Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:28]1([O:38][C:39](=[O:69])[C@H:40]([CH2:42][CH2:43][CH2:44][N:45]([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:46](=[NH:58])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[NH2:41])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]1([O:38][C:39](=[O:69])[C@H:40]([CH2:42][CH2:43][CH2:44][N:45]([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:46](=[NH:58])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[NH:41][C:18](=[O:20])[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](N)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 56.9 %

Procedure:
In 8 ml of DMF were dissolved 808 mg of benzoyl-L-phenylalanine and 2.05 g of Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester trifluoroacetate, after which 681 mg of DCC, 405 mg of HOBt and 304 mg of TEA were added thereto with ice-cooling, and the mixture was stirred for 3 hrs, and then at room temperature for a further 24 hrs. After the reaction, the DCU thus precipitated was removed by filtration, and ethyl acetate was added to the filtrate, after which the mixture was washed with 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue thus obtained was recrystallized from chloroform-diethyl ether to obtain 1.4 g (yield 57%) of benzoyl-L-phenylalanyl-Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester, m.p. 177°-185° C.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:4]1[C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1sc1ccccc12
Solvent: c1ccncc1
Product: Clc1ncnc2c1sc1ccccc12
Temperature: 110 °C
Yield: 169.7 %

Procedure:
Benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one (10.78 g, 26.7 mmol) was treated with pyridine (2.68 mL, 33.3 mmol) and phosphoryl trichloride (53.4 mL, 573 mmol), then heated to reflux at 110° C. for 1 hr. Excess POC3 was removed and cautiously quenched with ice water in an ice bath. The pH was adjusted to ˜5 with ammonium hydroxide. Solid was collected by filtration washed with water. The solid was dried to give 4-chlorobenzo[4,5]thieno[3,2-d]pyrimidine (10 g, 85% yield).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C(=O)=O.CC(C)=O>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([B:15]([OH:16])[OH:14])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cc1F
Agent: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Magnesium turnings (1.32 g) were stirred under nitrogen for 10 mins then anhydrous tetrahydrofuran (30 ml) followed by 1-bromo-3,4-difluorobenzene (7.0 g) were added over 5 mins. The mixture was maintained at reflux for 30 mins and then allowed to cool to room temperature. A solution of tri-isopropylborate (13.65 g) in dry tetrahydrofuran (80 ml) under nitrogen was cooled to -78° (dry ice-acetone) and the preformed Grignard solution was added over 10 mins. The mixture was stirred for 2 h and then allowed to warm to room temperature over 45 mins. The reaction was quenched with hydrochloric acid (4M, 80 ml) and stirred at room temperature overnight. The solution was extracted with ethyl acetate (3×100 ml) and the combined organic solutions extracted with aqueous sodium hydroxide (1M, 4×100 ml). The combined aqueous basic solutions were acidified to pH3 (4M hydrochloric acid), extracted with ethyl acetate (3×150 ml) and the combined organic fractions washed with acidified brine (200 ml) and dried (MgSO4). Removal of the solvent gave the title compound as a white solid (2.7 g). δ (d6 -DMSO+D2O) 7.42 (dt, 1H, J=10.5 and 7.5 Hz), 7.60-7.78 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].[NH2:11][NH2:12]>CCO>[F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5]1[NH:12][N:11]=[C:7]([NH2:8])[CH:6]=1
Reactant: NN
Reactant: N#CCC(=O)C1CC1(F)F
Solvent: CCO
Product: Nc1cc(C2CC2(F)F)[nH]n1
Yield: 78.5 %

Procedure:
To a solution of MeCN (1.1 g, 16.8 mmol) in THF (60 mL) was added dropwise n-BuLi in THF (11.2 mL, 40.3 mmol) at −78° C., and the reaction mixture was stirred at −78° C. under N2 for 30 min. Butyl 2,2-difluorocyclopropanecarboxylate (3.0 g, 16.8 mmol) was added at −78° C., and the reaction mixture was allowed to warm to RT over 3 h. The reaction mixture was quenched with water and adjusted to pH 7 with 1N HCl. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile. A mixture of crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile and hydrazine (2.0 g, 50.4 mmol, 85% pure) in EtOH (30 mL) was stirred at reflux for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by chromatography eluting with an EtOAc/petroleum ether gradient (12.5 to 100% EtOAc) to afford 2.1 g (78.5%) of 45 as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 11.40 (br s, 1H), 5.26 (s, 1H), 4.80 (br s, 2H), 2.78-2.66 (m, 1H), 2.04-1.75 (m, 1H), 1.73-1.21 (m, 1H); MS (ESI+) m/z=160.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[I:14][CH3:15]>CCOC(C)=O>[I-:14].[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N+:12]([CH3:15])[CH:11]=[N:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(C)cc(-n2cncn2)c1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-n2c[n+](C)cn2)c1
Product: [I-]
Yield: 11 %

Procedure:
A solution of 1-(3,5-dimethylphenyl)-1H-1,2,4-triazole (5 g, 28.9 mmol) and iodomethane (8.99 mL, 144 mmol) in EtOAc (50 mL) was stirred for 40 h. The precipitate was collected by filtration and washed with small amount of EtOAc to yield 1-(3,5-dimethylphenyl)-4-methyl-1H-1,2,4-triazol-4-ium iodide (1 g, 11%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O:23][C:24](=O)[C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)C>C(O)C>[OH:34][C:25]1[C:24](=[O:23])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(=O)Cc1ccc(O)cc1
Reactant: NCCCn1ccnc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: CCO
Product: O=C1C(O)=C(c2ccc(O)cc2)C(c2ccc3[nH]ccc3c2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 1H-Indole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(4-Hydroxy-phenyl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH2:5][N:6]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:9]=1.[Cl:37][C:38]1[C:39]([OH:49])=[C:40]([S:45](Cl)(=[O:47])=[O:46])[CH:41]=[C:42]([Cl:44])[CH:43]=1.CCN(CC)CC>C1COCC1>[Cl:37][C:38]1[C:39]([OH:49])=[C:40]([S:45]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:7]([N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:35]=[C:34]([Cl:36])[CH:33]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:47])=[O:46])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: O=C(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)-3-((4-fluorobenzylamino)methyl)benzamide (70 mg, 0.13 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (42 mg, 0.16 mmol) and Et3N (0.02 mL, 0.13 mmol). The resulting mixture was stirred at rt for 2 h, concentrated and the residue was dissolved in MeOH and purified by preparative HPLC to give the desired product as a white solid (51 mg, 51%). 1H NMR (CD3OD): δ 7.71 (s, 7.66 (d, J=4.0 Hz, 1H), 7.34-7.07 (m, 13H), 6.81 (t, J=8.0 Hz, 2H), 4.75-4.65 (m, 2H), 4.54 (s, 2H), 4.43-4.40 (m, 4H); MS (ESI): [M+H]+=751.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](OB(O)O)=[CH:8][CH:7]=1.Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[F-].[Cs+]>COCCOC.C(O)C.O.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][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:8][CH:7]=1
Reactant: COCOCc1ccc(OB(O)O)cc1
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COCOCc1ccc(-c2nccs2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis(triphenylphosphine)palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH3:7][C:8]([CH3:10])=O.N1C=CC=CC=1.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>O>[CH3:7][C:8]1([CH3:10])[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]1[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CNC(=S)NN
Reactant: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CNC1=NN(C(=O)c2cccc([N+](=O)[O-])c2)C(C)(C)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 21 g. portion of 4-methylthiosemicarbazide was reacted with 200 ml. of acetone at ambient temperature for 16 hours, and then 16 ml. of pyridine and 37.1 g. of 3-nitrobenzoyl chloride were added and the mixture was stirred for 3 hours at ambient temperature. Two hundred ml. of water was added, the mixture was stirred for 1 hour, the layers were separated, and the organic layer was evaporated to an oil under vacuum. The oil solidified upon standing overnight, and was recrystallized from hot acetone to obtain 26.3 g. of crude product, which was recrystallized again from 15 ml. of hot nitromethane to obtain 21.4 g. of product, m.p. 130°-133°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].O[C@H:25]1[CH2:30]C(=O)O[C@H](COC(=O)C2C=CC=CC=2)[CH2:26]1.COC(=O)C[C@H]1C[C@@H](COC(=O)C2C=CC=CC=2)OC(C)(C)O1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:25]([CH3:30])([CH3:26])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: O=C1C[C@H](O)C[C@@H](COC(=O)c2ccccc2)O1
Agent: COC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
93.8%; (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester: 2.3%; (2S,4R)-4-hydroxy-6-oxo-2-[(benzoyloxy)methyl]tetrahydro-2H-pyran: 0.1%; 2-[(4R,6S)-2,2-dimethyl-6-benzoyloxymethyl-1,3-dioxan-4-yl]acetic methyl ester: 0.1%.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:7][C:6]=2[C:5](=O)[NH:4][N:3]=1.O=P(Cl)(Cl)[Cl:18].CO.[OH-].[Na+]>C(Cl)Cl>[Cl:18][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c2cc3n(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Yield: 92 %

Procedure:
Compound XI (3.00 g, 15 mmol) was heated under reflux with excess POCl3 (25 mL) until no starting material remained (TLC, silic gel, 5% methanol in methylene chloride), then poured over ice, made basic with aqueous sodium hydroxide and the aqueous phase extracted with methylene chloride to isolate the product. The organic phase was dried (MgSO4), filtered, and evaporated to give a residue which was purified by flash column chromatography (silica gel, 5% methanol in methylene chloride) to give 1-chloro-4-methyl-6,7,8,9-tetrahydropyridazino[4,5-b]indolizine XII (3.00 g, 92%)
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([OH:19])=[O:18])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:23])(=O)=O>COP(OC)(OC)=O.O>[Cl:23][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]2[O:11][CH:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]([OH:19])=[O:18])=[CH:8][C:7]=2[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cccc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Solvent: O
Solvent: COP(=O)(OC)OC
Product: CCc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 117.4 %

Procedure:
8-Ethyl-2-(trifluoromethyl)2H-1-benzopyran-3-carboxylic acid (Example 28) (0.68 g, 2.5 mmol) was dissolved in trimethylphosphate (5 mL) and was treated with sulfuryl chloride (0.35 g, 2.62 mmol) at 0° C. After stirring at 0° C. for 45 minutes and 1 hour at room temperature, the reaction was diluted with cold water (15 mL). The resulting oily mixture was extracted with hexanes-ethyl acetate. The organic phase was washed with brine, dried, and concentrated in vacuo yielding the title compound as a solid (0.9 g, 117%): mp 197.2-199.1° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J=2.7 Hz), 7.30 (d, 1H, J=2.4 Hz), 5.88 (q, 1H, J=7.2 Hz), 2.65 (m, 2H), 1.19 (t, 3H, J=7.5 Hz). FABLRMS m/z 307 (M+H). Anal. Calc'd for C13H10ClF3O3: C, 50.92; H, 3.29. Found: C, 51.00; H, 3.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]([NH:16][C:17](=O)[CH3:18])=[CH:13][S:14][CH:15]=1)=[O:10].C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[CH3:18][C:17]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9](=[O:10])[C:11]2[C:12](=[CH:13][S:14][CH:15]=2)[N:16]=1
Reactant: CC(=O)Nc1cscc1C(=O)Nc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc2cscc2c(=O)n1-c1ccccc1Cl

Procedure:
A mixture of 3-acetamidothiophene-4carboxylic acid 2-chlorophenylamide (0.36 g, 1.23 mmol), toluene (15 mL), and phosphorous oxychloride (0.35 mL, 3.7 mmol) was refluxed 8 hours with azeotropic removal of water (Dean-Stark apparatus). The reaction was cooled and partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was flash chromatographed on silica gel (20×85 mm) eluting with 10% ethyl acetate/hexane. After an unweighed forerun, 2-methyl-3-(2-chloro-phenyl)-3H-thieno[3,4-d]pyrimidin-4-one was isolated as an off white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.C(P(C(C)C)C(C)C)(C)C.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:26][CH2:27]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)P(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A 100 mL round bottom flask was mixed with 4-triflouromethylbromobenzene (3.2 g, 15.0 mmol), triisopropylphosphine (10.0 mg, 0.062 mmol), Pd(OAc)2 (3.0 mg, 0.013 mmol) and xylenes (50 mL). The reaction mixture was allowed to heat at 110° C. for a period of 30 min at which it was mixed with tert-butyl piperidin-4-ylcarbamate (1.0 g 5.0 mmol). The reaction mixture stirred at 120° C. for 4.0 hours and then cooled to RT. The reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organics were dried over MgSO4 and concentrated to a crude oil. The oil was purified using silica gel chromatography (90% hexanes/10% EtOAc) to yield a total of 472 mg of mostly pure solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12]([N:11]([CH3:15])[CH3:10])=[O:13])=[N:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: NNc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NNc1ccc(F)cn1
Yield: 77 %

Procedure:
A solution of (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol), dimethylcarbamyl chloride (505 mg, 4.72 mmol) and DIPEA (1.01 g, 7.86 mmol) in DCM (20 mL) was stirred at reflux for 16 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo and then trituration with diethyl ether gave the title compound (600 mg, 77%). 1H NMR (400 MHz, CDCl3): 2.99 (6H, s), 6.46 (2H, m), 6.75 (1H, dd, J 9.1, 3.5), 7.22-7.32 (1H, m), 8.03 (1H, d, J 2.7).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][Cl:38]>CN(C=O)C.O.ClCCl>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([Cl:38])[CH3:2])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC(C)Cl)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt (3 g, 8.54 mmol) in DMF (30 ml) was added potassium carbonate (2.95 g, 21.35 mmol) and the mixture stirred at 60° C. for 1 hour under an atmosphere of nitrogen. The mixture was then cooled to room temperature and 1-bromo-6-chlorohexane (1.27 ml, 8.54 mmol) was added and the reaction heated to 50° C. and stirred overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water (ca. 50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic extracts were dried (MgSO4), filtered and the filtrate concentrated to give an orange oil (ca.3.5 g). This material was dissolved in dichloromethane and purified on a Flashmasterll (70 g aminopropyl cartridge) using a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil which solidified to a pale yellow solid (1.2 g).
Reaction SMILES: C(C1C=CC(S(N[C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=O)=O)=CC=1)(C)C.C(N(CC)CC)C.[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46].C[CH2:54][O:55]C(C)=O>ClCCl.CN(C)C1C=CN=CC=1>[Si:49]([O:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C:14]([O:55][CH3:54])=[O:37])=[C:18]([CH2:25][CH2:26][CH3:27])[CH:19]=1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51]
Reactant: CCOC(C)=O
Reactant: CCCc1cc(CO)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 2.50 g (6.98 mmol) of the product of Step A dissolved in 20 mL of dichloromethane was added 1.95 mL (14.0 mmol) of triethylamine, 1.26 g (8.38 mmol) of tert-butyldimethylchlorosilane, 85 mg (0.1 eq) of 4-dimethylaminopyridine and the reaction mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction was then diluted with 100 mL EtOAc, washed with water, 1.0N HCl, saturated aqueous NaHCO3, saturated NaCl, dried (MgSO4), filtered and evaporated in vacuo to afford 3.20 g (97%) of the title compound.