Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([F:13])[F:12].[CH3:14][S:15]([O-:17])=[O:16].[Na+].CNCCNC>CS(C)=O>[F:12][C:5]1([F:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: CS(=O)[O-]
Reactant: O=C1Nc2ccc(Br)cc2C1(F)F
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)C(F)(F)C(=O)N2
Temperature: 120 °C
Reaction time: 14 h
Yield: 58.7 %

Procedure:
To a stirred solution of 5-bromo-3,3-difluoroindolin-2-one (5.0 g, 20 mmol) in DMSO (50 mL), sodium methanesulfinate (3.0 g, 30 mmol), copper(I) trifluoromethane-sulfonate benzene complex (1.52 g, 3.022 mmol) and N,N′-dimethylethylenediamine (0.33 mL, 3.022 mmol) were added and stirred at 120° C. for 14 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and resulting residue was purified by flash column chromatography to give the title product (2.9 g, 58.2%); MS: 247.9 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]([CH2:23][CH2:24][CH3:25])[CH3:22]>>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:21]([CH2:23][CH2:24][CH3:25])[CH3:22])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCCC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
95% NaH (2.15 g, 89.0 mmol) and 5-benzyloxyindole (7) (10.0 g, 44.8 mmol) were added to a schlenk vessel, and the system was evacuated and refilled with nitrogen three times before being cooled to −78° C. DMF (100 mL) was added and the vessel was then cooled with an ice/water bath and kept stirring for another 30 min. 2-Bromopentane (2) (10.2 g, 67.2 mmol) was added dropwise and the resulting mixture was warmed to room temperature slowly and kept stirring overnight. The solvent was removed in vacuo. Toluene (200 mL) was added and the mixture was washed with water (150 mL) and dried with Na2SO4. After solvent was removed in vacuo, the resulting oil was purified using silica column chromatography (1:1 chloroform/hexanes) to give 5-(benzyloxy)-1-(pentan-2-yl)-1H-indole (8) (3.90 g, 30%) as an oil. 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J=7.5, 2H), 7.41 (t, J=8.0 Hz, 2H), 7.35-7.20 (m, 2H), 7.18 (dd, J=8.0, 2.0, 2H), 6.97 (dd, J=9.0, 2.5, 1H), 6.41 (d, J=3.0, 1H), 5.13 (s, 2H), 4.46 (m, 1H), 1.87 (m, 2H), 1.55 (d, J=7.5, 3H), 1.26 (m, 2H), 0.90 (t, J=7.5, 3H). See also Luo, J.; Hart, H.; J. Org. Chem., 52(22): 4833 (1987).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=12)=[O:33]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([C:32]([C:28]5[S:27][CH:31]=[CH:30][CH:29]=5)=[O:33])[N:35]=[CH:36][N:37]4[CH:41]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cccs3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccs5)c4s3)[C@H](C)[C@H]12
Yield: 79.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiophen-2-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (815 mg) was prepared in the same manner as in step a) of Example 1, except that 640 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 923 mg of 7-(thiophen-2-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH2:25][CH2:26][C:27]=23)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1CCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-benzofuran-4-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=474.4.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C>O>[CH2:17]([NH:24][C:8]([NH:7][N:6]=[CH:5][C:4]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=1[Cl:2])=[NH:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccccc1
Agent: I
Solvent: O
Solvent: CCO
Product: N=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 93.6 g of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 51.2 of benzylamine in 400 ml. of absolute ethanol is heated at reflux for 6 hours and then diluted while hot with 400 ml. of water, causing the separation of an oil. On standing, the oil crystallizes and the nearly colorless crystals are recovered by filtration. Recrystallization from aqueous ethanol gives the desired product as pale yellow crystals, m.p. 134°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:32]([NH:31][C:22]3[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=3[F:20])=[O:33])=[C:3]([F:19])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1F
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c1[N+](=O)[O-]
Yield: 85 %

Procedure:
Using Method F2 with 4-(4-amino-3-fluorophenoxy)-3-nitropyridin-2-amine and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound was obtained (yield 85%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)[N:21]([CH:33]([CH3:35])[CH3:34])[CH:20]=2)=[CH:15][C:14]=1[F:36])#[N:12].C(OP(=S)(OCC)[SH:41])C>COOOC>[F:36][C:14]1[CH:15]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)[N:21]([CH:33]([CH3:34])[CH3:35])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[C:11]([NH2:12])=[S:41]
Reactant: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Reactant: CCOP(=S)(S)OCC
Agent: COOOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)n1cc(-c2ccc(C(N)=S)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Yield: 90.4 %

Procedure:
Add a drop of di-isopropylethylamine and a drop of water to N-[3-(4-Cyano-3-fluoro-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (100 mg, 0.27 mmol) in 10 mL of dimethoxy ether. Heat to reflux, followed by addition of dithiophosphoric acid O,O′-diethyl ester (151 mg, 0.81 mmol), and reflux in a sealed tube overnight. Evaporate the solvent. Purification of the residue using silica gel chromatography eluted with EtOAc and hexane gradient to give 99 mg (91%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: O=C1CCC(=O)C1
Product: Cc1ccccc1[C@@H]1C(O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]21

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(2-methylphenyl)octahydropyrano[3,4-c]pyrrole and cyclopentane-1,3-dione according to the procedures used for example 3. MS: (MH)+554.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([C@H:6]([CH3:8])[OH:7])[NH2:5].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CO>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([C@H:6]([CH3:8])[OH:7])[NH:5][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](N)[C@H](C)O
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](NC(=O)c1ccccc1)[C@H](C)O
Temperature: 12 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A crude D-threonine methyl ester (39.49 g) was dissolved in 300 mL of methanol and than transferred to the 1 L 3-neck round bottom flask equipped with a thermocouple, magnetic stirrer and cooling ice bath. A solution was chilled to 12° C., and a total of 64.1 g (0.63 mol, 3 eq.) was added to the flask and then cooled to −10° C. A total of 30.9 g (0.21 mol) of benzoyl chloride was added to the solution and resulting mixture stirred at 0° C. for 1 hour. After this period of time the solvent was removed on rotovap to yield a viscous semi-solid. A total of 300 mL of cold water was added to the residue and organic material was extracted with ethyl acetate (2×300 mL). The organic phase was separated, washed with brine (200 mL) and dried over sodium sulfate. The solvent was removed on rotovap to yield 52.02 g (104%) of a clear yellow oil with Rf=0.39 in EtOAc/hexane=6:4). Obtained oil was crystallized from 200 mL of ether to give a white solid, which was filtered off, washed with hexane (2×100 mL) and dried under suction. An additional drying in a vacuum desiccator yielded 42.35 g (84.7% yield in 2 steps).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH2:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](OCC)=[O:27])[CH2:22][CH2:21]1)[CH3:19]>CCCCCC>[O:27]=[C:26]([C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:18][CH3:19])[CH2:21][CH2:22]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)[C@H]1CC[C@H](CC)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](C(=O)CP(=O)(OC)OC)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, 47 ml. of a 1.25M solution of n-butyllithium in n-hexane were added dropwise to a solution of 7.64 g. of dimethyl methylphosphonate in 120 ml. of tetrahydrofuran at -70° C. After one hour of stirring at -70° C., a solution of 5.63 g. of ethyl trans-4-ethylcyclohexanecarboxylate [c.f. N. L. Allinger and L. A. Freiberg, J. Org. Chem., 31, 894, (1966)] in 30 ml. of tetrahydrofuran was added dropwise at -70° C., and the mixture was stirred at the same temperature for one hour and further stirred at -5° C., for one hour. The reaction mixture was then acidified with acetic acid and concentration under reduced pressure. The residue was diluted with diethyl ether, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation to give 5.0 g. of the title compound having the following physical characteristics:-
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8]C)=O)[CH2:3][CH2:2]1.C1(NN)C=CC=CC=1.[CH:19]1([C:22]2[N:26]([CH:27](C)C)[N:25]=[CH:24][C:23]=2C=O)[CH2:21][CH2:20]1>>[CH:1]1([C:4]2[N:25]([C:24]3[CH:20]=[CH:21][CH:19]=[CH:22][CH:23]=3)[N:26]=[CH:27][C:5]=2[CH:6]=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: COC(=O)CC(=O)C1CC1
Solvent: NNc1ccccc1
Product: O=Cc1cnn(-c2ccccc2)c1C1CC1

Procedure:
5-Cyclopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from methyl 3-cyclopropyl-3-oxo-propionate and phenyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:13])([F:12])[CH:10]=[CH2:11].[SH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].COC(OC)(C1C=CC=CC=1)C(C1C=CC=CC=1)=O>[OH-].[Na+]>[F:8][C:9]([F:13])([F:12])[CH2:10][CH2:11][S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCS
Reactant: C=CC(F)(F)F
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Reaction time: 4 h

Procedure:
A 250 mL three-neck round bottomed flask was charged with toluene (81 mL) and cooled to <−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (10.28 g, 107.0 mmol) was bubbled into the solvent and the ice bath was removed. 3-Mercaptopropionic acid (9.200 g, 86.70 mmol) and 2,2-dimethoxy-2-phenylacetophenone (1.070 g, 4.170 mmol) was added and the long wave light (366 nm, 4 watt UVP lamp) was turned on (Starting temperature: −24° C.). The reaction reached a temperature of 27.5° C. due to heat from the lamp. The reaction was stirred with the black light on for 4 hours. After 4 hours the black light was turned off and the reaction concentrated by rotary evaporation (41° C., 6 mm Hg) giving a pale yellow oil (18.09 g, 51:1 linear:branched isomer, 90 wt % linear isomer by GC internal standard assay, 16.26 g active, 93%). The crude material was dissolved in 10% sodium hydroxide w/w (37.35 g) and was washed with toluene (30 mL) to remove non-polar impurities. The aqueous layer was acidified to pH˜2-3 with hydrochloric acid (2 N, 47.81 g) and was extracted with toluene (50 mL). The organic layer was washed with water (40 mL) and dried over magnesium sulfate, filtered, and concentrated by rotary evaporation giving a pale yellow oil (14.15 g, 34:1 linear:branched isomer, 94 wt % linear isomer by GC internal standard assay, 13.26 g active, 76%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:33][C:14]=1[C:15]([NH:17][C:18]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:41]1[CH2:40][CH2:39][CH:38]([O:37][C:34]2[CH:35]=[CH:36][C:13]([OH:12])=[C:14]([CH:33]=2)[C:15]([NH:17][C:18]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:16])[CH2:43][CH2:42]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OC2CCNCC2)ccc1O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.30 mL) and acetic anhydride (6.7 μL) were sequentially added to a methylene chloride (1 mL) suspension of 2-(2-hydroxy-5-(piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid hydrochloride (0.030 g), followed by stirring at room temperature for 1 hour. Pyridine (0.20 mL) and acetic anhydride (5.4 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (0.5 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the residue, followed by stirring at room temperature for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid (5 mL) and ethyl acetate were added. The organic layer was separated, washed with 1 mol/L hydrochloric acid, water, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dioxane (0.5 mL), methanol (0.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.32 mL) were added to the obtained residue, followed by stirring at 70° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 3 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.022 g of 2-(5-(1-acetylpiperidin-4-yloxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNS(=O)(=O)c1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNS(=O)(=O)c2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-amino-ethyl)-benzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCC2(CCCO2)CC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1nnc(NC2CCC3(CCCO3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (0.29 g) and 1-oxaspiro[4.5]decan-8-one (0.64 g) in acetic acid was added sodium cyanoborohydride (1.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 34%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:4].C(O)(C)(C)C.CC(C)([O-])C.[K+].Br[CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:3]([OH:4])([CH:2]([CH3:1])[CH3:14])[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[O:9]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(C)C(=O)c1ccccc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)C(C)C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
A stirred mixture of 2-(2-methylpropanoyl)benzoic acid (44.27 g) and tert-butanol (300 ml) was treated portionwise with potassium tert-butoxide (28.14 g) over 5 minutes at room temperature and the reaction mixture stirred for a further 10 minutes and then treated dropwise over 10 minutes with a solution of diethyl bromomalonate (55.1 g) in ethanol (200 ml). The stirred mixture was refluxed for 18 hours and then evaporated to dryness. The residue was treated with diethyl ether (400 ml) and washed with water (400 ml). The aqueous phase was re-extracted with diethyl ether (200 ml) and the combined ethereal extracts washed with water (200 ml), saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and evaporated to give crude 3,3-bis(ethoxycarbonyl)-4-hydroxy-4-isopropyl-3,4-dihydroisocoumarin (76 g) as an amber oil.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1C=C(Cl)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1C=C(c2cccnc2)CCC1
Temperature: 95 °C
Reaction time: 7 h

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-DCM complex (313 mg, 0.383 mmol) was added to a stirred mixture of 8a (500 mg, 3.83 mmol), pyridin-3-yl-boronic acid (565 mg, 4.60 mmol) and sodium carbonate (2.87 mL of a 2M aq. solution, 5.74 mmol) in dioxane (14.0 mL) and water (2.00 mL). The resulting mixture was degassed and heated to 95° C. After 7 h, the reaction mixture was cooled to rt, diluted with EtOAc, filtered through a short column of Celite®, eluting copiously with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (0-90% EtOAc/hexanes as eluent) to afford the title compound, 8b. m/z (ES) 174 (MH)+
Reaction SMILES: Cl.[OH:2][NH2:3].[OH-].[K+].[Cl:6][C:7]1[C:11]([C:12](Cl)=[O:13])=[C:10]([Cl:15])[N:9]([CH3:16])[N:8]=1.Cl>O.O1CCCC1>[Cl:6][C:7]1[C:11]([C:12]([NH:3][OH:2])=[O:13])=[C:10]([Cl:15])[N:9]([CH3:16])[N:8]=1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(=O)NO)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
In a solution of hydroxyamine hydrochloride (106.9 g, 1.538 mol) in water (200 ml), a solution of 85% potassium hydroxide (101.5 g, 1.538 mol) in water (200 ml) was added at 5 to 15° C., and stirred at room temperature for 5 minutes. Then, a solution of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride (100.0 g, 0.5128 mol) in tetrahydrofuran (170 ml) was added dropwise at 3 to 8° C. over 2 hours. After stirring at 5° C. for 0.5 hour, the mixture was adjusted to pH 3-4 by adding 35% hydrochloric acid. Precipitated solid was filtered off, washed with water, and dried to obtain the aimed product (94.9 g). Melting point 200-202° C. (decomposition). Proton nuclear magnetic resonance chemical shift values δ (ppm) (in dimethylsulfoxide-d6) 3.79 (s, 3H), 9.24 (brs, 1H), 10.83 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[CH:6]3[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:24])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1
Reactant: CC(F)(F)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
To a mixture of 2-chloro-5-(2,2-difluoropropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (466 mg, 1.46 mmol) and iodomethane (0.365 ml, 5.84 mmol) in DMSO (8 ml) at 0° C. was added sodium 2-methylpropan-2-olate (211 mg, 2.19 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude solid. The solid was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 2:1) to afford 2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (264 mg, 0.793 mmol, 54% yield) as a white solid. MS [M+H] found 333.