Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(O)=O.N>O>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:12]1
Reactant: CC1CCCNC1
Reactant: O=Cc1cccc(O)c1
Agent: N
Solvent: O
Solvent: O=CO
Product: CC1CCCN(Cc2cccc(O)c2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
24.4 g (0.2 mol) of 3-hydroxybenzaldehyde are mixed with 40 ml (about 0.4 mol) of 3-methylpiperidine and 20 ml (about 0.52 mol) of 100% formic acid with cooling and then stirred for 2 hours at 120° C. When the reaction mixture has cooled to room temperature, it is poured into water and rendered alkaline with ammonia, and the precipitated solid is filtered off and recrystallised from ethanol.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:10]1[CH:19]=[C:18]([O:20]CC2C=CC(OC)=CC=2)[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=1.O>CN1CCCC1=O>[OH:20][C:18]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:6]2[CH:7]=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:19]=1
Reactant: CC(C)c1cc[nH]n1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of compound 233b (350 mg, 1 eq.) and compound 221b (480 mg, 6 eq.) in N-methylpyrrolidone (5 mL) was heated at 200° C. for 30 min. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (EtOAc/DCM). Recrystallisation in diethylether gave compound 236b as a white solid in 49% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 1.35 (s, 3H), 1.36 (s, 3H), 2.85 (s, 3H), 3.97 (s, 3H), 6.40 (d, J=2.65 Hz, 2H), 7.01 (d, J=9.00 Hz, 1H), 8.00 (brs, 1H), 8.23 (d, J=9.00 Hz, 1H), 9.81 (brs, 1H); MS (ESI, EI+): m/z=298 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(C)c2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(=O)O)cc1)c1ccccc1OCc1ccccc1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
Methyl 4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoate (0.5 g, 1.4 mmol) was dissolved in THF (5 ml) and methanol (5 ml). The solution was treated with sodium hydroxide (1N, 6 ml) and the reaction heated at 60° C. for 3 hours. The solvent was removed at reduced pressure and the reaction mixture diluted with water and extracted with ethyl acetate. The aqueous phase was acidified (pH1) with concentrated HCl and extracted with ethyl acetate (3×). The organic phases were combined, dried (MgSO4) and evaporated to give the title compound as a white solid (0.33 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([B:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1.O>[CH3:39][N:40]([CH3:44])[C:41]([N:15]1[C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]([C:24]3[CH:29]=[CH:28][C:27]([B:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]4)=[CH:26][CH:25]=3)=[N:10][C:11]=2[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16]1)=[O:42]
Reactant: CN(C)C(=O)Cl
Reactant: CC1(C)OB(c2ccc(-c3nc4c(-c5ccccc5)n[nH]c4c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)n1nc(-c2ccccc2)c2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)n(-c3ccc(Cl)cc3)c(=O)c21
Temperature: 80 °C

Procedure:
To a solution of 6-(4-chloro-phenyl)-3-phenyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (100.0 mg, 0.191 mmol) in anhydrous pyridine (1.0 mL) is added dimethylcarbamyl chloride (87.4 μL, 0.953 mmol). The reaction mixture is heated at 80° C. overnight before removal of the solvent. The residue is taken in water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with brine, concentrated, and purified by silica gel chromatography to provide 6-(4-chloro-phenyl)-7-oxo-3-phenyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-6,7-dihydro-pyrazolo[4,3-d]pyrimidine-1-carboxylic acid dimethylamide as a white solid product; HPLC-MS calculated for C32H31BClN5O4 (M+H+) 596.2, found 596.2.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:10]=1[CH2:11][OH:12].[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=1)[C:25]#[N:26])#[CH:19]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[F:8][C:9]1[CH:16]=[CH:15][C:14]([C:19]#[C:18][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=2)[C:25]#[N:26])=[CH:13][C:10]=1[CH2:11][OH:12]
Reactant: C#Cc1cncc(C#N)c1
Reactant: OCc1cc(I)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cncc(C#Cc2ccc(F)c(CO)c2)c1
Temperature: 60 °C
Yield: 61.6 %

Procedure:
Dissolve zinc (II) bromide (374 mg, 14.3 mmol) in tetrahydrofuran (30 mL) and treat with triethylamine (7.96 mL, 57.1 mmol). After 5 min add 2-fluoro -5-iodobenzyl alcohol, (prepared as described in PREPARATION 33), (3.00 g, 11.9 mmol), 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (1.83 g, 14.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (688 mg, 0.595 mmol) to the reddish solution. Heat to 60° C. for 2 h, cool to room temperature, and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a yellow crystalline solid (1.85 g, 62%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1OCCCBr
Temperature: 20 °C

Procedure:
254.5 g of potassium carbonate and 654 cm3 of 1,3-dibromopropane are added to a solution of 153 g of methyl (2-hydroxyphenyl)acetate in 1400 cm3 of acetonitrile. The suspension obtained is refluxed for 20 hours, cooled to 20° C. and then filtered The filtrate is concentrated to dryness at 50° C. under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 8.8 cm, height 43 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 300 cm3. Fractions 18 to 53 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 130.6 g of methyl 2-(3-bromopropoxy)phenylacetate are obtained in the form of an orange-coloured oil.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2cc(C=O)c(C)o2)cn1
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 82%) as a yellow crystal.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:12]=[C:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)(=[O:3])C.C1(S(OC2C=CC(SCC#C)=CC=2)(=O)=[O:30])C=CC=CC=1.Cl[O-].[Na+].Cl>O1CCOCC1>[C:17]1([S:14]([O:13][C:11]2[CH:10]=[CH:9][C:6]3[S:7][CH:8]=[C:4]([C:1]([OH:30])=[O:3])[C:5]=3[CH:12]=2)(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Temperature: 11 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
The compound (9) (6.65 g, 20 mmol) prepared in above (2) was dissolved in dioxane (50 ml), and 10% sodium hypochlorite (46.2 ml) was added over 20 minutes with stirring while maintaining the temperature at 10-12° C. After 7 hours, the reaction mixture was diluted with ice-water (80 ml) and acidified with conc. hydrochloric acid (5.2 ml). The deposited crystals were filtered, washed with water, dried to provide 5.84 g of crude crystals. The 5.84 g of the crude crystals were recrystallized from methanol (66 ml) and water (16 ml) to provide 5.51 g of the title compound (6). Yield: 82.4%. mp 203-204° C.
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]3C(OC(=O)[C:11]=3[CH:10]=2)=O)=[O:8])=[CH:5][C:4]2C(OC(=O)[C:3]=2[CH:2]=1)=O.C(O)C>CN1CCCC1=O>[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CCO
Solvent: CN1CCCC1=O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
32.21 Gram of 3,3',4,4'-benzophenonetetracarboxylic dianhydride in 69.1 g of N-methyl-2-pyrrolidone was heated to 80° C., and 9.21 g of ethanol was added and reacted at 100° C. for 2 hr to form a solution of benzophenone-tetracarboxylic ester. To this solution was added 20.01 g of 4,4'-diaminodiphenyl ether and reacted at 80° C. for 3 hr. The thus obtained solution of poly(amic acid) ester oligomer was found to have a viscosity of 2 poises at 25° C.
Reaction SMILES: [Li+].CCC[CH2-].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CCCCCC.O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCN1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N2CCCC2=O)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
15.75 cm3 of a 1.6M solution of N-butyllithium in hexane is added to 2.22 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran and cooled to -25° C., the temperature being maintained between -25° C. and -20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 g of 3-methoxybenzene sulphonyl chloride [J. Chem. Soc. P.T.2., 579 (1982)]in 40 cm3 of tetrahydrofuran is poured drop by drop into the mixture, operating between -25° C. and -20° C. After agitation for 30 minutes at -25° C., the whole is allowed to return to ambient temperature. The solvent is evaporated under reduced pressure; the residue is taken up in water, filtered and crystallized from isopropanol. 3.5 g of expected product is obtained
Reaction SMILES: Cl.[Cl:2][C:3]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:20]([C:21]2[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=2[F:31])[C:19]2[C:18](=[O:32])[CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][C:14]=2[NH:13][C:12]=1[CH3:40])=[O:10].CO.Cl.[H][H]>[Pd].O>[Cl:2][C:3]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:20]([C:21]2[C:22]([F:31])=[C:23]([F:30])[C:24]([F:29])=[C:25]([F:28])[C:26]=2[F:27])[C:19]2[C:18](=[O:32])[CH2:17][NH:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH3:40])=[O:10]
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCCOc2cccc(Cl)c2Cl)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CN(Cc3ccccc3)CC2=O)N1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)OCCOc2cccc(Cl)c2Cl)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CNCC2=O)N1
Reaction time: 72 h

Procedure:
The hydrochloride from above (10 g), 500 ml of methanol, 25 ml of water, 5 ml of concentrated hydrochloric acid and 0.5 g of 10% palladium on carbon were shaken with hydrogen (45 psig initial pressure) for 4 hours. The catalyst was separated and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and shaken with dilute sodium hydroxide solution. The ethyl acetate solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in methanol and saturated with hydrogen chloride. The solution was evaporated to dryness. The residue crystallized on standing with ethyl acetate for 3 days. The solid was treated with boiling ethyl acetate and filtered to obtain the title compound as the hydrochloride, m.p. 228°-231° C. dec.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)cc1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
N-bromosuccinimide (NBS) (0.178 g, 1 mmol), in one lot, was added to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327 g, 1 mmol, Example 206B) in chloroform (12 ml). The reaction mixture was stirred for 10 min then diluted with dichloromethane (50 ml). This was washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (350 mg, 86% yield, m.p. 153-156° C.).
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([S:12]([C:14]1[S:15][C@@H:16]2[C@H:23]([C:24]([OH:27])([CH3:26])[CH3:25])[C:22](=[O:28])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])=[O:13])[CH3:11].[Li+]>CN(C=O)C.CCOC(C)=O>[CH2:10]([S:12]([C:14]1[S:15][C@@H:16]2[C@H:23]([C:24]([OH:27])([CH3:25])[CH3:26])[C:22](=[O:28])[N:17]2[C:18]=1[C:19]([O:21][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:20])=[O:13])[CH3:11]
Reactant: CC(C)(C)C(=O)OCBr
Reactant: CCS(=O)C1=C(C(=O)[O-])N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pivaloyloxymethyl bromide (29.3 mg, 0.15 mmol) is added to a suspension of lithium (5R,6R)-2-ethylsulfinyl-6-(2-hydroxy-2-propyl)-pen-2-em-3-carboxylate (29.5 mg, 0.1 mmol) in anhydrous DMF (0.5 ml). The resulting mixture is stirred under a N2 atmosphere at room temperature for 4 hours. The mixture is diluted with EtOAc, washed repeatedly with water, dried with MgSO4, filtered, and evaporated under vacuum to afford a residue of the title compound. This material is purified by preparative TLC.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16]I)[CH2:12][CH2:13][CH3:14].O>C1COCC1>[CH2:11]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(CI)CCCC
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(CCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (5.71 g, 67.9 mmol) in dry THF (60 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (26.0 mL, 2.5 M, 65.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of 2-butyloctyliodide (16.0 g, 54.0 mmol) in dry THF (30 mL) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature slowly and stirred at room temperature for 38 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ether. The organic layer was washed with water and brine, dried over MgSO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (4.95 g, 36.3%).
Reaction SMILES: [NH2:1][C:2]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1.[CH2:21]([O:28][C:29]([N:31]([CH2:33][C:34](O)=[O:35])[CH3:32])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([N:31]([CH2:33][C:34]([NH:1][C:2]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1)=[O:35])[CH3:32])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C1(N)CCc2cc(OC)c(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NC(=O)CN(C)C(=O)OCc2ccccc2)CCc2cc(OC)c(OC)cc2C1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a solution of ethyl 2-amino-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate (430 mg, 1.5 mmol), N-benzyloxycarbonylsarcosine (357 mg, 1.6 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride in dichloromethane (5 ml) was added triethylamine (160 mg, 1.6 mmol) under stirring at 0° C. After stirring for 2 hr, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 1N hydrochloric acid, sat. sodium bicarbonate, sat. sodium chloride, dried, and evaporated. The residue was purified with silica gel column chromatography [eluent; hexane-ethyl acetate (1:1 to 1:2)] to give the titled compound (550 mg, 74%).
Reaction SMILES: OS(O)(=O)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1.[CH3:18]O>>[CH3:18][O:16][C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][N:7]=1)=[O:17]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 61 %

Procedure:
Concentrated H2SO4 (1 mL) was added to a solution of indazole-3-carboxylic acid (2.0 g, 12 mmol) in MeOH (40 mL). The reaction mixture was heated at reflux for 3 h, the MeOH was removed under reduced pressure and the residue was partitioned between diethyl ether (100 mL) and H2O (100 mL). Saturated sodium hydrogen carbonate solution was added (100 mL) and the diethyl ether layer was separated. The aqueous layer was further extracted with 2×200 mL of diethyl ether. The combined extracts were dried (MgSO4) and solvent removed under reduced pressure and the solid was recrystallised from cyclohexane/ethyl acetate to afford the title compound (1.29 g, 61%). Mp 158-159° C., lit 168-169° C. v.Auwers, Dereser Chem. Ber. 1919, 52, 1343. 1H-NMR (300 MHz, CDCl3) ppm 4.09 (s, 3H), 7.33-7.38 (m, 1H), 7.46-7.52 (m, 1H), 7.71-7.74 (m, 1H), 8.23-8.26 (m, 1H), 12.03 (s, 1H). MS(EI) m/z 176 [M+].
Reaction SMILES: [CH3:1][S:2][CH:3]([S:16][CH3:17])[C:4]1([O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]([OH:9])[C@H:6]1[OH:7])[OH:5].[CH2:18](O)C1OC(=O)C(O)C(O)C1O.CSC([Li])SC>>[S:2]1[CH2:1][CH2:18][CH2:17][S:16][CH:3]1[C:4]1([O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]([OH:9])[C@H:6]1[OH:7])[OH:5]
Reactant: CSC(SC)C1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C1OC(CO)C(O)C(O)C1O
Agent: [Li]C(SC)SC
Product: OC[C@H]1OC(O)(C2SCCCS2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Process 1", i.e. a process to produce, for example, 1-C-[bis(methylthio)methyl]-D-glucopyranose derivative (2") from D-glucono-δ-lactone derivative (1"), is conducted by allowing the compound (1") to react with bis(methylthio)methyllithium, or a process to produce 1-C-(1,3-dithian-2-yl)-D-glucopyranose (2"), is conducted by allowing the compound (1") to react with 2-lithio-1,3-dithiane. In this reaction, usually 1 to 5 mole equivalents, preferably 2-2.5 mole equivalents, of bis(methylthio)methyllithium or 2-lithio-1,3-dithiane for D-glucono-δ-lactone derivative (1") is used. This reaction is conducted in an appropriate solvent which is inactive to this reaction, such as tetrahydrofuran, 1,4-dioxane, ethyl ether, and hexane, which are used separately or in combination, preferably in an atmosphere of an inert gas such as nitrogen and argon. Reaction temperature is usually -20° C.--78° C., preferably -50° C.--78° C. in the initial stage of the reaction and -20° C.--40° C. in the later stage. Reaction time is appropriately about 1-8 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([CH3:12])=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][N:16]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[S:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[C:4]([F:13])[C:5]=3[CH3:12])[NH:9][C:8]=2[CH3:11])=[N:16]1
Reactant: Clc1nsc2ccccc12
Reactant: Cc1cc2c(C)c(F)cc(Cl)c2[nH]1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1[nH]c2c(Cl)cc(F)c(C)c2c1-c1nsc2ccccc12
Reaction time: 1 h

Procedure:
A solution of the product from step b) (200 mg) and 3-chloro-1,2-benzisothiazole (171 mg) in NMP (2 ml) and 4M hydrogen chloride in dioxan (0.2 ml) was stirred at 140° C. overnight and then at 150° C. for 1 hour, and evaporated. The residue was taken up in ethyl acetate, washed with brine (3×), dried (MgSO4) and evaporated. The residue was purified by silica chromatography using 20% acetone in isohexane as eluent to give the title compound (219 mg).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH:2]=[CH:16]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=c1cccn[nH]1
Product: O=C(O)c1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
50 g of 4-acetylbenzoic acid are converted into the pyridazinone in accordance with GWP 1.