Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C@@H:3]([SH:19])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7].[C:20](=[S:22])=[S:21].C(O[C@H:27]1[NH:30][C:29](=[O:31])[C@@H:28]1[C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH3:33])(=O)C>CO.C(OCC)(=O)C.C(O)(=O)C>[Si:35]([O:34][C@@H:32]([C@@H:28]1[C@@H:27]([S:21][C:20]([S:19][C@H:3]([CH3:2])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[S:22])[NH:30][C:29]1=[O:31])[CH3:33])([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36]
Reactant: S=C=S
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C[C@@H](S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
To a solution of sodium (518 mg, 22.5 mmole) in methanol (100 ml) was added at -10° C. (R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethanethiol (6.61 g, 23.1 mmole). The mixture was stirred for 5 minutes, and then carbon disulphide (1.76 g, 23.1 mmole) was added and stirring was continued for a further 10 minutes. (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one (6.46 g, 22.5 mmole) was then added at the same temperature, after which the bath temperature was raised to 0° C. over about 1 hour. About 300 mg of acetic acid was then added, and the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. After the solution had been dried, the solvent was distilled off under reduced pressure and the residue was purified through column chromatography (200 g of silica gel), eluted with a 10% v/v solution of ethyl acetate in benzene, affording the desired compound (10.8 g, 84%) in the form of a yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10](O)=[O:11]>O1CCOCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([Cl:3])=[O:11]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride 3.7 mL, (50 mmol) was added drop wise, at room temperature, to a stirred solution of 3-methoxy-4-nitro-benzoic acid (1.0 g, 5.07 mmol) in 15 mL of dioxane under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to stir at room temperature for 1 hr. The reaction flask was then fitted with a distillation head, and excess thionyl chloride and about ½ of the solvent was removed by distillation in a 120° C. oil bath. The remaining solvent was removed by rotary evaporation, and the residue was taken up in 20 mL toluene and again about 1 of the solvent was removed by distillation. The remaining solution was then cooled to 0° C., and the white solid which precipitated, was collected by suction filtration, and rinsed with 1-1 Et2O-hexane. 1H-NMR (400 MHz, CDCl3) δ7.87 (d, J=7.83 Hz, 1H), 7.82 (d, J=7.83 Hz, 1H), 7.77 (s, 1H), 4.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>O1CCOCC1>[CH3:33][N:34]([CH3:38])[C:35]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea (0.8 mmol), prepared as described in general procedure (G), steps 1-3, and 1.2 equivalents of DIPEA in 10 mL dioxane was added dimethylcarbamoyl chloride (1.2 equivalents) in 1 ml dioxane. The reaction was stirred overnight at room temperature, concentrated in vacuo and purified by flash chromtography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].Br[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1>C1COCC1.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[S:13]1[CH:14]=[CH:15][C:11]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:12]1
Reactant: Cc1ccc(Br)cc1
Reactant: Brc1ccsc1
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-c2ccsc2)cc1
Reaction time: 0.17 h

Procedure:
A solution of 4-bromotoluene (0.9 ml, 7.3 mmol) in THF (3 ml) is added to dried magnesium turnings (0.815 g, 33.5 atoms) under nitrogen atmosphere. After the exothermic reaction initiates, a solution of 4-bromotoluene (3.16 ml, 25.7 mmol) in THF (3 ml) is dropped to the reaction mixture. The stirring is continued for 10 min. The mixture is dropped to a suspension of 3-bromothiophene (2.8 ml, 29.9 mmol) and [1,2-bis(diphenylphosphino)-ethane]nickel(II) chloride (0.72 g, 1.4 mmol) in diethyl ether (50 ml), which has been stirred for 10 min. The reaction mixture is cooled and quenched with 1N hydrochloric acid and extracted with ether. The organic layer is washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. The residue is recrystallized from ethanol to give 4-(3-thienyl)toluene.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH2:10]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][O:5][C:3]([CH2:2][CH2:7][CH2:8][CH2:9][N:20]1[CH2:21][CH2:22][CH:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)=[O:4]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN1CCC(Cc2ccccc2)CC1
Yield: 77.7 %

Procedure:
A mixture of methyl bromovalerate (1.56 g, 8.0 mmol), 4-benzylpiperidine (1.49 g, 8.5 mmol) and potassium carbonate (2.93 g, 21.25 mmol) in 30 mL of acetonitrile was refluxed under N2 for 12 hr. The inorganic salt was removed through a short column of silica gel and washed with ethyl acetate (3×30 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography, giving 1.8 g (78%) of the product as a pale yellow oil. 1H NMR (CHCl3), 1.312 (m, 2 H), 1.505-1.593 (m, 7 H), 1.831 (m, 2 H), 2.292 (m, 4 H), 2.505 (d, J=6.9 Hz, 2 H), 2.860 (d, J=11.4 Hz, 2 H), 3.647 (s, 3 H), 7.136 (m, 5 H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([S:9][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[NH2:18])=[N:6][C:5]=2[CH:10]=1
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Reactant: Nc1ccccc1CCl
Agent: Cl
Product: Cc1cc2nc(SCc3ccccc3N)[nH]c2cc1C

Procedure:
The title compound was prepared by the method of Example 1 using 2.56 g of 5,6-dimethyl-2-mercaptobenzimidazole instead of 2-mercaptobenzimidazole and 2.56 g of 2-(chloromethyl) aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Instead of using sodium carbonate in an extraction, the crude precipitate was neutralized with triethylamine in methanol. Trituration of the resultant crude title compound with methanol and diethyl ether gave 2.0 g of analytically pure title compound. Anal. Calc'd. for C15H15N3S: C, 67.81; H, 6.05; N,14.83; S, 11.31. Found: C, 67.21; H, 6.16; N, 14.50; S, 11.06.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([CH3:10])[Cl:9]>[Pt].C1(C)C(C)=CC=CC=1>[CH:1]([Si:8]([CH3:10])([CH3:7])[Cl:9])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[SiH](C)Cl
Reactant: C=CCCC=C
Agent: [Pt]
Solvent: Cc1ccccc1C
Product: CCCCC=C[Si](C)(C)Cl
Temperature: 50 °C
Yield: 56 %

Procedure:
All glassware and syringes were oven dried at 110° C. overnight. 1,5-Hexadiene and dimethylchlorosilane were distilled under nitrogen prior to use. A three necked flask fitted with reflux condenser, septum, magnetic stirrer, nitrogen inlet and outlet connected to a paraffin oil bubbler was charged with 1,5-hexadiene (8.2 g, 100 mmole) and dimethylchlorosilane (4.7 g, 50 mmole). A platinum catalyst solution (3.5% Pt in xylene) (100ppm) was added to the reaction mixture, maintained at 50° C., with a syringe through the septum. The mixture was refluxed for several hours. The rate of reaction was followed by infrared spectroscopy. At the end of the reaction the desired product distilling at 56° C./0.32 mm was obtained in 56% yield.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1.O.Cl.N[CH:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14].C(=O)([O-])[O-:19].[K+].[K+].O>CO>[C:7]([NH:8][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14])(=[O:19])[C:3]1[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: NC(CS)C(=O)O
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NC(CS)C(=O)O)c1cccnc1

Procedure:
41.6 g (0.4 mole) nicotinic acid nitrile, 70.5 g (0.4 mole) D,L-cysteine hydrochloride monohydrate and 55.2 g (0.4 mole) potassium carbonate were heated in 500 ml methanol and 500 ml water for 6 hours at the boiling point. Then, the solvent was removed under reduced pressure, the residue taken up in 300 ml water, adjusted with concentrated hydrochloric acid to pH 5 and heated 45 minutes at the boiling point. After the mixture cooled off, 78.7 g (87% of theory) colorless product with a melting point of 195° C. were recovered by suction.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:1]1([CH2:7][C:8]([C:14]2[CH:15]=[CH:16][C:11]([S:17][CH3:18])=[CH:12][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Reaction time: 3.5 h
Yield: 898.2 %

Procedure:
To a solution of 46.8 g (0.030 mole) of phenylacetyl chloride in dry methylene chloride (330 ml) was added 37.6 g (0.030 mole) of thioanisole. The solution was cooled to 5° in an ice-acetone bath, and anhydrous aluminum chloride (40.9 g, 0.031 mole) was added portionwise over 30 minutes at a rate to maintain the temperature constant at 5°. The reaction mixture was stirred at 5° for 3.5 hours, after which time the mixture was carefully poured into 1300 ml of aqueous 1N HCl and was stirred overnight. The layers were separated and the aqueous layer was extracted with methylene chloride (2×1l). The organic fractions were combined and washed with 1N hydrochloric acid (2×500 ml), 5% aqueous sodium hydroxide (2×500 ml) and brine (2×500 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crystalline product was collected by filtration and washed with cold ethanol to afford 65.3 g (89%) of 2-phenyl-1-(4-methylthiophenyl)ethanone as a white solid, m.p. 98°-100°.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6][OH:7].[C:20](OC(=O)C)(=[O:22])C>C(O)=O>[CH:20]([NH:1][CH2:2][C:3]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH2:6][OH:7])=[O:22]
Reactant: NCC(CCCO)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCC(CCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In formic acid (80 ml) was dissolved 5-amino-4,4-diphenylpentanol (10 g) followed by addition of acetic anhydride (13 ml) and the mixture was stirred at room temperature for 4 hours. This reaction mixture was concentrated to dryness and the group was partitioned into chloroform and water. The water layer was made basic by aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The group was dissolved in ethanol (30 ml) and the solution was stirred in 1N-aqueous sodium hydroxide (20 ml) at room temperature for 20 minutes. This reaction mixture was diluted with water and the crystals that separated out were harvested by filtration. This crystal crop was washed serially with water and ethyl acetate to provide the title compound (9 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Product: Cl
Product: O=S(=O)(CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)N1CCOCC1

Procedure:
The compound was prepared analogously to example 82 from 3-({1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)propane-1-sulfonyl chloride using morpholine in place of 1-propylamine.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:11]=1Cl)(=O)[CH3:8].C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:7]([CH3:8])=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:11]1=2
Reactant: COCCOCn1c(Cl)c(C(C)=O)c2ccccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCCOCn1c2ccccc2c2c(C)c(C(=O)OC)sc21
Reaction time: 48 h

Procedure:
400 μl of methyl 2-mercaptoacetate was added to a slurry of 1050 mg of (80) and 1.1 g of K2CO3 in 10 ml of MeOH, and left with stirring for 48 hours. 20 ml of water was added, and the precipitate filtered off and dried. This material was thoroughly washed with pentane, filtered, dried, and recrystallized from EtOH giving 230 mg of (81) as a white powder. M.p. 85.4°-86° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)NC(=O)C=[CH:9]3)[CH2:6]1)=[N+]=[N-].[H][H].[CH3:21][N:22](C)[CH:23]=[O:24]>[C].[Pd]>[NH2:1][CH2:4][CH:5]1[O:17][C:16]2=[C:15]3[C:21](=[CH:9][CH:8]=[C:7]2[CH2:6]1)[NH:22][C:23](=[O:24])[CH:13]=[CH:14]3
Reactant: CN(C)C=O
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Agent: [Pd]
Product: NCC1Cc2ccc3[nH]c(=O)ccc3c2O1

Procedure:
The compound obtained in Example 158 (0.50 g, 2.06 mmol) dissolved in dimethylformamide (12 ml) was combined with 10% palladium-carbon (0.30 g), then stirred in the stream of hydrogen for 1.5 hour. From the reaction mixture, palladium-carbon was filtered off. The filtrate was condensed under reduced pressure, and purified by silica gel column chromatography (eluent; chloroform: ammonia=methanol 15:1). 0.33 g of the tile compound was obtained as pale yellow crystals (74.0%). They were recrystallized from a solvent mixture of chloroform--methanol--n-hexane to obtain pale yellow prisms of the title compound (mp.: 233°-236° C. (dec.)).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH2:41][CH3:42])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[C:22]([O:40][CH2:41][CH3:42])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OCC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (265 mg) and 4-(4-chloromethyl-2-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (447 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (548 mg, yield: 82%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13](=[O:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:23][Mg]Br.OC1(C)C2SC(C(N)=O)=NC=2C2C=C(C#CC(O)(C)C)C=CC=2OC1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:16])([CH3:23])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CCOC(=O)c1nc2c(s1)C(=O)COc1cc(F)c(Br)cc1-2
Reactant: C[Mg]Br
Agent: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Product: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(Br)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (415 mg) was reacted with methylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo{e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (272 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 23.3 mg and 27.4 mg (17.4% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15](O)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.Cl>C(OCC)(=O)C>[Cl:26][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (1.00 g) and DMF (66 μL) in ethyl acetate (11 mL) was added oxalyl dichloride (1.11 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. A small amount of 1N hydrochloric acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (929 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[N:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.[OH:26]S(O)(=O)=O.O>C(O)(C)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:4]([C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[N:6][C:7]3[C:12]2=[N:11][CH:10]=[N:9][C:8]=3[OH:26])=[CH:15][CH:16]=1
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a suspension of 2-chloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-benzamide I-(4A-7)a (1.00 g, 2.54 mmol) in isopropanol (20 ml) was added neat H2SO4 (410 μl, 7.4 mmol) at room temperature. The reaction was refluxed for 8 hours followed by cooling to room temperature and stirring for 16 hr. To the heterogeneous solution was added 20 ml of water to promote further product precipitation. After stirring for 1 an additional hour at room temperature, the solid was collected on a sintered glass funnel, rinsing with water followed by hexanes. The product was further dried under reduced pressure to give I-(4A-7)b as a colorless solid (0.72 g, 80%): 1H NMR: (400 MHz, DMSO-d6): δ 12.57 (s, 1H), 8.08 (d, J=4.1 Hz, 1 H), 7.66 (dd, J=7.4, 1.2 Hz, 1H), 7.51–7.41 (m, 5H), 7.33–7.29 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
4-(t-Butyloxycarbonyl)-1 -methoxycarbonyl-2-methoxybenzene (770 mg, 2.9 mmol) from Step 3 was dissolved in 1:1 THF:H2O (10 mL) and to the solution was added 1N NaOH (4 mL, 4 mmol). After being stirred at ambient temperature for 24 h, the solution was acidified to pH 2 with 1N HCl and the solvents were removed under reduced pressure. The residue was dissolved in CHCl3 and washed with water. The CHCl3 layer was dried (MgSO4), filtered, and evaporated under reduced pressure to give 4-(t-butyloxycarbonyl)-2-methoxybenzene 1-carboxylic acid as a white solid (86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br.CCCCCC.CCOC(C)=O.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4cccc(N)c4)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Nc1cccc(C(=O)Nc2ccc(-c3nc4ccc(O)cc4s3)cc2)c1
Yield: 61.7 %

Procedure:
Prepared as described in the Demethylation section using 3-amino-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (50 mg, 0.13 mmol) in dry DCM (3 ml) and BBr3 (1.0 M solution in DCM, 0.67 ml, 0.67 mmol) to give the title compound (29 mg, 60%) as a pale brown solid after work-up and flash chromatography (1:1 Hexane/EtOAc followed by EtOAc).