Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]=[C:15]([F:17])[C:14]([CH:18]([C:20]4[C:28]5[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=5[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=4)O)=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH2:18][C:20]4[C:28]5[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=5[NH:22][CH:21]=4)=[C:15]([F:17])[N:16]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1ncnc2c1c(C(O)c1ccc(Nc3ccc(C4CC4)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ncnc2[nH]cc(Cc3ccc(Nc4ccc(C5CC5)nc4)nc3F)c12
Temperature: 80 °C
Reaction time: 4 h
Yield: 25.2 %

Procedure:
To [6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol (73, 70 mg, 0.12 mmol) in 10.0 mL of 1,2-dichloroethane, triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.60 mL, 7.8 mmol) are added and the reaction stirred at 80° C. for 4 hours. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-4004, 11.8 mg). MS (ESI) [M+H+]+=390.9.
Reaction SMILES: [N+]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]1)([O-])=O.C(=O)([O-])O.[Na+].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH:26]=[C:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:19]=1>O.CC(C)=O>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH:26]=[C:27]2[CH2:28][CH2:29][N:30]([C:8]3[NH:4][CH:5]=[N:6][C:7]=3[N+:9]([O-:11])=[O:10])[CH2:31][CH2:32]2)[N:19]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C#CC=C2CCN(c3[nH]cnc3[N+](=O)[O-])CC2)n1

Procedure:
To a solution of 1,4-dinitroimidazole (207 mg, 1.31 mmol) and sodium hydrogencarbonate (242 mg, 2.88 mmol) in 4 mL of water and 0.16 mL of acetone was added drop wise a solution of the compound of Example 3 (278 mg, 1.31 mmol) in acetone. The reaction mixture was refluxed for 2 h, poured into water and extracted with EtOAc. The crude residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with EtOAc-MeOH gradient from 1:0 to 92:8; affording the title compound not enough pure. So, it was purified again by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording 4 mg of the title compound.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]([C:15]12[CH2:22][CH2:21][C:18]([CH2:23][OH:24])([CH2:19][CH2:20]1)[CH2:17][CH2:16]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(C(CC)(CC)CN)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:12][C:13]([C:15]12[CH2:20][CH2:19][C:18]([CH:23]=[O:24])([CH2:21][CH2:22]1)[CH2:17][CH2:16]2)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)C12CCC(CO)(CC1)CC2
Agent: CCC(CC)(CC)CN
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC12CCC(C(=O)OCc3ccccc3)(CC1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (COCl)2 (16.5 ml, 188 mmol) in methylene chloride (150 ml) is cooled to −63°. DMSO (18 ml, 362 mmol) is then added dropwise. The resulting mixture is stirred for 30 minutes and then a mixture of 4-hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid benzyl ester (XVIII, Example 93, 34.5 g, 125 mmol) in methylene chloride (100 ml) is added over 15 minutes. After another 30 minutes, triethylethylamine (70 ml, 502 mmol) in methylene chloride (30 ml) is added over 25 minutes. (Extra Caution: extremely exothermic reaction when the first equivalent of the triethylamine is added.) The reaction mixture then stirred for another 45 minutes and the cooling bath is removed and allowed to warm up to 20-25°. Water (50 ml) is added and the organic layer is separated, dried over anhydrous sodium sulfate and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 9.51, 7.32, 5.11, 1.88 and 1.64.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:8])CC1)#[N:2].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[C:1]([CH2:3][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:39]3[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]3)=[CH:19][C:18]=2[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:8])#[N:2]
Reactant: CCN1CCNCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccc(F)cc2)CC1
Product: CCN1CCN(c2ccc(S(=O)(=O)[C@H]3C[C@@H](COc4ccc(F)cc4)[C@H](C(=O)NCC#N)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(4-fluoro-phenoxymethyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 145) and 1-ethyl-piperazine. Yellow oil. MS (EI): 563.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][C:14]=2[N+:28]([O-])=O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:31](O)(=O)[CH3:32]>[Fe]>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH2:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[C:31]([CH3:32])=[N:28][C:14]=2[CH:15]=1
Reactant: COC(=O)c1cccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Fe]
Product: COC(=O)c1cccc(Cn2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)c1
Yield: 64 %

Procedure:
To 2-(2-(3-methoxycarbonylphenylmethyl)aminonitrobenzen-5-yl)benzoxazole (see Working Example 117-1) (220 mg, 0.545 mmol) was added iron powder (91.4 mg, 1.64 mmol) and acetic acid (5 mL), and this was heated to reflux for 12 hours. After the reaction solution was cooled, it was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (139 mg, 64% yield) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O.OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1CCc2ccc(OCc3ccccc3)cc2C1
Reactant: O=[N+]([O-])O
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of acetic acid 7-benzyloxy-1,2,3,4-tetrahydronaphthalen-2-yl ester (5.77 g, 19.5 mmol) in AcOH (30 mL) is added a solution of 90% HNO3 (3.0 mL, ca. 64 mmol) in AcOH (5 mL), copper(II) nitrate hemipentahydrate (3.71 g, 19.8 mmol) and conc. H2SO4 (3 drops) at room temperature. The mixture is stirred at room temperature for 1.5 h and partitioned between EtOAc and aq. KOH. The organic layer is dried over MgSO4, concentrated and chromatographed to afford acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl ester with some impurities. Crystallization from DCM-hexanes yields a precipitate, which is quickly rinsed with Et2O-hexanes to afford pure acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl ester: 1H NMR (CDCl3) δ 7.66 (s, 1H), 7.48-7.29 (m, 5H), 6.80 (s, 1H), 5.22-5.15 (m, 1H), 5.19 (s, 2H), 3.10 (dd, J=16.0, 8.0 Hz, 1H), 2.95-2.72 (m, 3H), 2.05 (s, 3H), 2.05-1.95 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)[N:6]=[CH:5]2.[C:23]([C@@H:27]1[CH2:32][CH2:31][C@H:30](O)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1COCC1>[C:23]([C@H:27]1[CH2:32][CH2:31][C@H:30]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)C1CCN(Cc2ncc3cc(O)ccc3n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCN(Cc2ncc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 mL round bottom flask was added methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (0.5 g, 1.6 mmol), cis-4-tert-butylcyclohexanol (0.38 g, 0.24 mmol, 1.5 eq), PPh3 (0.87 g, 3.3 mmol, 2 eq) and dry THF (0.5 mL) under N2 atmosphere. Then DIAD (0.53 g, 0.33 mmol, 2 eq) was quickly added in one portion at room temperature. The reaction mixture was stirred at rt for 0.5 h, diluted with water (20 mL) and extracted with DCM (20 ml*3). The combined organic lays were dried over MgSO4 and concentrated. The residue was purified by prep-TLC (DCM/MeOH=15/1) to give methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)quinazolin-2-yl)methyl)piperidine-4-carboxylate (300 mg, yield: 20%) as brown oil. 1HNMR (400 MHz, CDCl3) δ: 9.27 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 4.30˜4.20 (m, 1H), 3.94 (s, 2H), 3.59 (s, 3H), 3.00˜2.98 (m, 2H), 2.28˜2.18 (m, 4H), 1.85-1.82 (m, 6H), 1.40˜1.34 (m, 2H), 1.18˜1.03 (m, 4H), 0.86 (s, 9H); ESI-MS: m/z 440.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.O>C(Cl)Cl>[CH3:22][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:4]2[C:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:6][C:7](=[O:8])[C:2]([CH3:1])=[C:3]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccccc2)n(-c2ccc(S(C)=O)cc2)c(-c2ccccc2)cc1=O
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Dissolved in 30 ml of methylene chloride was 1.1 g (0.0029 mole) of 3-methyl-1-(4-methylthiophenyl)-2,6-diphenyl-4(1H)-pyridinone, followed by addition of 0.6 g (0.0034 mole) of m-chloroperbenzoic acid (as oxidizing agent). After stirring the reaction mixture for 15 minutes, it was poured into water, followed by extraction with methylene chloride. The organic layer (the extract) was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and then with water. The organic layer was thereafter dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting crystals were recrystallized form a 2:1 mixed solvent of acetone and hexane, affording 1.1 g of 1-(4-methanesulfinylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 242°-244° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[NH:17][CH:16]=1)=[O:11].[OH-].[Na+]>C(O)(=O)C>[CH3:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[NH:17][C:16]=1[Br:1])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(Br)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
N-bromo succinimide (0.89 g, 5 mmol) was added to a solution of melatonin (1.16 g, 5 mmol) in acetic acid (20 mL). The reaction mixture was stirred under N2 at room temperature for 4 h, then cooled at 0° C., neutralized with a 50% solution of NaOH and extracted with ethyl acetate. The combined organic layers were washed with NaCl solution, dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel; ethyl acetate/cyclohexane 6:4) and crystallization gave 0.467 g (30% yield) of 4k as white solid, mp 141°-142° C. IR νmax : 3460, 3300, 1650. 1H NMR: 1.99 (s, 3H, COCH3); 2.92(t, 2H, β -CH2), 3.54(q, 2H, α-CH2), 3.86(s, 3H, OCH3), 5.53(br s, 1H, NH), 6.85-7.23(m, 3Harom), 8.15(br s, 1H, NHindole).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH3:14][NH2:15]>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:15][CH3:14])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and methylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-2,5-difluoro-N-methylbenzenesulfonamide (0.17 g) after purification. HPLC purity 100.0% at 210-370 nm, 9.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C7H6BrF2NO2S−H+, 283.91979; found (ESI-FTMS, [M−H]1−), 283.92003
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[Cl:15][C:16]1[CH:35]=[CH:34][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27](O)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]([F:36])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C.O>[Cl:15][C:16]1[CH:35]=[CH:34][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]([F:36])[CH:17]=1
Reactant: COc1cc(CO)ccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc3ncnc(Nc4ccc(Cl)cc4F)c3cc2OC)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
Thionyl chloride (0.6 ml) was added to a solution of 4-hydroxymethyl-2-methoxypyridine (0.59 g, 4.2 mmol) in toluene (10 ml) and the mixture stirred at ambient temperature for 1.5 hours. The volatiles were removed by evaporation and the residue was azeotroped with toluene and dried under vacuum to give crude 4-chloromethyl-2-methoxypyridine hydrochloride (0.50 g, 2.6 mmol) which was used directly. This product was then added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (420 mg, 1.3 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (1.0 g 7 mmol) in DMF (8 ml) and the resulting mixture was heated at 75° C. for 2 hours. The mixture was allowed to cool, diluted with water and the precipitated solid collected by filtration, washed with water and dried to give 4-(4-chloro-2-fluoroanilino)-7-((2-methoxy-4-pyridyl)methoxy)-6-methoxyquinazoline (140 mg, 25%).
Reaction SMILES: [OH-].[Na+:2].C1(C)C(C)=CC=CC=1.[CH:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[OH:21])[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[O-:21])[CH2:13][CH2:12]1.[Na+:2]
Reactant: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cccc(C2CC2)c1[O-]
Temperature: 50 °C
Yield: 67.3 %

Procedure:
115.4 g of pure water was added to 54.1 g (1.312 mol) of 97% sodium hydroxide and heated to 50° C. to dissolve sodium hydroxide, and then xylene (1,000 ml) was added to the resultant solution at room temperature. To the mixture was added dropwise 200 g (1.317 mol) of 2-cyclopropyl-6-methylphenol at room temperature over 20 minutes. The resultant two-phase solution was subjected to thermal dehydration at 140° C., and, after completion of the distilling off of water, the resultant solution was cooled to 5° C. to obtain a slurry. The obtained slurry was subjected to filtration under a reduced pressure, and the resultant solids were washed with 500 ml of hexane twice. The solids were dried under a reduced pressure, and the resultant solids were quantitatively determined by an HPLC internal standard analysis method, which showed that 150.2 g of sodium 2-cyclopropyl-6-methylphenoxide (yield: 67%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:23]2[CH2:24][CH2:25][N:26]([CH2:28][C:29]#[CH:30])[CH2:27][C:22]=2[C:5]2[C:6]([OH:21])=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=2[O:3]1.[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:32].[CH3:31][C:2]1([CH3:1])[C:23]2[CH2:24][CH2:25][N:26]([CH2:28][C:29]#[CH:30])[CH2:27][C:22]=2[C:5]2[C:6]([O:21][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(-c3ccccc3C(C)CCC)cc1OC2(C)C
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3)cc(-c3ccccc3C(C)CCC)cc1OC2(C)C
Reaction time: 16 h

Procedure:
A mixture of 1.45 g. (4.26 mm) of 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-8-(1-methylbutylphenyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 0.89 g. (4.28 mm.) of γ-piperidinobutyric acid hydrochloride and 0.93 g. (4.50 mm.) of dicyclohexylcarbodiimide in 200 ml. of methylene chloride are stirred at room temperature for 18 hours. After cooling the reaction mixture for 11/2 hours, the by-product of dicyclohexylurea is removed by suction filtration. A rotary evaporator is used to remove the methylene chloride, and a mixture of 25 ml. of methylene chloride and 50 ml. of cyclohexane is added. After standing at room temperature for 2 hours and a 5° C. for 16 hours, gravity filtration is used to separate the resulting solid. This material is generally a mixture of the starting acid hydrochloride and the hydrochloride salt of the starting benzopyran. The mother liquid is evaporated and the residue crystallized from a mixture of 2 ml. of methylene chloride and 15 ml. of diethyl ether. After filtration and drying, the pure product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]1(=[O:41])[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][O:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH:36]6[CH2:35][O:34][C:33](=[O:41])[CH:37]6[CH2:38]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C1OCC2CNCC12
Product: O=C1N=C(N2CC3COC(=O)C3C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-hexahydro-furo[3,4-c]pyrrol-1-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and hexahydro-furo[3,4-c]pyrrol-1-one following General Procedure B.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1)=[O:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].S(=O)(=O)(O)O>C1C=CC=CC=1.[Zn]>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:10])=[CH:21][CH:22]=1)[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1ccc(COC(=O)C=Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: COC(=O)CC(O)c1ccc(C=CC(=O)OCc2ccc(OC)cc2)cc1

Procedure:
Next, 296 mg of p-anisyl 4-formylcinnamate and 0.14 ml of methyl bromoacetate were dissolved in 4 ml benzene, and mixed with 95 mg of zinc powder to form a suspension, followed by heating under a stream of argon for 5 hours. The reaction mixture was allowed to cool, mixed with 10% sulfuric acid, extracted with ether and then washed with 5% sulfuric acid. The organic layer was washed with 10% aqueous sodium carbonate, and dried over magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated under reduced pressure and dried to give p-anisyl 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]-cinnamate of interest (51 mg, 14%) as a pale yellow liquid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][C:20]4[C:19]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[N:18][C:17]([C:29]5[CH:30]=[N:31][C:32]([NH:35]C(=O)OC(C)(C)C)=[N:33][CH:34]=5)=[N:16][C:15]=4[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[O:5])[CH2:3][CH2:2]1.C(Cl)Cl.FC(F)(F)C(O)=O.CO>C(Cl)(Cl)Cl>[NH2:35][C:32]1[N:31]=[CH:30][C:29]([C:17]2[N:18]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:20]3[N:21]=[CH:22][C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[CH:12]=[CH:11][CH:10]=4)=[CH:14][C:15]=3[N:16]=2)=[CH:34][N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)C5CC5)c4)cc3n2)cn1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)C5CC5)c4)cc3n2)cn1
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.1 %

Procedure:
To a 50 mL round bottom flask, tert-butyl (5-(7-(3-(cyclopropanecarboxamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.15 g, 0.00026 mol) and DCM (10 mL) were added and then cooled to 0° C. To the same reaction flask, trifluoroacetic acid (0.12 g, 0.00104 mol) was added at 0° C. and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with 10% methanol in chloroform. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude product. The crude product was subjected to flash column chromatography using 3-4% methanol in chloroform. The obtained solid was washed diethyl ether, filtered and dried under vacuum to afford the title compound (0.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.23 (s, 2H), 9.04 (d, J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 7.68-7.50 (m, 3H), 7.24 (br s, 2H), 4.55 (br s, 4H), 3.86 (d, J=4.0 Hz, 4H), 1.85-1.83 (m, 1H), 0.87-0.85 (m, 4H): LC-MS (ESI): Calculated mass: 468.2; Observed mass [M+H]+: 469.1. (RT=0.35 min).