Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4](O)=[N:5][CH:6]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:22])=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:4]1[C:3]2=[CH:8][CH:9]=[CH:10][N:2]2[N:1]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnn2cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnn2cccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of pyrrolo[2,1-f][1,2,4]triazin-4-ol (3.70 g, 27.4 mmol, see generally, PCT Appi. WO 2000/071129 the disclosure of which is herein incorporated by reference in its entirety) in 40 mL of toluene at room temperature was added 4.77 mL (27.4 mmol) of diisopropylethylamine followed by 7.70 mL (82.6 mmol) of phosphorus oxychloride. The reaction mixture was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was slowly added to a solution of 5% aq NaHCO3 solution (100 mL) at 0° C. Upon completion of the addition, the biphasic mixture was allowed to stir at room temperature for 30 min. The aqueous layer was extracted with EtOAc (3×100 mL) and the pooled organic extracts were washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (4.10 g, 97%) as a yellow solid. 1H NMR (CDCl3) δ 8.14 (s, 1H), 7.80 (dd, 1H, J=2.4, 1.5 Hz), 6.91 (m, 2H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.CCCCCC>C(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(SCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: ClCc1cccc(SCc2ccccc2)c1
Yield: 51 %

Procedure:
One hundred milligrams of the alcohol obtained above was dissolved in 10 ml of chloroform, and 0.3 ml of thionyl chloride was added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 20 ml of water and 20 ml of ethyl ether. The ether layer was separated, and the solvent was evaporated. The residue was purified by medium-pressure liquid chromatography column: Lobar column, size A, Lichroprep Si 60F (a product of E. Merck Co.); eluting solvent: hexane] to give 55 mg (yield 51%) of 3-benzylthiobenzyl chloride as a colorless oil.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][N:17]=[C:16](Cl)[C:15]=3[Cl:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(OCC)(=O)C>CS(C)=O>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:15]=3[Cl:21])=[O:22])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Yield: 72.9 %

Procedure:
N-(1-Adamantylmethyl)-2,3-dichloroisonicotinamide (0.4 g) and tert-butyl 3-aminopropylcarbamate (0.4 g) in DMSO (4 ml) were heated in a sealed tube at 160 C for 5 hrs. Ethyl acetate was added and the solution was washed with NaHCO3 solution, water, KHSO4 solution and water. The solution was dried and the solvent was evaporated. The resulting oil was subjected to flash chromatography, using ethyl acetate/hexane as eluant, to give the title compound as a colourless oil (0.41 g).
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][C:9]=2[C:8]([CH3:16])=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>C(O)C.Cl>[CH3:16][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[C:10]2[C:11]3([CH2:13][CH2:12]3)[CH2:14][O:15][C:9]=12
Reactant: COCOc1ccc(C)c2c1C1(CC1)CO2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(O)c2c1OCC21CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.1 %

Procedure:
To a solution of 4-(methoxymethoxy)-7-methyl-spiro[2H-benzofuran-3,1′-cyclopropane] (Intermediate 12, 38 mg, 0.17 mmol) in ethanol (5 ml), HCl 6N in water (0.1 mL, 0.6 mmol) was added and the reaction mixture was stirred for 4 days at room temperature. Combined solvents were removed under reduced pressure and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound (24 mg) as a light orange solid.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=1)=[O:15])=[O:11].[C:36](=O)([O:44]C1C=CC([N+]([O-])=O)=CC=1)[O:37][CH:38]([O:40][C:41](=[O:43])[CH3:42])[CH3:39].O>CN(C)C=O>[C:41]([O:40][CH:38]([O:37][C:36]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][C:2]([C:10]([NH:12][CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=3)=[O:15])=[O:11])=[CH:3][C:4]=2[CH2:5]1)=[O:44])[CH3:39])(=[O:43])[CH3:42]
Reactant: CCOC(=O)COc1ccc(C(=O)CNC(=O)c2cc3c(s2)CCNC3)cc1OCC(=O)OCC
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)OC(C)=O)C3)cc1OCC(=O)OCC
Temperature: 25 °C
Yield: 16.3 %

Procedure:
To a suspension of 126 mg of diethyl [[4-[[[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]acetyl]-o-phenylen]dioxy]diacetate synthesized according to the method described in WO 9421599 in 3 ml of N,N-dimethylformamide was added 105 mg of 1-acetoxyethyl 4-nitrophenyl carbonate under stirring at room temperature, and the mixture was stirred at 40° C. for 20 hours. The reaction was poured into 3 ml of water, and extracted with 5 ml of ethyl acetate. The separated organic layer was dried over magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by chromatography on an LH-20 column (chloroform:methanol=1:1) and a silica gel column (chloroform:acetone=8:1) to give the title compound (25.8 mg, 16%) as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[O:19][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)[OH:10].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[O:19][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)c1cc2c(C(O)Cc3c(Cl)cncc3Cl)ccc(OC)c2o1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Ethyl 4-[2-(3,5-dichloro-4-pyridyl)-1-hydroxyethyl]-7-methoxybenzofuran-2-carboxylate (10 g) was dissolved in acetone (200 ml), a Jones reagent (a 2.76 mmol/L solution, 9.7 ml) was dropwise added thereto under cooling on ice, and the mixture was stirred for 20 minutes. Isopropanol was added thereto, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in isopropanol and the precipitated crystals were collected by filtration to give the desired compound (8.34 g, 84%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:20][CH:21]([CH3:23])[CH3:22])=[C:7]([C:10]([CH3:19])=[C:11]([C:13]#[C:14][Si](C)(C)C)[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[C:1]([C:5]1[C:6]([O:20][CH:21]([CH3:23])[CH3:22])=[C:7]([C:10]([CH3:19])=[C:11]([C:13]#[CH:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C#C[Si](C)(C)C)cc(C(C)(C)C)c(OC(C)C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(C(C)(C)C)c(OC(C)C)c(C=O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A solution of 3-tert-butyl-2-isopropoxy-6-methyl-5-trimethylsilanylethynyl-benzaldehyde (Intermediate 142, 0.45 g, 1.37 mmol) in methanol (5 mL) and tetrahydrofuran was treated with potassium carbonate (0.2 g, 1.45 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated in vacuo and the residue was extracted with diethyl ether and washed with water and brine. The organic phase was dried, filtered and evaporated in vacuo to afford the title compound (0.35 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C:17]([O-:19])=[O:18])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:26][C:27]([NH2:29])=[NH:28])=[N:4][CH:3]=1.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:26][C:27]([NH2:29])=[NH:28])=[N:4][CH:3]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CC(=O)[O-])c3ccccc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CC(=O)O)c3ccccc3)cc12

Procedure:
A solution of t-butyl DL-3-{[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]amino}-3-phenylpropanoate (153 mg, 0.33 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give DL-3-{[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]amino}-3-phenylpropanoic acid trifluoroacetate (132 mg, 0.25 mmol).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C([Li])CCC.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:5][CH:2]([CH3:1])[C:3]#[C:4][C:19]1([OH:22])[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:21][CH2:20]1
Reactant: C#CC(C)O
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(O)(C#CC(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-butyn-2-ol (42 g, 0.6 mol) in dry THF (8OO ml) under nitrogen was cooled with a dry-ice/acetone bath. n-Butyl lithium (390 ml of 2.5M and 230 ml of 1.5M) in hexane was added rapidly, dropwise. The suspension became gelatinous and another 800 mls of dry THF was added. The reaction was stirred at approximately -78° for 1 hour and then at 0° for 20 minutes. The reaction was cooled to -78° and 1-ethoxycarbonyl-4-piperidinone (104 g, 0.607 mol) in 300 ml of dry THF was added rapidly dropwise. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction mixture was cooled in an ice-bath, diluted with THF (1.51), decomposed with saturated NH4Cl, and the THF layer was washed three times with 200 ml of saturated ammonium chloride. The aqueous layers were back-washed with THF (200 ml×3). The organic layers were combined and dried over MgSO4 and evaporated to give an oil. A one-fifth portion of the oil was purified by flash chromatography on silica gel and elution with 30% ethyl acetate/ether afforded the desired product diol (19.7 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)(O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(CN3CCCC3)cc2)CC(COCc2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: c1ccc(COCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-benzyloxymethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol (1.0 g, 2.8 mmol) in 10 mL of 1,2-dichlorethane was added triethyl silane (4.5 mL, 28.5 mmol) followed by the addition of trifluoroacetic acid (4.4 mL, 57.0 mmol). The reaction was then heated to 75 C (oil bath). After 1 hour the reaction was cooled to room temperature and then concentrated under reduced pressure. The crude material was taken up in EtOAc and washed with an aqueous solution of 1M NaOH. The layer were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 45 g ISCO column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH, through 10% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (yield not determined due to presence of TFA) as a colorless oil and a 1:1 mixture of cis:trans isomers. Further purification of this material is not required.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[H][H]>CC(O)=O.CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:6]2[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:15])[CH:7]=2)=[CH:18][C:19]=1[S:26]([F:30])([F:31])([F:27])([F:28])[F:29]
Reactant: [H][H]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(N)c(S(F)(F)(F)(F)F)c2)cc1C
Yield: 95.3 %

Procedure:
3.80 g of methyl 5-methanesulfonyl-4-(4-nitro-3-pentafluorosulfanyl-phenoxy)-2-methylbenzoate (example 1) were dissolved in 30 ml of HOAc and 30 ml of MeOH, admixed with 200 mg of Pd/C (10%) and hydrogenated under 6 bar of hydrogen pressure for 24 h. Since the reaction was not yet complete, a further 300 mg of Pd/C (10%), 30 ml of HOAc and 30 ml of MeOH were added and the mixture was hydrogenated under 6 bar of hydrogen pressure for a further 24 h. Subsequently, the catalyst was filtered off and the solvents were removed under reduced pressure. 3.4 g of a light gray solid were obtained, mp 175° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.Cl>C(O)CCC>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:1][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Solvent: CCCCO
Product: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Temperature: 150 °C

Procedure:
A mixture of 5-amino-2-(trifluoromethyl)pyridine (0.5 g, 3.0 mmol, 1.0 equiv) and 5-bromo-2-fluoropyridine (0.47 mL, 4.6 mmol, 1.5 equiv) in 2 mL 1-butanol was charged with 0.15 mL of 4.0 M HCl (in dioxane) and heated to 150° C. via microwave heating. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated bicarbonate, and the organic extracts were washed with brine and dried over sodium sulphate. Purification of the crude product by flash chromatography afforded the title compound: 1H NMR (400 MHz, CDCl3) δ 6.63 (br. s., 1H) 6.67 (d, J=9.35 Hz, 1H) 7.56 (d, J=8.59 Hz, 1H) 7.62 (dd, J=8.84, 2.53 Hz, 1H) 8.22-8.66 (m, 2H) 8.57 (d, J=2.78 Hz, 1H); (M+H)+320.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Br[CH2:31][CH3:32].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:31][CH3:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCBr
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC)C3)cc1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (130 mg, 0.33 mmol) in DMF (2.5 mL) was added bromoethane (29 μL, 0.39 mmol) and DIPEA (69 μL, 0.39 mmol). The reaction mixture was then heated by microwave at 100° C. for 1 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (2-10% MeOH/DCM) to give a light brown solid (79 mg, 57%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][N+:5]=1[O-:13].[CH3:14][CH:15]([OH:17])[CH3:16]>>[CH:15]([O:17][C:8]1[CH:7]=[CH:6][N+:5]([O-:13])=[C:4]([CH3:3])[CH:9]=1)([CH3:16])[CH3:14]
Reactant: CC(C)O
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OC(C)C)cc[n+]1[O-]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 1.06 g) in 2-propanol (30 ml) was added 2-methyl-4-nitropyridine N-oxide (3.08 g), and the mixture was stirred at 60° C. for 1 hour. The residue was evaporated under reduced pressure and purified by column chromatography (silica gel 75 g, 5% methanol in dichloromethane) to give 4-isopropyloxy-2-methylpyridine N-oxide (0.78 g).
Reaction SMILES: [C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:24][CH:25]([F:40])[C:26]([F:39])([F:38])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=1[OH:37])=[O:28].N1C2C(=CC=CC=2)C=CC=1.Cl>O1CCOCC1>[Cl:24][CH:25]([F:40])[C:26]([F:38])([F:39])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:15]=[CH:16][C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])=[CH:18][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:13][CH3:14])=[CH:32][C:31]=1[OH:37])=[O:28]
Reactant: Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccc2ncccc2c1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1
Reaction time: 1.5 h

Procedure:
A solution of 33.85 g (0.1 mole) of 2-(2,4-di-tert-pentylphenoxy)butyryl chloride in 80 ml of dioxan was added to a solution of 26.85 g (0.1 mole) of 2-(3-chloro-2,2,3-trifluoropropionamido)-5-aminophenol and 23.7 ml (0.2 mole) of quinoline in 500 ml of dioxan at room temperature. The mixture was stirred for 90 minutes and left standing overnight. Next it was poured out in 2 l of icewater and 100 ml of concentrated hydrochloric acid. The sticky residue was extracted with ether, rinsed with water until free from acid, and dried. The solvent was evaporated and the residue recrystallized from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)c2ccc(Br)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(C(Cl)c2ccc(Br)cc2)c1
Reaction time: 8 h

Procedure:
The crude alcohol from above (6.5 g, 22 mmole) was dissolved in 50 ml of dichloromethane, and 2.4 ml (33 mmole) of thionyl chloride was added dropwise at room temperature. The reaction was allowed to stir overnight and the solvent was removed under vacuum. The crude product was redissolved in 50 ml of toluene and the solvent was again removed under vacuum in order to eliminate excess thionyl chloride, providing 6.85 g of crude 4-bromo-3'-methoxybenzhydryl chloride as a dark oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 3-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.83 g (82%) of the product 4-(3-methoxy-phenyl)-1H-indole as colorless syrup.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([NH:11][C:12]([NH:14][CH3:15])=[S:13])[C@@H:9]([O:16][C:17](=[O:19])[CH3:18])[C@H:8]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:6]1)(=O)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[C:21]([O:20][C@@H:8]1[C@@H:7]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:6][CH:5]2[CH:10]([N:11]=[C:12]([NH:14][CH3:15])[S:13]2)[C@H:9]1[O:16][C:17](=[O:19])[CH3:18])(=[O:23])[CH3:22]
Reactant: CNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CNC1=NC2C(O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
(2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-methylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.457 g, 1.09 mmol) was added to dry DCM, and SnCl4 (1.13 g, 4.33 mmol) was added dropwise. The reaction was stirred at room temperature overnight (16 h). The reaction was quenched with saturated aqueous NaHCO3 until the solution was basic and no more gas was evolved. The aqueous layer was extracted three times with DCM and the combined organic layers were dried with MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, EtOAc), providing (5R,6S,7R)-5-(acetoxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (22) as an oil (0.30 g, 77% yield). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.90 (s, 3H), 3.84 (m, 1H), 4.12 (m, 2H), 4.34 (dd, 1H, J=4.3, 6.2 Hz), 4.90 (ddd, 1H, J=0.8, 2.8, 9.6 Hz), 5.39 (dd, 1H, J=2.9, 4.1 Hz), 6.21 (d, 1H, J=6.5 Hz). 13C NMR (125 MHz, CDCl3) δ 21.00, 21.10, 21.23, 31.19, 63.40, 68.67, 69.40, 72.24, 73.01, 90.03, 161.21, 169.72, 169.90, 170.89.