Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:42])([F:41])[C:31]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][NH:33][N:32]=1>C(Cl)Cl.CN(C)C=O>[CH2:39]([O:38][C:36]([C:35]1[C:31]([C:30]([F:41])([F:42])[F:29])=[N:32][N:33]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)nc1C(F)(F)F
Temperature: 25 °C
Yield: 55 %

Procedure:
(S)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.57 mmol, 692 mg) was dissolved in DCM (10 mL), thionyl chloride (5.14 mmol, 0.373 mL, 611 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with dichloromethane (4×10 mL) to give a yellow oil. To this oil was added dimethylformamide (10 mL) and potassium carbonate (7.71 mmol, 1.07 g) followed by ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.57 mmol, 0.54 g). The mixture was heated to 70° C. with stirring for 1 h. The reaction was concentrated to remove DMF before partitioning between EtOAc/water. The phases were mixed and separated and the aqueous phase further washed with EtOAc (×2). Combined organics were dried and concentrated to give a light yellow oil which was purified on silica eluting with 30% EtOAc/heptane. Desired fractions were collected and concentrated to give (S)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a colourless solid (0.65 g, 55.1%). 1H NMR (400 MHz, CDCl3) δ 1.33 (t, 3H) 1.39 (d, 6H) 2.9 (m, 2H) 3.17 (sept, 1H) 3.30 (m, 2H) 4.30 (m, 4H) 5.29 (s, 2H) 7.12 (m, 2H) 7.24 (d, 1H) 7.89 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].CC1C=C([OH:18])C=C(C)C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([OH:18])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1cc(C)cc(O)c1
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 100 g. (819 m. moles) of 2,6-dimethylphenol were used instead of 3,5-dimethylphenol, 1.04 g. (7.5 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenol was 14.7 percent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].ClS([N:38]=[C:39]=[O:40])(=O)=O>CC#N>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([C:39](=[O:40])[NH2:38])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(C(N)=O)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (150 mg) was dissolved in MeCN (6 mL) under N2 and chlorosulfonyl isocyanate (45 μL) was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated and 1N HCl (8 mL) was added. The mixture was stirred at room temperature overnight, extracted with AcOEt, dried (MgSO4), filtered and evaporated. The crude product was purified by preparative TLC (silica gel; eluent: AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-carbamoylphenyl)-L-phenylalanine methyl ester (156 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][C:5]([NH2:17])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.[Zn]>[NH2:17][C:5]1[CH:6]=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:2]([F:1])=[CH:3][C:4]=1[NH:18][C:33](=[O:34])[O:35][CH2:36][CH3:37]
Reactant: Nc1cc(NCc2ccc(F)cc2)c(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.2 %

Procedure:
To a stirred solution of compound 3 (0.400 g, 1.40 mmol, 1.00 equiv) in methanol (10 mL) was added zinc powder (0.470 g, 7.10 mmol, 5.00 equiv) followed by ammonium chloride solution (0.380 g, 9.10 mmol, 5.00 equiv) drop wise. After being stirred for 5 h at RT, DIPEA (0.155 g, 1.54 mmol, 1.10 equiv) and ethyl chloroformate (0.151 g, 1.40 mmol, 1.00 equiv) were added to reaction mixture at 0° C. and the stirring was continued for another 3 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and Extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to afford to compound 3A (0.100 g, 21.0%) as brown solid. TLC: 40% EtOAc/Hexane (Rf: 0.50); 1HNMR (400 MHz, DMSO-d6): δ 8.27 (br s, 1H), 7.39-7.34 (m, 2H), 7.12 (t, J=8.8 Hz, 2H), 6.81-6.78 (m, 1H), 5.93 (d, J=9.2 Hz, 1H), 5.79 (t, J=6.4 Hz, 1H), 4.42 (s, 2H), 4.22 (d, J=6.0 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H); LC-MS: m/z=322 (M++1) at RT 3.54 (95.8% purity); UPLC purity: 98.8%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCCCC2=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCCCC2=O)c(Cl)c1

Procedure:
Prepared analogously to Example 39d from methyl 3-chloro-4-(piperidin-2-on-1-yl)-benzoate and 8% lithium hydroxide solution in ethanol.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[CH:9]=1
Reactant: Fc1ccnc(CCl)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2cc(F)ccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-4-fluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 228-231° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.52 (dd, J=8.38, 5.56 Hz, 1H), 7.24-7.14 (m, 2H), 7.06-6.90 (m, 3H), 6.85 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.15 (d, J=16.0 Hz, 1H), 5.02-4.91 (m, 2H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 171.0, 167.6, 158.9 (2), 155.3, 152.0 (2), 144.7, 141.9, 138.4, 132.2, 128.9, 124.0, 123.7, 120.9, 111.7, 111.0, 110.8, 109.7, 109.5, 109.3, 99.4, 80.1, 64.5, 63.9, 58.1, 45.8, 11.9; MS (ES+) m/z 404.9 (M+1).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>O1CCCC1>[CH3:6][Si:7]([CH3:9])([CH3:8])[O:4][C:1]([O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])=[CH:2][O:3][Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)CO
Solvent: C1CCOC1
Product: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
The reagent 1,1,2-tris-trimethylsilyloxyethylene (80) and its use for the conversion of acid chlorides to hydroxyketone (for example 96 to 98 and 90 to 92) are claimed in this invention. The reagent preparation is described hereinbelow in Flowsheet M. The reaction of glycolic acid with 1,1,1,3,3,3-hexamethyldisilazane and trimethylsilylchoride in pyridine gives bis-trimethylsilated glycolic acid (113). Addition of (113) to a tetrahydrofuran solution of one equivalent of lithium 1,1,1,3,3,3-hexamethyldisilazane amide at -78° C. generates a lithium enolate which is trapped with trimethylsilylchloride to produce the desired reagent (80). ##STR97##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.CCO.O>[Fe].CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOc1cc(Br)ccc1N
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a refluxing solution of 62A (3.0 g, 12.2 mmol), EtOH (60 mL), water (15 mL) and AcOH (10 mL) was added portion-wise Fe powder (5 g, 89.3 mmol) over 30 min. The mixture was heated for 1 h before cooling to ambient temperature and filtering through celite. The filtrate was concentrated in vacuo to afford 62B (2.5 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3 H) 4.02 (q, J=6.88 Hz, 2 H) 6.57 (d, J=7.91 Hz, 1 H) 6.85-6.90 (m, 2 H).
Reaction SMILES: Cl.C([N:9]1[C:13]([C:14]([OH:38])([C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:27][CH:26]=2)[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][C:14]([C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)([OH:38])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:27][CH:26]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2cncn2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CCO
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2c[nH]cn2)cc1
Yield: 79 %

Procedure:
1-benzyl-5-[4-(4-fluorophenyl)-1-hydroxy-1-(4-tert-butylaminocarbonylphenyl)butyl]-1H-imidazole hydrochloride (12,95 g) is dissolved into aqueous ethanol (400 ml) and 1,3 g of 10% Pd/C is added. Ammonium formate (8,17 g) is added to the boiling solution in small portions. The mixture is refluxed for three hours. Then the reaction mixture is filtered through siliceous earth and the filtrate is evaporated to dryness. The residue is dissolved to methylene chloride, washed with 2M sodiumhydroxide and water, dried and evaporated to dryness. Yield 79%.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[S:16]=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1.CC(C)([O-])C.[K+].C(O)(=O)C.O.C(OCC)(=O)C>C(O)C>[O:22]=[C:19]1[NH:18][C:17](=[S:16])/[C:21](=[CH:1]/[CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)/[S:20]1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C=C2\SC(=O)NC2=S)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
tert-Butyl 4-formylpiperidine-1-carboxylate (7.6 g) and 4-thioxo-1,3-thiazolidin-2-one (4.98 g) were suspended in ethanol (200 mL), potassium tert-butoxide (4.80 g) was added, and the reaction mixture was stirred at 80° C. for 4 hr. Acetic acid/water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and washed with diethyl ether to give the title compound (7.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH:5]=[CH:6][C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH:5]=[CH:6][CH2:7][OH:8]
Reactant: CCOC(=O)C=Cc1ccc(OC2CCCCO2)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Product: Cc1cc(C=CCO)ccc1OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a tetrahydrohydrofuran solution containing 27.5 g of ethyl 3-methyl-p-(2-tetrahydropyranyloxy)cinnamate was added dropwise 118 ml of diisobutyl aluminium hydride (25% by weight/volume) at a room temperature. After 2 hours, the reaction mixture was poured into an ice-cooled ammonium chloride aqueous solution, and the insoluble matters were removed by filtration. The filtrate was washed with water then dried with anhydrous sodium sulfate and concentrated. The residue thus obtained was purified by means of silica gel column chromatography to yield 12.7 g of 3-methyl-p-(2-tetrahydropyranyloxy)cinnamyl alcohol in the form of colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C:10]2([CH3:17])[CH3:16])=[CH:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])SC)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.[Hg](Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29]/[C:26](/[NH:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C:10]2([CH3:17])[CH3:16])[CH:6]=1)=[N:25]\[C:23](=[O:24])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:36])([CH3:34])[CH3:35]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Cc1ncc(C2CCN(C)CC2(C)C)cc1N
Agent: Cl[Hg]Cl
Solvent: ClCCl
Product: Cc1ncc(C2CCN(C)CC2(C)C)cc1N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of 2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-amine (0.814 g, 3.49 mmol) in DCM (50 mL) were added 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.52 g, 5.23 mmol), mercury (II) chloride (1.42 g, 5.23 mmol) and TEA (2.92 mL, 20.9 mmol). The reaction mixture was allowed to stir overnight at rt then filtered through a Celite® pad and washed with DCM. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give di-tert-butyl((Z)-{[2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-yl]amino}methylylidene)biscarbamate (0.79 g, 48%) as a white solid. LCMS (FAL): Rt=5.08 min, m/z=476.6 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[Cl:39]/[CH:40]=[CH:41]/[C:42](O)=[O:43].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:39]/[CH:40]=[CH:41]/[C:42]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:20]([Cl:30])=[C:21]([O:28][CH3:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=2[Cl:25])=[O:17])[N:12]=[CH:13][N:14]=1)=[O:43]
Reactant: O=C(O)/C=C/Cl
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3NC(=O)/C=C/Cl)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (10 mg, 0.022 mmol), triethylamine (10.9 g, 0.11 mmol), and (E)-3-chloroacrylic acid (2.76 g, 0.026 mmol) in DCM (0.4 ml, 6.22 mmol), cooled to 0° C., was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.023 ml, 0.039 mmol, 50% solution in EtOAc). The resulting mixture was stirred at room temperature for 4 h and concentrated. The remaining residue was purified by silica gel flash chromatography to obtain the title compound (7.2 mg, yield: 61%). 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H) 3.90 (s, 6H) 6.02 (s, 1H) 6.36 (d, J=12.92 Hz, 1H) 6.49 (s, 1H) 7.21-7.33 (m, 2H) 7.36-7.50 (m, 2H) 7.75 (d, J=6.53 Hz, 1H) 7.93 (br. s., 1H) 8.41 (s, 1H) 12.50 (s, 1H); MS (ESI): 551.0 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12]S(C(C)(C)C)=O)[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[ClH:19]>ClCCl.C(OCC)(=O)C.CCCCCC>[ClH:19].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:12])[CH2:9][O:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(Br)cc2)COC1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC1(c2ccc(Br)cc2)COC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[3-(4-bromophenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (284 mg) in dichloromethane (17 mL) was added a solution of hydrogen chloride in ethyl acetate (4 M, 427 μl) dropwise at room temperature. After being stirred at the same temperature for 30 min, the reaction mixture was diluted with hexane. Filtration gave 3-(4-bromophenyl)oxetan-3-amine hydrochloride. To a solution of 3-(4-bromophenyl)oxetan-3-amine hydrochloride in THF (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) was added a solution of di-tert-butyl dicarbonate (403 mg) in THF (10 mL) dropwise. After being stirred at room temperature for 48 h, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (5-30% ethyl acetate in hexanes) gave the product (194 mg, 2 steps 69%). 1HNMR (CDCl3) 400 MHz δ: 7.53 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 5.29 (br s, 1H), 5.01-4.90 (m, 2H), 4.85-4.73 (m, 2H), 1.50-1.26 (m, 9H). LCMS: 328, 330 [M+H].
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-c1cnn(C)c1
Product: COc1cc(NC(N)=S)ccc1-c1cnn(C)c1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Step K (4): Methanolic ammonia (2.0 M, 20 mL, 40 mmol) was added to a flask charged with 4-(4-isothiocyanato-2-methoxyphenyl)-1-methyl-1H-pyrazole (1.46 g, 5.95 mmol). After 3 h, the reaction mixture was concentrated in vacuo. The solid was triturated with diethyl ether. The solid was collected by vacuum filtration and dried under high vacuum to afford 1-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)thiourea (1.35 g, 86% yield). LC-MS (M+H)+ 263.1.
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117, see example 72) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1ccc(C2=CCNCC2)nc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Clc1ccc(C2CCNCC2)nc1
Reaction time: 3 h

Procedure:
Platinum dioxide (58 mg) was added to a mixture of 5-chloro-1′,2′,3′,6′-tetrahydro[2,4′]bipyridinyl (500 mg) and ethyl acetate (50 ml) under argon. The atmosphere was replaced by hydrogen and the mixture was vigorously stirred for 3 hours. The catalyst was filtered off with suction and the filtrate was concentrated. The product with the molecular weight of 196.68 (C10H13ClN2); MS (ESI): 197 (M+H+) was obtained in this way.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=CC=C[CH:27]=1.NC1C=CC(CN/C=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.C(Cl)(=O)C(C)C>>[OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[CH:26]([CH3:27])[CH3:31]
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Agent: CC(C)C(=O)Cl
Agent: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with isobutyryl chloride (38 μL, 0.33 mmol). Following desilylation and precipitation, N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]-2-methylpropanamide is obtained (31 mg, 56%).