Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36]/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[C:31]([CH3:42])[CH:30]=1.[NH2:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:57][C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH:47]=[CH:48][CH:49]=1.C(N(CC)CC)C>C(#N)C>[CH2:61]([O:60][C:58]([NH:57][C@@H:50]([C:46]1[CH:47]=[CH:48][CH:49]=[C:44]([NH:43][C:39](=[O:41])/[CH:38]=[CH:37]/[CH2:36][C:32]2[C:31]([CH3:42])=[CH:30][C:29]([Br:28])=[CH:34][C:33]=2[CH3:35])[CH:45]=1)[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:59])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: Cc1cc(Br)cc(C)c1C/C=C/C(=O)O
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)/C=C/Cc2c(C)cc(Br)cc2C)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 53.9 %

Procedure:
BOP (1.3 g, 3.0 mmol) was added to a solution of 53C (675 mg, 2.5 mmol), 39C (1.0 g, 2.75 mmol) and triethylamine (5.0 mmol) in acetonitrile (25 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at ambient temperature for 15 h. The mixture was concentrated in vacuo and purified by flash chromatography (0% to 60% EtOAc in hexanes) to afford 53D (800 mg, 54%) as a white solid. MS (ESI) m/z 593.3/595.3 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CO
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCO)cc2)cc1
Temperature: 100 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (1.00 g, 4.29 mmol), 2-(4-bromophenyl)ethanol (0.862 g, 4.29 mmol), 2M Na2CO3 (2.145 mL, 4.29 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.149 g, 0.129 mmol) in toluene (3 mL) and MeOH (0.857 mL) was heated at 100° C. under microwave irradiation for 2.5 h. The mixture was extracted with EtOAc, toluene and DCM. The combined organics were concentrated. The residue was purified by column chromatography and recrystallized from EtOAc to give the title compound. LCMS m/z=310.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].[H-].[Na+]>>[CH:8]1([C:7]2[C:2]([O:16][CH2:15][CH:14]([F:17])[F:13])=[CH:3][C:4]([C:11]#[N:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: OCC(F)F
Reactant: N#Cc1cc(Cl)c(C2CC2)cn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(OCC(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-cyclopropyl-pyridine-2-carbonitrile (example 145b), 2,2-Difluoro-ethanol (CAN 359-13-7) as starting materials and sodium hydride as reagent. The title compound was isolated (508 mg, 81%) as a yellow solid; MS (ESI, m/z): 225.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (2.98 g; 11.7 mmol) in anhydrous dichloromethane (32 mL) were added pyridine (1.54 mL; 19.0 mmol) and 4-bromobenzenesulfonyl chloride (1.49 g; 9.5 mmol) in one portion. The reaction mixture was heated at 45° C. for 71 hours, allowed to cool to room temperature, and then diluted with dichloromethane (100 mL). The resulting mixture was successively washed with aqueous hydrochloric acid (50 mL; 2N) and aqueous saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to yield an off-white solid. The crude product was dissolved in dichloromethane (100 mL) and treated with aqueous sodium hydroxide (60 mL; 2N) resulting in a white precipitation. The white solid was isolated by filtration and washed with dichloromethane (50 mL). The white solid was then acidified with aqueous hydrochloric acid (60 mL; 6N) and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a pale yellow solid (2.53 g).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2]>C(OC(=O)C)(=O)C>[CH3:6][N:5]1[C:3](=[O:4])[N:1]([CH3:2])[C:12](=[O:13])[C:11]2[N:10]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]3=[N:8][C:7]1=2
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)c2c(nc3n2C(=O)CCC3)n(C)c1=O

Procedure:
Theophylline-8-butyric acid, 24 g (example 1), was dissolved in 500 ml of acetic anhydride with heating. The mixture was gently refluxed for 30 minutes, then filtered through a preheated funnel to remove insoluble material. The product crystallized upon cooling. The product was collected, washed with ether and hexane then dried in vacuum at 50° C. to give 20 g of theophylline-8-butyric acid lactam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:15])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)(C)NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and t-butylamine (36 mg, 0.39 mmol). The title compound was obtained as a solid (25 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.57 (1H, s), 8.23 (1H, s), 1.31 (9H, s). MS m/z: 404.09, 406.07 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1Cl
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-chloro-3-(cyclopentylamino)benzoate (0.550 g, 1.65 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.08 g, 3.31 mmol) and methyl iodide (1.17 g, 8.25 mmol). The reaction mixture was heated at 80° C. for 12 h. On completion, the reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated and purified by column chromatography to afford methyl 5-bromo-2-chloro-3-(cyclopentyl(methyl)amino)benzoate (0.350 g, 61%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](O)(=[O:10])[CH3:9]>>[CH3:9][C:8]([C:4]1[CH:3]=[CH:2][C:1]([OH:7])=[CH:6][CH:5]=1)=[O:10]
Reactant: CC(=O)O
Reactant: Oc1ccccc1
Product: CC(=O)c1ccc(O)cc1

Procedure:
The same type of reaction is disclosed in U.S. Pat. Nos. 4,560,789 and 4,568,763 in which phenol is reacted with acetic acid in HF to form 4-hydroxyacetophenone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[C:11]([C:12](OCC)=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[N:8]2)=[C:5]([N+:22]([O-])=O)[C:4]([CH3:25])=[N:3]1.[H][H]>[C].[Pd].C(O)(=O)C>[OH:13][C:12]1[C:11]2[N:7]([N:8]=[CH:9][C:10]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:25])[C:5]=2[N:22]=1
Reactant: CCOC(=O)c1cnn(-c2c([N+](=O)[O-])c(C)nn2C)c1C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1c(O)nc1c(C)nn(C)c12

Procedure:
50 gms. of 1-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1H-pyrazole-4,5-dicarboxylic acid, diethyl ester, are hydrogenated with 0.2 gms. of palladium-carbon in 100 ml. of glacial acetic acid at 60° until the uptake of hydrogen stops. On cooling, the product, 5-hydroxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, crystallizes in the form of white filamentous needles. On evaporating the solvent, the product is recrystallized from dimethylformamide, yield 22 gms. of white needles, m.p. 246°-247°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[C:10](=[O:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:13]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[C:10](=[O:22])[CH:11]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[O:13]2
Reactant: COc1ccc(C(=O)CC(=O)c2c(F)cc(F)cc2F)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2cc(=O)c3c(F)cc(F)cc3o2)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
In a 100 mL 3-neck round-bottomed flask fitted with condenser and magnetic stirrer were placed dry THF (20 mL) and p-methoxy acetophenone (0.386 g, 2.57 mmol) under nitrogen. To this solution, LHMDS (2.69 mL as a 1M solution in THF, 2.57 mmol) was added drop wise at 25° C. After completion of addition, the mixture was stirred for 30 min at rt, then 2,4,6-trifluoro-benzoyl chloride (0.5 g, 2.57 mmol) in THF (5 mL) was added slowly at rt via syringe. The reaction mixture was stirred overnight at rt. The reaction was quenched with saturated NH4Cl solution (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was dries over Na2SO4, concentrated to give crude product, which was purified by column chromatography using 20% EtOAc in hexane, to give 215 mg of 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (27%). 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (100 mg) in DMSO (2 mL) was heated at 100-110° C. for 1 h. Then the reaction mixture was cooled to rt and diluted with water. The product was filtered and dried to give 62 mg of 5,7-difluoro-2-(4-methoxy-phenyl)-chromen-4-one (68%). MS (ES) m/z: 289.07 (M+1); 19F-NMR (DMSO-d6): δ −101.9, −109.2.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:4]=1
Reactant: Cc1cccc(-c2c(-c3ccncc3)[nH]c(=O)n(C)c2=O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1

Procedure:
A mixture of 3-methyl-5-(3-methylphenyl)-6-(4-pyridyl)-2,4(1 H,3 H)-pyrimidindione (12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml) was refluxed for 16 h. The excess of phosphorus oxychloride was evaporated followed by co-distillation with toluene. The remainder was carefully partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with water, dried and evaporated to leave the title compound. MS (m/z): 312 (M)+ ; C17H14ClN3O requir. 311.8.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[CH:17][C:18]([C:19]([O:21]CC)=[O:20])=[C:12]3[N:11]=2)[C@@H:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O1CCOCC1>[F:30][C:26]1[CH:25]=[C:24]([C@H:7]2[CH2:6][C@H:5]([OH:4])[CH2:9][N:8]2[C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[C:12]3[N:11]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@@H](OC(C)=O)C[C@@H]3c3cccc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.6 %

Procedure:
A mixture of ethyl 5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (225 mg, 0.546 mmol) and NaOH (131 mg, 1.64 mmol) in MeOH (1.0 mL) was stirred at ambient temperature for 60 hours followed by 3 hours at 60° C. The mixture was cooled to ambient temperature and 4M HCl in dioxane (1 mL) was added. The mixture was concentrated and the residue was treated with DCM. The mixture was filtered through Celite and concentrated to afford 5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (188 mg, 10% yield) as a white solid. MS (apci) m/z=343.0 (M+H).
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](=[O:17])([O:14][CH2:15][CH3:16])N.C([Sn](=O)CCCC)CCC>C(O)C>[CH2:15]([O:14][C:12](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:16]
Reactant: Nc1ccccc1
Reactant: CCOC(N)=O
Agent: CCCC[Sn](=O)CCCC
Agent: NC(N)=O
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1
Temperature: 170 °C

Procedure:
Following the procedure of example 23 60.1 g of urea, 93.1 g of aniline, 8.9 g of ethyl carbamate and 0.5 g of dibutyl-tin-oxide are heated to 170° C. Subsequently 84 g of ethanol are added dropwise at such a rate that the reaction temperature can be maintained between 170° and 175° C. After a total reaction time of 10 hours the reaction is stopped by cooling to room temperature. 161 g (98% of the theoretical yield) of N-phenyl-carbamic acid ethyl ester are found by HPLC analysis.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN
Solvent: c1ccncc1
Product: CCOC(=O)CNC(C)=O
Yield: 34.4 %

Procedure:
31 gm of acetic acid anhydride were slowly added to a solution of ethyl glycinate (prepared from 31 gm ethyl glycinate hydrochloride in ether and sodium hydroxide) in 70 ml of pyridine, while stirring and cooling the solution. The resulting mixture was then stirred for one hour at room temperature and subsequently evaporated, yielding 15 gm (55% of theory) of ethyl N-acetyl-glycinate.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([O:28]CC)=[O:27])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrole-2-carboxylate (1.5 g) in a mixed solvent of ethanol (15 mL) and tetrahydrofuran (15 ml) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 70° C. for 3 hr. After cooling to room temperature, the reaction mixture was concentrated, the residue was diluted with ethyl acetate, and 1N hydrochloric acid (10 mL) was added. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.3 g, yield 93%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 404 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([C:22]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:6][CH:5]=[CH:4][N:3]2[CH:21]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ncccc1OCCCCN1C(=O)CSC1=O
Product: CCOC(=O)c1cn2cccc(OCCCCN3C(=O)CSC3=O)c2n1

Procedure:
Using 5.69 g (20 mmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]thiazolidine-2,4-dione and 2.51 ml (20 mmol) of ethyl bromopyruvate, the same procedure as in Reference Example 27 was followed, to yield 3.28 g (43.5%, light orange oily substance) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:48][CH:47]([OH:49])[C:44]2([CH2:46][CH2:45]2)[CH2:43]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:49][CH:47]1[C:44]2([CH2:46][CH2:45]2)[CH2:43][N:42]([CH2:41][CH2:40][CH2:39][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:48]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (110 mg, 0.25 mmol) in DMA (2 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (125 mg, 0.50 mmol) and Cs2CO3 (243 mg, 0.75 mmol). The reaction was then stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (110 mg, 75%).
Reaction SMILES: C([O:8][C:9]([Cl:12])(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[Si:13]([O:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([C:9]([Cl:12])=[O:8])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of ditrichloromethyl carbonate (2.38 g, 8.02 mmol, 1.50 equiv) in dichloromethane (20 mL) was added a solution of 3-[(tert-butyldimethylsilyl)oxy]azetidine (1 g, 5.34 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at 0° C. over 30 min. Stirring was continued for 30 min whereupon a solution of triethylamine (810 mg, 8.00 mmol, 1.50 equiv) in dichloromethane (5 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined, washed with 2×40 mL of sodium chloride (sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). Purification afforded 1.3 g (97%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carbonyl chloride as a light yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1C(O)=O)([O-:3])=[O:2].[N-:17]=[N+]=[N-].[Na+]>OS(O)(=O)=O.O=S(=O)=O>[NH2:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:12]([CH3:13])[CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(N)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
2.43 grams of 2,5-dinitro-3-methylbenzoic acid was dissolved in 21.5 grams of oleum (20% SO3, 80% H2SO4). While the solution is stirred with the temperature maintained at 5°-10° C., 0.84 grams of powdered sodium azide was added cautiously in portions of less than 0.1 g over one hour. Rapid addition of the sodium azide was avoided to prevent any explosion from occurring. Stirring was continued for one hour at 0°-10° C. (gas evolution occurs), 10°-30° C. for two hours and 30°-60° C. for three hours. The resulting dark mixture was then poured over 200 ml of crushed ice to yield a yellow-orange precipitate. The mixture was filtered, washed with water and dried to give 2.02 g of 3-amino-2,5-dinitrotoluene (m.p. 125°-127° C.). Recrystallization from 95% ethanol gave rust colored flakes.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=[CH2:28].C(N(C(C)C)C(C)C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1/[CH:27]=[CH:28]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: C=Cc1scnc1C
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncsc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol), 4-methyl-5-vinylthiazole (44 mg, 0.35 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(o-MeC6H4)3 (16 mg, 0.052 mmol) in anhydrous MeCN (2 mL) were heated with stirring in a sealed tube under Ar at 90° C. for 1 d. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound (30 mg, 43%): 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 8.64 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=8.28 Hz, 1H), 7.83 (d, 1H), 7.64 (d, J=16.06 Hz, 1H), 7.12 (d, J16.31 Hz, 1H), 5.82 (s, 2H), 3.62 (t, J=8.28 Hz, 2H), 2.62 (s, 3H), 0.92 (t, J=8.28 Hz, 2H), −0.05 (s, 9H); MS ESI 400.2 [M+H]+, calcd for [C20H25N3O2SSi+H]+ 400.6.