Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][C:25]4=[CH:28][CH:29]=[C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[N:37]([S:39]([CH3:42])(=[O:41])=[O:40])[CH3:38])[N:24]4[N:23]=3)=[C:17]([O:43][CH3:44])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:44][O:43][C:17]1[CH:16]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[NH:21][C:22]1[N:27]=[CH:26][C:25]2=[CH:28][CH:29]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:37]([CH3:38])[S:39]([CH3:42])(=[O:41])=[O:40])[N:24]2[N:23]=1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Into a 8-dram vial, 4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.450 g, 0.724 mmol), Methylene chloride (15 mL, 230 mmol), and Trifluoroacetic Acid (3 mL, 40 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as an orange solid (0.37 g, 98%). LCMS (E/I+) 522.12 (M+H). NMR 1H (DMSO-d6)-8.95 (s, 1H), 7.95-7.99 (m, 1H), 7.87 (d, 1H, J=7.99 Hz), 7.72 (s, 1H), 7.60-7.67 (m, 1H), 7.50-7.57 (m, 2H), 7.07 (d, 1H, J=4.59 Hz), 6.96 (d, 1H, J=4.59 Hz), 6.93 (s, 1H), 6.72 (d, 1H, J=7.94 Hz), 3.83 (s, 3H), 3.37 (s, 3H), 3.04 (s, 3H), 2.88 (s, 3H), 2.73 (t, 4H, J=4.02 Hz), 2.29 (bs, 4H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cccc3ccc(NC(=O)c4ccccc4)cc23)CC1
Agent: B
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3ccc(NCc4ccccc4)cc23)CC1
Yield: 45.9 %

Procedure:
The title product of example 1 (0.12 g, 0.348 mmol) was dissolved in toluene (4 mL) and borane-dimethyl sulfide (0.3 mL, 3 mmol) was added. The mixture was refluxed 3 hours and cooled. 6N HCl and ethyl acetate were added and the mixture was refluxed until all the solids had dissolved. The organic phase was separated and discarded. The aqueous phase was made basic with 4N NaOH and extracted with methylene chloride. This organic phase was washed with brine, dried over calcium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (0.5×4 inches). Elution with 50% and then 75% ethyl acetate/hexane gave 0.053 g of product. This material was further purified by trituration with hexane to provide 0.03 g, (26%) of the title product as a tan powder: mp 115°-117° C.; 1H NMR δ 7.64 (d, J=8.5 Hz, 1H), 7.46-7.24 (m, 6H), 7.14 (t, J=7.5 Hz, 1H), 7.0 (d, J=2.5 Hz, 1H), 7.00 (ss, J=1, 7.5 Hz, 1H), 6.94 (dd, J=2.5, 8.5 Hz, 1H), 4.50 (br s, 2H), 4.34 (br m, 1H), 3.01 (br s, 4H), 2.53 (br s, 4H), 2.38 (s, 3H). Analysis calculated for C22H25N3 ·0.5 H2O: C, 77.61; H, 7.70; N, 12.34. Found: C, 77.78; H, 7.48; N, 12.07.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>C1COCC1.[Br-].[Na+]>[CH3:4][C:2]([NH:5][C:6]([C:8]1[C:13]([CH2:14][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:1])[CH3:3]
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a cooled (-40° C.) solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide (38.4 g, 0.2 mole) in dry THF (250 mL) is added n-butyl lithium (185 mL, 0.44 mole). Then sodium bromide (1.9 g, 18 mmol.) is added and is allowed to stir for 15 minutes. 4-Fluorobenzylchloride (31.8 g. 0.22 mole) was added and the reaction is allowed to stir for 21/2 hours while warming up to -5° C. The reaction is then quenched with water and the product is extracted twice with ethyl acetate followed by washing twice with brine. The organic phase is dried over Na2SO4, filtered and solvent is removed to give desired compound (60.0 g) in 99% yield, m.p. 59°-61° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23]([CH3:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>CS(C)=O.[Cu]I.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH3:25])[N:22]([CH3:26])[C:21]=3[CH:27]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1nc2ccc(Br)cc2n1C
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2n1C
Temperature: 90 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
To a suspension of 4-benzyloxy-2(1H)-pyridone (21.5 g), 6-bromo-1,2-dimethyl-1H-benzo[d]imidazole (16 g), N,N′-dimethylethylenediamine (7.57 ml) and potassium carbonate (29.5 g) in DMSO (160 ml) was added CuI (13.5 g), and the mixture was stirred at 90° C. for 5 h under Ar atmosphere. After the mixture was cooled, 28% NH3 solution (160 ml) and water (160 ml) were added. The precipitate was collected by filtration, washed with water and diisopropyl ether successively, and dried to give a solid. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (14.5 g) as an off-white solid.
Reaction SMILES: C(OC(=O)C[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)C.FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=CN4)=CC=3)=CC=2)=C(OC)C=1.[CH2:62]([O:64][C:65](=[O:68])CBr)[CH3:63]>>[CH2:62]([O:64][C:65](=[O:68])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:63]
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Reactant: CCOC(=O)CBr
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Product: CCOC(=O)Cn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21

Procedure:
[6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid ethyl ester was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester from starting materials 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and bromo-acetic acid ethyl ester to yield the product as a white solid/wax (25 mg, 56%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([NH:40][CH2:41][C:42](O)=[O:43])=O)(C)(C)C>>[ClH:28].[NH2:40][CH2:41][C:42]([NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)=[O:43]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: NCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)-phenyl)urea hydrochloride and tert-butoxycarbonyl-glycine by using the same method as in Example 96.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[F:25][C:10]([F:9])([F:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20]([CH:22]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[CH:19][CH:18]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Product: Oc1ccccc1N=Cc1ccc(-c2ccccc2C(F)(F)F)o1

Procedure:
Using 2-Aminophenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.53 g of 2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 89%).
Reaction SMILES: [CH:1]1([Si:7]([CH3:10])([CH3:9])Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].O>CN(C=O)C>[CH:1]1([Si:7]([CH3:10])([CH3:9])[O:25][C:17]2[CH2:18][C:19]3[C:24]([CH:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(Cl)C1CCCCC1
Reactant: O=C1Cc2ccccc2C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(OC1=Cc2ccccc2C1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of cyclohexyldimethylchlorosilane (84.62 g, 478.7 mmol) and imidazole (32.59 g, 478.7 mmol) in DMF (300 mL) was reacted with 2-indanone (57.62 g, 436.0 mmol). The reaction mixture was stirred overnight at room temperature, treated with water (300 mL) and extracted with Et2O (3×200 mL). The combined organic phases were washed with water (3×300 mL) and dried over sodium sulfate. The solvents were removed to leave an orange oil. Distillation under reduced pressure gave 81.67 g (68.8%) of the title compound as a yellow oil (bp. 140-142° C./0.2 mbar). 1H NMR (CDCl3, δ): 7.25-7.11 (m, 3H); 7.01 (td, 3J=7.3 Hz, 4J=1.4 Hz, 1H); 5.76 (d, 4J=0.7 Hz, 1H); 3.29 (s, 2H) 1.77-1.74 (m, 5H); 1.27-1.13 (m, 5H); 0.90 (m, 1H); 0.24 (s, 6H). 13C NMR (CDCl3, δ): 162.44; 145.24; 136.60; 126.47; 123.07; 122.37; 118.91; 106.32; 39.52; 27.69; 26.77; 26.46; 26.33; −3.55.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][C:25]=2[C:26]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[N:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:7][CH2:6]2)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3cnc4ccccc4c3)CC2)c1

Procedure:
Prepared in analogy to example 1.1(b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [OH:1]O.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[O:15][C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2>CO>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]1[C:16]2[O:15][C:14]([C:12]([NH:11][C@@H:5]3[CH:6]4[CH2:7][CH2:8][N+:3]([O-:1])([CH2:10][CH2:9]4)[CH2:4]3)=[O:13])=[CH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Reactant: OO
Solvent: CO
Product: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3C[N+]4([O-])CCC3CC4)oc12
Reaction time: 18 h

Procedure:
35.8 μl (0.35 mmol) of 30% strength hydrogen peroxide are added to a solution, cooled to 0° C., of 110 mg (0.29 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide (Example 130) in 2 ml of methanol. After 18 h at room temperature, a further 35.8 μl (0.35 mmol) of 30% strength hydrogen peroxide are added. After a further 18 h at room temperature, the reaction solution is concentrated, and the residue is dried under high vacuum. 111.5 mg (97.2% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]([O:21][CH2:39][CH3:40])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH:33]=[CH:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Reaction time: 8 h

Procedure:
10 mg (0.019 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-7-carboxylic acid was dissolved in 2 ml of dichloromethane. 0.022 ml (0.38 mmol) of ethanol, 4 mg (0.023 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.038 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Sn].Cl>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Sn]
Product: Cc1ccc(N)cc1C(=O)O
Yield: 75 %

Procedure:
The desired titled compound was prepared by reducing 2- methyl-5-nitrobenzoic acid using a tin/hydrochloric acid mixture (m.p. 142°-144° C.).
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:12]=[C:10]([I:11])[C:9]([O:13][C:14]2[CH:21]=[C:19]([I:20])[C:18]([OH:22])=[C:16]([I:17])[CH:15]=2)=[C:7]([I:8])[CH:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>[NH4+].[OH-].CN(C=O)C.O.CCO.[OH-].[Na+]>[C:26]([NH:2][C@H:3]([C:23]([OH:25])=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([I:8])[C:9]([O:13][C:14]2[CH:15]=[C:16]([I:17])[C:18]([OH:22])=[C:19]([I:20])[CH:21]=2)=[C:10]([I:11])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reaction time: 1.5 h
Yield: 90 %

Procedure:
L-Thyroxine sodium salt, pentahydrate (1) (10 g, 11 mmol) was nearly completely dissolved in 400 mL of ETCH/2 N NH4OH (1/1, v/v), filtered, and filtrate poured into 425 mL of 5% HCl. The resulting precipitate was isolated by vacuum filtration and dried under high vacuum to afford a white solid. This material was dissolved in 1.60 mL DMF, 100 mL (1.06 mol) of acetic anhydride added, and reaction stirred for 1.5 hours, then diluted with 850 mL H2O and allowed to stand at 4° C. for 16 hours. The resulting precipitate was isolated by filtration, then dissolved in 350 mL EtOH and 41 mL of 1N NaOH, stirred for 2.5 hours, 680 mL of 5% HCl added, and mixture allowed to stand at 4° C. for 16 hours. The resulting precipitate was isolated by vacuum filtration and dried under high vacuum to yield 8.1 g (90%) of the desired N-acetyl L-thyroxine (5) as a white solid; 1H NMR (200 MHz, CD3OD) d 7.8 (s, 2H), 7.1 (s, 2H), 4.6-4.7 (m, 1H), 2.8-3.0 (m, 2H), 2.0 (s, 3H); mass Spec (FAB) (M+H)+820.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:34]C(=O)C)=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:34])=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)=C(C)C1=O
Yield: 68.4 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-morpholinoaniline (0.060 g, 0.110 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.037 g, 0.0752 mmol, 68%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]([NH2:14])[CH3:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:18])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:16]([NH:14][CH:12]([C:9]1[NH:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:13])([CH3:18])[CH3:15]
Reactant: CC(N)c1nc(-c2ccccc2)c[nH]1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NC(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and acetone (0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL), followed by the addition of NaBH(OAc)3 (0.34 g, 1.61 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with saturated NaHCO3 solution. The mixture was extracted with EtOAc and the combined extracts were dried over Na2SO4. Filtration followed by evaporation to dryness under reduced pressure gave the crude isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.23 g, 100%) which was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl3): δ 1.10 (3H, d), 1.18 (3H, d), 1.57 (3H, d), 2.86 (1H, m), 4.32 (1H, m), 7.24 (2H, m), 7.36 (2H, m), 7.69 (2H, m). MS (ES+): 230.2 (100%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[I-].[Na+].[C:20]([O:28][CH2:29]Cl)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:20]([O:28][CH2:29][N:4]1[C:3](=[O:17])[C:2]([F:1])=[CH:15][N:6]([C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:5]1=[O:16])(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(=O)OCCl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCC(=O)OCn1c(=O)c(F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c1=O
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To 70 ml of acetone was added 4.95 g of 5-fluoro-2'-deoxyuridine and 12 g of sodium iodide. With stirring at room temperature, thereto was added 7.19 g of chloromethyl n-heptanoate and 15 g of anhydrous potassium carbonate. After the mixture was reacted with stirring at room temperature overnight, the obtained mixture was concentrated under reduced pressure. To the concentrate was added 150 ml of ethyl acetate, and then the insoluble matter was separated by filtration. The flitrate was washed with water, saturated aqueous solution of sodium chloride and water successively, followed by concentrating. The obtained concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give 4.77 g of 3-n-heptanoyloxymethyl-2'-deoxy-5-fluorouridine in the form of colorless solid matter (yield: 61.1%). The melting point of the obtained solid matter was 104° to 106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[C:14](=O)[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(C(=O)Cc1cccs1)[C@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(CCc1cccs1)[C@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A5-1 when using 340 mg (0.99 mmol) (S)-N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide ((S)-A4-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using a mixture of hexane/ethyl acetate 40/1 in the presence of 0.5% (v/v) dimethylethylamine.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:5]([CH2:8][CH2:9][CH2:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:26])=[CH:17]/[CH2:18][CH:19](C(O)=O)[C:20]([OH:22])=[O:21])[CH2:6][CH3:7])[CH3:4]>>[CH2:3]([N:5]([CH2:8][CH2:9][CH2:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:26])=[CH:17]/[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:6][CH3:7])[CH3:4]
Reactant: CCN(CC)CCCC/C(C)=C/CC/C(C)=C/CC(C(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCN(CC)CCCC/C(C)=C/CC/C(C)=C/CCC(=O)O
Yield: 34 %

Procedure:
450.5 g of geranylmalonic ester, 34.9 g of sodium and 227.3 g of diethylaminopropylchloride (b.p., 73°-78° C/20 mm) isolated from 423.3 g of hydrochloride, are heated in toluene to obtain 329.4 g of diethylaminopropylgeranylmalonic ester having a boiling point of 185°-210° C/2 mm, n20 1.4709. The 329.4 grams of diethylaminopropylgeranylmalonic ester are saponified with a concentrated solution of potassium hydroxide in alcohol to prepare 524.7 g of moist diethylaminopropylgeranylmalonic acid. The diethylaminopropylgeranylmalonic acid, either moist or dried, is then decarboxylated in vacuum (after dehydration of the acid in vacuum). 156 g of diethylaminopropylgeranylacetic acid are produced. The boiling point of the acid is 190°-200° C/2 mm, n20 1.4951.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]2[C:8](=[C:9](Br)[N:10]=1)[NH:7][CH:6]=[CH:5]2.NN>CCO.[Pd]>[CH3:13][O:12][C:3]1[CH:2]=[N:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: COc1c(Br)nc(Br)c2[nH]ccc12
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: COc1cncc2[nH]ccc12
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 5,7-Dibromo-4-methoxy-6-azaindole 36 (680 mg, 2.22 mmol), 5% Pd/C (350 mg, 0.17 mmol) and hydrazine (2.5 mL, 80 mmol) in EtOH was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt, filtered through celite and the filtrate concentrated. Aqueous NH4OH (11% in H2O, 45 mL) was added to the residue and the solution was extracted with CH2Cl2 (3×30 mL). The combined organics were dried (MgSO4), filtered and concentrated to yield 4-methoxy-6-azaindole 37 (290 mg, 1.95 mmol, 88%) as an orange solid.