Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]#[CH:24]>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.[Cu]I.C(N(CC)CC)C>[CH:16]1([CH2:15][N:8]([C:4]2[CH:3]=[C:2]([C:24]#[C:23][CH2:22][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:7]=[CH:6][CH:5]=2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(N(CC1CCCCC1)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(N(CC2CCCCC2)C(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Triethylamine (45 mL) was added to a mixture of N-(3-bromophenyl)-N-(cyclohexylmethyl)-2,2,2-trifluoroacetamide (3.8 g, 10.4 mmol), tert-butyl prop-2-ynylcarbamate (2.42 g, 15.6 mmol), Pd(Ph3P)4 (0.6 g, 0.52 mmol) and CuI (0.1 g, 0.52 mmol) and flushed for 15 min with argon. The reaction mixture was stirred for 16 h at 90° C. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite bed and the filtrate was concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh 5% to 10% EtOAc—hexane) gave tert-butyl 3-(3-(N-(cyclohexylmethyl)-2,2,2-trifluoroacetamido)phenyl)prop-2-ynylcarbamate as a yellow semi-solid. Yield (2.1 g, 50%); 1H NMR (400 MHz, DMSO-d6) δ 7.49-7.48 (m, 2H), 7.43-7.41 (m, 2H), 3.99 (bs, 2H), 3.58 (bs, 2H), 1.64-1.57 (m, 6H), 1.39 (s, 9H), 1.19-1.12 (m, 3H), 0.95-0.89 (m, 2H).
Reaction SMILES: [F:1]/[C:2](/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[C:3](/[F:8])\[Si](C)(C)C.[F-].[K+].O>C(#N)C>[F:1]/[C:2](/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[CH:3]/[F:8]
Reactant: CCCc1ccc(/C(F)=C(\F)[Si](C)(C)C)cc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCc1ccc(/C(F)=C\F)cc1
Yield: 82.7 %

Procedure:
Then, 19.1 g (0.075 mol) of the obtained (Z)-1,2-difluoro-1-(4-n-propylphenyl)-2-trimethylsilylethylene was dissolved in 50 ml of acetonitrile, and then 8.70 g (0.15 mol) of potassium fluoride and 4.05 g (0.225 mol) of water were added thereto. The mixture was reacted for one hour at 70° C. The reaction mixture was cooled, and then 200 ml of water was added thereto. The mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over CaCl2. After filtration, the solvent and low boiling substances were distilled off, and the residue was further distilled under reduced pressure to obtain 11.3 g (yield: 83%) of (E)-1,2-difluoro-1-(4-propylphenyl)ethylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:9][C:6]1[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(C)nc1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
To the 3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine synthesized above (1.3 g, 4.86 mmol) and NBS (1.04 g, 5.83 mmol) in CCl4 (25 mL) was added benzoyl peroxide (0.12 g, 0.49 mmol). The reaction was stirred at 80° C. under N2 for 20 h. The reaction was cooled to room temperature and concentrated. The residue was dissolved in mixture of dichloromethane and hexanes (1:1, 8 mL) and purified by silica gel column chromatography using 1:1 dichloromethane-hexanes to afford 0.74 g (44%) of 6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine as off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][NH:5][CH2:6]2.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=2)[N:12]=1.C(N(C(C)C)CC)(C)C.N>O1CCOCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=3)[N:12]=1)[CH2:6]2
Reactant: CN1C2CCC1CNC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2

Procedure:
A mixture of 8-methyl-3,8-diazabicyclo[3.2.1]octane (3.8 g, 30 mmol), 2-chloro-6-nitroquinoline (6.2 g, 30 mmol), diisopropylethylamine (10.5 ml, 60 mmol) and dioxane (100 ml) was stirred at reflux for 15 h. Aqueous ammonia (50 ml, 1 M) was added followed by extraction with dichloromethane (3×50 ml). Chromatography on silica gel with methanol:dichloromethane:aqueous ammonia (1:9:1%) as solvent gave the title compound as a solid. Yield 3.1 g (35%). Mp 152.1-154.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[OH-:20].[Na+].Cl>COCCOC>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([OH:20])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: Nc1nc(O)nc2nc(-c3ccco3)nn12
Reaction time: 2 h

Procedure:
A stirred suspension of 7-amino-2-(2-furyl)-5-methylsulphonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.4 g) in 1,2-dimethoxyethane (25 ml) was treated with an aqueous solution of 1M sodium hydroxide (25 ml). After 3 hours at room temperature the reaction mixture was acidified with 1M hydrochloric acid (pH 2-3) and stirred for 2 hours. The precipitated yellow solid was collected by filtration and washed with water. Crystallisation from boiling distilled water gave 7-amino-2-(2-furyl)-5-hydroxy-1,2,4-triazolo[1,5-a][1,3,5]triazine (0.47 g) as a pale yellow solid m.p. >300° C.; microanalysis, found: C,44.3; H,2.5; N,38.7%, C8H6N6O2 requires: C,44.0; H,2.8; N,38.5%; NMR: 6.69(dd,1H, furyl-4H), 7.10(d,1H, furyl-3H), 7.90(d,1H, furyl-5H), 8.36(br s, 2H, NH2) and 12.1(br s, 1H,OH); m/e 219 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Si:19]([O:9][CH2:8][CH2:7][N:6]1[C:2]([NH2:1])=[CH:3][CH:4]=[N:5]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Nc1ccnn1CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCn1nccc1N)(c1ccccc1)c1ccccc1
Reaction time: 15 h
Yield: 96.1 %

Procedure:
To a suspension of 2-(5-amino-1H-pyrazol-1-yl)ethanol (2.07 g, 16.0 mmol) and 1H-imidazole (5.43 g, 79.8 mmol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (4.96 mL, 19.1 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (40 mL). The organic layer was washed with 1N HCl (10 mL), water (10 mL) and brine (10 mL), then concentrated to give crude desired product (5.62 g, 96.4% yield), which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24]CC)=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([OH:24])=[O:23])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoate (0.4 g) was dissolved in a mixture of THF (5 mL) and methanol (5 mL). 1 M NaOH (10 mL) was added and the mixture stirred for 3 hours at room temperature followed by 1 hour at 50° C., by which stage a clear solution had formed. Concentrated HCl was added and the precipitate collected as a white solid. The solid was dissolved in ethyl acetate and dried with Na2SO4. Evaporation gave the title compound as a white solid, recrystallised from ethyl acetate/petrol. 13C NMR (250 MHz, DMSO-d6): δ 122.4, 124.1, 125.0, 126.3, 126.5, 127.7, 129.6, 130.4, 131.9, 132.2, 132.5, 133.8, 137.1, 137.9, 138.9, 142.0 and 166.8. MS, m/z: Calcd, 420.99. Found, 421.22 (M).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:23][CH2:24][CH3:25])([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([O:23][CH2:24][CH3:25])([CH3:22])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(OCC)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxy-3-hydroxy-2-methyl propanoic acid ethyl ester (0.358 g; 1 mmole) and triethylsilane (0.32 ml; 2 mmole) were dissolved in dry dichloromethane (4 ml) and cooled to 0° C. whereafter borontrifluoride etherate (0.284 g; 2 mmole) was added. The reaction mixture was then stirred at 0° C. for 2.5 hours and then quenched by addition of saturated sodium hydrogencarbonate (10 ml) and dichloromethane (10 ml). The aqueous layer was extracted three times with diethyl ether. The organic phases were combined and dried over sodium sulfate. Evaporation of the solvent gave 0.349 g (100% yield) of 3-(4-benzyloxyphenyl)-2-ethoxy-2-methyl propanoic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCI
Reactant: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate (1.0 g, 3.17 mmol) is dissolved in dimethylformamide (16 mL). Cesium carbonate (1.03 g, 3.17 mmol) is added, followed by 1-iodohexane (0.47 mL, 3.17 mmol), and the reaction is stirred overnight at room temperature. The reaction is then partitioned between water and ethyl acetate, the aqueous layer is extracted well with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give ethyl 2-[[4-hexyloxybenzenesulfonyl](isobutyl)amino]acetate.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)(Cl)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C.C(O)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC1(c2cc3ccccc3o2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(c3cc4ccccc4o3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-benzhydryl-3-(benzofuran-2-yl)-3-chloroazetidine (458 mg, 1.23 mmol) and 10% palladium on carbon (130 mg) in ethyl acetate (6 mL) and ethanol (6 mL) was stirred at room temperature under hydrogen atmosphere (˜1 atm) for 1 day. An additional amount of 10% palladium on carbon (130 mg) was added as well as triethylamine (171 μL, 1.23 mmol) and hydrogenation was continued under same conditions for 3 days. After removal of hydrogen, the mixture was diluted with dichloromethane (50 mL), filtered through Clarcel® and concentrated. The residue was taken up in dichloromethane (30 mL) and washed with aqueous saturated sodium hydrogencarbonate (30 mL). The aqueous layer was back-washed with dichloromethane (2×30 mL) and all the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (100:0 to 95:5) as eluent. The title compound was obtained as a yellow gum (111 mg, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20](Cl)[N:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>[Pd].CCN(CC)CC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][N:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 6 h

Procedure:
A 50 mL round-bottomed flask was charged with methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-2-chloropyrimidine-4-carboxylate and MeOH (4 mL) and Et3N (0.4 mL). 10% Pd/C (104 mg, 0.25 equiv.) was added under argon. The reaction mixture was stirred for 6 h under 1 atm H2. The catalyst was filtered and the solvent was evaporated to give the crude desired product (150 mg, 110% crude yield) which was used directly in the next step. LC-MS m/z 351 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]O)[CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: OCc1cccnc1
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2cccnc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
A solution of the product from Example 24 (0.3 g, 0.63 mmol), 3-pyridylmethanol (0.061 mL, 0.63 mmol) and triphenylphosphine (0.165 g, 0.63 mmol) in 10 mL of tetrahydrofuran at 0° C. was treated with diethylazodicarboxylate (0.11 g, 0.63 mmol). The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was concentrated, and the residue was taken up in EtOAc and washed with sat. aqueous NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered, and concentrated. The residue was purified by HPLC to give the title compound (0.047 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:20])[CH3:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[C:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[S:14]2)[CH2:10][C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.406 g, 0.961 mmol) in dry DCM (20 mL) was added DMP (0.615 g, 1.45 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated. The residue was diluted with saturated aqueous NaHCO3 solution (20 mL) and 1 M Na2S2O3 aqueous solution (5 mL), and extracted with EtOAc (2×20 mL). The combined extract was dried over Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:4 to 2:3), affording tert-butyl ((3aR,5S,6S,7aR)-5-acetyl-6-(benzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.32 g), which was impure and used in the next step without further purification.
Reaction SMILES: S(=O)(=O)(O)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18]1([CH2:24][C:25](=[O:33])[C:26]([O:28][CH2:29]CCC)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC1C=CC=CC=1C>[C:18]1([CH2:24][C:25](=[O:33])[C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCOC(=O)C(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)C(=O)Cc1ccccc1

Procedure:
Following the procedure of step (iii) of Example 1 but charging 1 g of sulfuric acid into the three-necked flask in lieu of p-toluenesulfonic acid monohydrate, and the whole o-xylene solution containing 95 g (0.43 mole) of butyl phenylpyruvate and sulfuric acid as obtained in step (ii) of Example 8 into the dropping funnel in place of methyl phenylpyruvate, the reaction was carried out in the same manner as in step (iii) of Example 1. The total reaction time was prolonged to 6 hours. The conversion of butyl phenylpyruvate was 97 percent and the selectivity toward butyl α-acetamidocinnamate 85 mole percent (yield of butyl α-acetamidocinnamate: 93 g). The reaction mixture was washed with water in the same manner as in step (iii) of Example 1 to give about 650 ml of an o-xylene solution containing butyl α-acetamidocinnamate in a concentration of about 0.55 mole per liter.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(N)cc1C#N

Procedure:
The thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib were prepared following scheme 1: N-Boc Protection of 2-amino-5-nitrobenzonitrile using di-tert-butyl dicarbonate in a suitable solvent, such as dichloromethane, in presence of suitable bases such as triethylamine and 4-(dimethylamino)pyridine and preferably at room temperature, provides tert-butyl (2-cyano-4-nitrophenyl)carbamate I in high yield. Reduction of the nitro intermediate I, for example by treatment with ammonium formate and a catalytic amount of 10% palladium charcoal preferably in ethanol under microwave irradiation for preferably 30 min at 600 W, provides tert-butyl 4-amino-2-cyanophenylcarbamate II in high yield. Treatment of intermediate II by a solution of bromine in dichloromethane in a suitable solvent, such as acetic acid, preferably at room temperature provides tert-butyl 4-amino-3-bromo-2-cyanophenylcarbamate III in a quantitative yield. Intermediate III is reacted with Appel's salt (4,5-dichloro-1,2,3-dithiazolium chloride) (Appel, R. et al., Chem. Ber., 1985, 118, 1632) preferably in dichloromethane at room temperature to afford (Z)-tert-butyl-3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-cyanophenylcarbamate IV. N-Boc deprotection of intermediate IV using di-tert-butyl dicarbonate in a suitable solvent, such acetic acid, preferably under microwave irradiation at 118° C. provides (Z)-6-amino-2-bromo-3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitrile V in a quantitative yield. Cyclization of intermediate V may be accomplished by treatment with copper iodide in a suitable solvent, such as pyridine, preferably under microwave irradiation at 400 W at 130° C. for 20 min to obtain 6-aminobenzo[d]thiazole-2,7-dicarbonitrile VI in good yield (Besson, T. et al., J. Chem. Soc., Perkin Trans. 1, 1998, 3925). Treatment of intermediate VI in a suitable solvent, such as dimethylformamide dimethylacetal, preferably under microwave irradiation at 70° C. (600 W) gives (E)-N′-(2,7-dicyanobenzo[d]thiazol-6-yl)-N,N-dimethylformimidamide VII in good yield. Cyclization of intermediate VII in thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib may be accomplished by a Dimroth rearrangement using the appropriate aniline or primary amine R3NH2 (preferably 1.5 equivalent) in a suitable solvent, such acetic acid and preferably under microwave irradiation at 118° C. (600 W) (Foucourt, A. et al., Tetrahedron, 2010, 66, 4495).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([N:16]=[C:17]=[S:18])(=[O:15])[O:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[C:7]2[N:8]=[C:17]([NH:16][C:11](=[O:15])[O:12][CH2:13][CH3:14])[S:18][C:2]=2[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1nc2c(Cl)nc(C)nc2s1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a mixture of 4,6-dichloro-2-methylpyrimidin-5-amine (1 g, 5.62 mmol) and O-ethyl carbonisothiocyanatidate (0.66 mL, 5.62 mmol) was added toluene (2 mL) to wet the solids completely. The mixture was placed on 100° C. oil bath for 1.5 hours, at which time, the mixture had seized to give a solid mass. The solids were cooled to ambient temperature and triturated with ether, then the resulting solids were collected by filtration to give ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (1.08 g, 3.96 mmol, 70.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (br. s., 1H) 4.30 (q, J=7.19 Hz, 2H) 2.69 (s, 3H) 1.30 (t, J=7.15 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C@H:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[C:18]([OH:19])=[N:17][C:5]2=[N:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.0 equiv) in refluxing anhydrous THF (5 volume equivalents) was added carbonyldiimidazole (CDI). Successive portions of CDI were added until the starting material was consumed (approx. 3.6 equiv total) as judged by TLC (50% EtOAc/Hexanes). After complete reaction, the mixture was cooled to room temperature and quenched by the careful addition of water until gas evolution had ceased. The mixture was diluted with 25 volume equivalents of EtOAc and washed with 3×7.5 volume equivalents of water and 1×7.5 volume equivalents of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (66%) as a white solid. LCMS m/z (APCI)=319.0, 321.0 (M+H).