (44.6 g, 159 mmol) in DMF (159 mL) was added N-chlorosuccinimide (23.4 g, 175 mmol) in portions. The solution was heated at 50° C. and the reaction was monitored periodically by NMR analysis of aliquots. After 6 hours, the reaction was approximately 80% complete by NMR analysis. The reaction mixture was allowed to cool to room temperature and stand overnight. After reheating to 50° C., additional N-chlorosuccinimide (2.12 g, 15.9 mmol) was added. Monitoring by NMR was continued, and after 4.5 hours another portion of N-chlorosuccinimide (2.12 g, 15.9 mmol) was added. After another 3 hours, the reaction was allowed to cool to room temperature and stand overnight. Most of the DMF was removed by evaporation at reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water (4 times) and brine and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure gave crude ethyl 4-chloro-2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate. This material was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[F:20][C:21]([F:33])([F:32])[O:22]C1C=CC=C2C=1NC=C2>>[F:20][C:21]([F:33])([F:32])[O:22][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: FC(F)(F)Oc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CC1(C)OB(c2cc3cccc(OC(F)(F)F)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-trifluoromethoxy-1H-indole.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:15][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCCCCC2)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCCCCC3)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 4-chloro-6-(hexahydro-1H-azepin-1-yl)-2-pyrimidinamine (600 mg, 2.65 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.437 g, 2.65 mmol) in 1,4-dioxane (10.6 mL). Saturated aqueous NaHCO3 (2.65 mL) was added, and the resulting mixture was degassed with nitrogen for 5 minutes. Pd(Ph3P)4 (0.153 g, 0.13 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature, and the organic layer was separated and concentrated. The resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (eluent: 90/10/1 CHCl3/CH3OH/NH4OH) afforded the title compound (547 mg, 62%) as a yellow solid. LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH3:40])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([C@@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[NH:18][C:17]=3[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:49])[CH3:48]>C1COCC1>[C:47]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C:19]1[NH:18][C:17]2[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:37])[F:38])=[O:29])[CH:14]=[C:13]([C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=3[CH3:40])=[O:12])[C:21]=2[N:20]=1)(=[O:49])[CH3:48]
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3)nc12
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC[C@H]1c1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (Example 71) (26 mg) in THF solution (0.5 mL), was added pyridine (12 μL), and the mixture was stirred under ice-cooling. To the mixture was added acetyl chloride (5.1 μL), and it was stirred at room temperature for 1 hour. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (15 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[N:4][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:34]3[CH2:33][CH2:32][CH2:31][NH:30][C:29]=3[CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[N:4][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([N:30]2[CH2:31][CH2:32][CH2:33][C:34]3[N:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[N:27]=[CH:28][C:29]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C(=O)O)C(C)C
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)C(C)C
Yield: 74 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-methylbutanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 89 mg (74%) of the title compound as a glassy white solid. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.44 (m, 2H), 7.16 (m, 2H), 5.03 (d, J=10.9 Hz, 1H), 3.89 (ddd, J=2.7, 8.2, 10.9 Hz, 1H), 3.78 (ddd, J=2.7, 7.8, 10.9 Hz, 1H), 2.96 (m, 1H), 2.79 (m, 2H), 2.37 (s, 3H), 1.99 (m, 1H), 1.82 (m, 1H), 1.12 (d, J=6.3 Hz, 3H), 0.79 (d, J=7.1 Hz, 3H); MS: (ES) m/z calculated for C22H23ClF4N5O [M+H]+ 484.1, found 484.1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:28]C1C=CC=CC=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>C1COCC1>[C:22]1([O:21][C:20](=[O:28])[NH:17][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:4]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(OCc2ccc(F)cc2)ncc1F)Oc1ccccc1
Yield: 21 %

Procedure:
To a stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.20 g, 0.84 mmol) in dry THF (3 mL) at ice-bath temperature was added NaH (0.034 g of 60 wt. % suspension in mineral oil, 0.84 mmol). When bubbling ceased, the resulting mixture was transferred (dropwise) via cannula to an ice-cold, stirred mixture of diphenyl carbonate (1.8 g, 8.4 mmol) in dry THF (5 mL). The mixture was stirred overnight, poured into EtOAc, and washed with saturated aq. NH4Cl solution followed by brine solution. The EtOAc layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica gel using a gradient of EtOAc and hexanes to give 0.063 g (21%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.3 Hz, 1H), 7.43 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.38 (s, 2H); HPLC-MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [CH2:1]([Si:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[C:4]#[C:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].[I-:14].[I-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C(#N)C>[CH2:1]([Si:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[C:4]#[C:5][CH2:6][CH2:7][CH2:8][I:14])[CH3:2]
Reactant: [I-]
Reactant: CC[Si](C#CCCCO)(CC)CC
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC[Si](C#CCCCI)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(triethylsilyl)-4-pentin-1-ol (416 g, 2.1 mmol) in absolute acetonitrile (20 mL was added in drops to a solution of triphenylphosphine diiodide (2.80 g, 5.4 mmol) and imidazole (1.04 g, 15.4 mmol) with argon and stirred overnight at room temperature. The raw product was purified by means of flash chromatography (38 g, 20×2.5 cm) with cyclohexane/ethyl acetate (9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:39])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:33])(=[O:32])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22]C(=O)OC(C)(C)C)=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:20]1[C:19]([CH3:31])([CH3:30])[S:18](=[O:32])(=[O:33])[C@@H:17]2[CH2:34][CH2:35][O:36][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:5]4[C:4]([CH3:39])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[CH:38][C:15]=3[C@@:16]2([CH3:37])[N:21]=1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Yield: 97.9 %

Procedure:
A solution of trans-isomer tert-butyl ((4aR,11bR)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (110 mg, 0.191 mmol) in DCM (2 ml) was treated with TFA (0.7 ml, 9.53 mmol) for 10 min at RT. The mixture was concentrated to dryness, redissolved in 0.5 ml of MeOH and neutralized with saturated solution NaHCO3. Precipitated material was extracted with ethyl acetate, organic extract was washed with water, brine, filtered through pad of celite and concentrated to afford N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-methylpicolinamide (89 mg, 0.187 mmol, 98% yield). LC/MS (ESI+) m/z=477.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:23])[C:20]([OH:22])=[O:21])=[CH:17][C:18]=1[Cl:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COC(=O)C(CCOc1ccc(C(=O)C(=O)O)cc1)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(CCOc1ccc(C(=O)C(=O)O)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18.7 h
Yield: 118 %

Procedure:
DL-p-(3-tert-Butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxylic acid (750 mg.) was dissolved in a mixture of chloroform (15 ml.) and methanol (10 ml.), and to the solution was added 1,3,5-trichloroisocyanuric acid (180 mg.) in the course of 5 minutes, whereafter the mixture was stirred at ambient temperature for 18.7 hours. The insoluble materials were filtered off from the reaction mixture and the filtrate was evaporated to dryness under reduced pressure. The resultant residue was dissolved in ethyl acetate, and the solution was washed with water and then dried over magnesium sulfate. This solution was evaporated to dryness under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (11 g.). Elution was carried out with a mixture of chloroform and methanol (99:1 by volume) and the fractions containing a desired compound were collected. The solvent was removed by evaporation from the eluate under reduced pressure to give DL-p-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-3-chlorophenylglyoxylic acid (380 mg.).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]([O:17]CC)=O)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:20]1([C:23](=[N:25]O)[NH2:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[N:25]=[C:15]([C:14]3[N:13]=[CH:12][N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:11]=[C:2]([CH3:1])[C:3]=34)[O:17][N:24]=2)[CH2:22][CH2:21]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)c1ncn2c1c(C)nc1ccccc12
Product: Cc1nc2ccccc2n2cnc(-c3nc(C4CC4)no3)c12

Procedure:
M.p. 188°-189° C., from ethyl 4-methylimidazo[1,5-a]quinoxaline-3-carboxylate and cyclopropancarboxamide oxime. (Compound 10)
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2([CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[C:20]1[CH2:24][O:23][C:22](=[O:25])[CH:21]=1.O=C1OCC(N2CCCC3(CCNCC3)C2=O)=C1>>[O:25]=[C:22]1[O:23][CH2:24][C:20]([N:14]2[C:13](=[O:16])[CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]3)[CH2:15]2)=[CH:21]1
Reactant: O=C1C=C(Br)CO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Agent: O=C1C=C(N2CCCC3(CCNCC3)C2=O)CO1
Product: O=C1C=C(N2CC3(CCNCC3)CC2=O)CO1

Procedure:
The title compound was prepared from 3-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester and 4-bromofuran-2(5H)-one in two steps in an analogous fashion to that described for 2-(5-Oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (I-18) above. LC/MS: [(M+1)]+=237
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:19]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]ncc2c(Cl)nc(-c3ccccc3)n12
Solvent: c1ccncc1
Product: S=c1[nH]ncc2c(Cl)nc(-c3ccccc3)n12
Temperature: 100 °C

Procedure:
To a solution of 8-chloro-6-phenyl-imidazo[1,5-d]-as-triazine-4(3H)-one (5.84) gm.) in pyridine (100 ml.) is added phosphorus pentasulfide (5 gm.) The mixture is heated at 100° C for 6 hours, filtered hot, and poured into dilute hydrochloric acid. The title product is isolated as a solid.