Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccc(C(F)(F)F)cc3)c2c1
Yield: 76 %

Procedure:
This compound was prepared from 6b using 4-trifluoromethylphenylboronic acid according to method P. Yellow crystals; Yield: 76%; mp 299–300° C.; 1H-NMR (400 MHz, DMSO-d6) δ 7.07 (dd, J=8.8, 8.8 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.94 (dd, J=8.4, 2.1 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 8.07 (dd, J=13.0, 2.0 Hz, 1H), 9.91 (s, 1H), 10.21 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.58 (dd, J=13.2, 9.3 Hz), −61.43 (s); MS (ESI) m/z 398 ([M−H]−), 400 ([M+H]+); Anal. Calcd for C22H13F4NO2: C: 66.17, H: 3.28, N: 3.51. Found: C: 66.09, H: 3.41, N: 3.45.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N:8]1[CH2:9][CH2:10][CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=3[S:14][C:13]=12>>[N:8]1[CH2:9][CH2:10][CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([NH:21][C:5](=[O:7])[CH3:6])[CH:19]=[CH:20][C:15]=3[S:14][C:13]=12
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)N1CCCN=C1S2
Reaction time: 1 h

Procedure:
To 25 parts of acetic acid anhydride are added portionwise 1.3 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine (exothermic reaction: temp. rises to 30° C.). Upon completion, stirring is continued for one hour at room temperature. After cooling to 5°-10° C., the precipitated product is filtered off and dissolved in water. The solution is treated with activated charcoal. The latter is filtered off over hyflo and the filtrate is alkalized with a few drops of ammonium hydroxide. Upon stirring, the product is allowed to crystallize. It is filtered off and dried, yielding 0.8 parts of N-(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-yl)acetamide; mp. 178° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
To a solution of methyl 3-(6-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}pyridin-3-yl)propanoate (0.170 g, 0.45 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.017 g, yield 10%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.Br[C:24]1[C:29](OC)=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:16]
Reactant: COc1cccc(B(O)O)c1Br
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-bromo-3-methoxyphenylboronic acid in step 1.F.
Reaction SMILES: [C:1]1(=O)[C@H:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[C:4](=O)[CH2:3][NH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]1[C@H:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1
Reactant: O=C1NCC(=O)N2c3ccccc3C[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)C[C@@H]1CNCCN21
Yield: 98.6 %

Procedure:
To a solution of (10aR)-2,3,10,10a-tetrahydropyrazino[1,2-a]indole-1,4-dione (200 mg, 0.99 mmol) in 5 mL THF was added LAH. The reaction mixture was refluxed for 1 h. Standard work up afforded 170 mg of pure (10aR)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([NH:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:21])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:12](=[O:13])[N:24]2[CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:23]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NCc1cccnc1
Product: O=c1c2ccc(Cl)cc2n(Cc2cccnc2)c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 16.6 %

Procedure:
580 mg (2.68 mmol) of 4-chlorobenzenesulfonylisocyanate and 600 mg (2.28 mmol) of 4-chloro-2-(3-pyridylmethyl)aminobenzoic acid were treated in the same way as in Example 1 to obtain 175 mg of the above-identified compound (yield 16.6%). Properties: colorless crystal, Melting point: >190° C. (decomposition), PMR (δppm, DMSO-d6):5.29 (2H,s), 7.3-7.4 (2H,m), 7.39 (1H,s), 7.68 (1H,d), 7.79 (2H,d), 7.97 (1H,d), 8.20 (2H,d), 8.46 (1H,d), 8.57 (1H,d).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:15]=[C:14]([F:16])[C:13]([S:17](Cl)(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>O1CCOCC1>[Cl:6][C:7]1[CH:15]=[C:14]([F:16])[C:13]([S:17]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Yield: 92 %

Procedure:
tert-Butyl amine (77 mL, 0.7 mol, 10 equiv) was added to 300 mL dioxane at 0° C. Ice chips were added to the flask for several minutes before the addition of 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (20 g, 73.24 mmol, 1 equiv). Both the internal and external temperature of the reaction was maintained at or below 0° C. for 2 h. The reaction was then concentrated half-way and acidified to pH 2 with 1N HCl. The product was extracted into EtOAc. The organics were dried over Na2SO4, filtered and concentrated down to give 2-chloro-5-{[(1,1-dimethylethyl)amino]sulfonyl}-4-fluorobenzoic acid 883-4a as a brown solid (21 g; 92% yield).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][C:28](Cl)=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C1COCC1.[Pd]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Cl)nn4)ccc32)n1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccnn4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.1 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-(6-chloropyridazin-3-yl)-benzimidazol-1-yl]pyrimidine (24.0 mg) was dissolved in 2 mL ethanol and 2 mL THF. Added 10%Pd/C (23.0 mg), fitted the system with a balloon of hydrogen and purged 3 times, and the system was left stirring for 20 h at room temperature. No apparent progress at this point so 1-drop of glacial acetic acid was added and refitted with the balloon and purged. Stirred approximately 20 h longer then filtered off the catalyst, the solvent was removed and the residue purified by preparative thin layer chromatography (1:1 hexanes:acetone then another in 90:10 CH2Cl2:MeOH to yield 2.0 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 9.20 (dd, J=1.5, 4.9 Hz, 1H); 8.54 (br s, IH); 8.44 (d, J=5.3 Hz, 1H); 8.42 (s, 1H); 8.23 (br s, 1H); 7.97 (dd, J=1.5, 8.5 Hz, 1H); 7.59 (dd, J=4.9, 8.6 Hz, 1H); 7.47 (d, J=7.3 Hz, 2H); 7.42 (t, J=7.5 Hz, 2H); 6.82 (d, J=5.3 Hz, 1H); 1.66 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 394.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1([C:10](=[O:12])[CH3:11])[CH2:7][CH:6]([CH2:8][CH3:9])OC1=O.[ClH:13]>>[Cl:1][CH:2]([CH2:7][CH:6]([Cl:13])[CH2:8][CH3:9])[C:10](=[O:12])[CH3:11]
Reactant: CCC1CC(Cl)(C(C)=O)C(=O)O1
Reactant: Cl
Product: CCC(Cl)CC(Cl)C(C)=O

Procedure:
The title compound is prepared according to the method described in Example 1 starting from 49 g (0.26 moles) of α-chloro-α-acetyl-γ-ethyl-γ-butyrolactone and 98 cm3 of abs. hydrochloric acid. After distillation 22 g (47%) of the title compound is obtained. Its boiling point is 68°-70° C. at a pressure of 133.3 Pa, nD20 =1,4600.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(Cl)c2)CC1
Reactant: NN
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cccc(Cl)c2)CC1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of trans-4-(3-chloro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.25 g, 0.93 mmol) and hydrazine hydrate (0.044 ml, 0.91 mmol) was heated at 120° C. for 22 h. Addition of further hydrazine hydrate (0.020 ml, 0.42 mmol) was followed by stirring at 120° C. for 5 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted with a 50-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.21 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 269 (M+H+)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]=[O:43])[CH:37]=1.[Li+].CC([N-]C(C)C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:42]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccnc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3cccnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), pyridine-3-carboaldehyde and LDA
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C>[CH3:22][C:19]([CH3:21])([CH3:20])[CH2:18][N:17]1[C:10]2[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH:27]=[CH:31][CH:30]=[CH:29]2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC(C)(C)Cn1c(Cc2ccc(-n3cccc3)cc2)cc2cnc(C#N)nc21
Yield: 60.2 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.32 mmol) in acetic acid (1 ml) is slowly added 2,5-dimethoxy-tetrahydro-furan (0.35 mmol). The reaction mixture is refluxed for 2 h and cooled. The mixture is quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with saturated ammonium chloride and brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: n-hexane:AcOEt=6:1 (v/v) and n-hexane:AcOEt=4:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 60.2%, Rf=0.55 (n-hexane:AcOEt=2:1). 1H-NMR (400 MHz, CDCl3) δ 1.06(s, 9H), 4.09(s, 2H), 4.24(s, 2H), 6.27(s, 1H), 6.35-6.36(m, 2H), 7.16-7.17(m, 2H), 7.21(d, 2H), 7.38(d, 2H), 8.84(s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22](C=CC)=[CH:21][CH:20]=[C:19]([F:26])[C:18]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:14]=[CH2:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:15][C:22]3[C:17](=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:19]([F:26])=[CH:20][CH:21]=3)[O:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(C=CC)ccc(F)c1-c1ccccc1Cl
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Yield: 51.1 %

Procedure:
Treatment of (2R)-2-(2′-chloro-6-fluoro-3-(prop-1-enyl)biphenyl-2-yloxy)but-3-enyl 4-methylbenzenesulfonate (1.5 g, 3.08 mmol) with benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (0.50 g, 0.61 mmol) in 1,2-dichloroethane (30 mL) according to the procedure described for Example 69, Step 7 provided 0.7 g (51%) of ((2R)-8-(2-chlorophenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzene-sulfonate as a thick dark oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([OH:28])[CH2:10][N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])(C)(C)C.N(CCO)(CCO)CCO>CO.[C].[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([CH2:10][C@@H:9]([OH:28])[C@@H:8]([NH2:7])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: OCCN(CCO)CCO
Solvent: CO
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The compound of formula 3a (100 g), 10% palladium carbon (10 g) and triethanolamine (2 g) were suspended in methanol and then hydrogenated at 40-45° C. for 2 h. After completion of the reaction (TLC monitoring), filtered the reaction mass to remove palladium carbon. cp. HCl (62 mL) was added to the filtrate, heated to reflux and maintained for 2 h. The reaction mass was cooled to ambient temperature, pH of the reaction mass was adjusted to 6.0-7.0 with 20% sodium hydroxide solution. Methanol was distilled off under vacuum at below 50° C. The resultant residue was dissolved in a mixture of isopropyl alcohol (300 mL) and purified water (600 mL) and pH was further adjusted to 9.0-10.0 with 20% sodium hydroxide solution at ambient temperature. The reaction mass was maintained for 10 h, cooled to 0-5° C., filtered and washed with purified water. The wet cake was suspended in isopropyl alcohol (350 mL), heated to reflux, and maintained for 30 min. The reaction mass was cooled to 2-4° C., maintained for 1 h., filtered and washed with isopropyl alcohol. The wet product was air dried to obtain the compound of formula 4 in 71.3 g (yield-95%) with HPLC purity of 99.76%.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([O:26][C@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:28]3)=[CH:20][C:21](=[O:25])[NH:22]2)=[CH:17][C:16]=1[CH:43]=[CH2:44].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:6]([O:25][C:21]1[CH:20]=[C:19]([O:26][C@H:27]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:28]2)[C:18]2[C:23](=[CH:24][C:15]([O:14][CH3:13])=[C:16]([CH:43]=[CH2:44])[CH:17]=2)[N:22]=1)[CH3:7]
Reactant: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(=O)[nH]c2cc1OC
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(OCC)nc2cc1OC

Procedure:
Triethyloxonium tetrafluoroborate (1.28 g, 6.75 mmol) was added to a solution of the product from step 3 (2.0 g, 4.5 mmol) in DCM (41 mL). DIEA (0.236 mL, 1.35 mmol) was then added after 15 min. After 45 additional min, the reaction mixture was worked up with NaHCO3 and DCM. The organic layer was then dried over MgSO4, and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 10-60% EtOAc/hexanes) to yield the title compound as an oil. LRMS (M+H)+=473.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH:11]=[CH:10][CH2:9][CH:8]=[CH:7]1)[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(C#N)C=CCC=C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1(C#N)CCCCC1
Yield: 94.3 %

Procedure:
Added 1% Pd/C catalyst (1.67 g, 0.157 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester (3.00 g, 15.7 mmol) in MeOH (75 mL). After shaking the reaction under 20 psi H2 at room temperature for 2 hours, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure to afford 2.89 g (94%) of product as an oil.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH3:41][NH2:42]>>[CH3:41][NH:42][C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CN
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Product: CNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and methylamine were reacted to give the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([CH2:9][CH2:10][OH:11])[N:7]=[C:6]([OH:12])[C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[Cl-].[NH4+]>CN(C)C(=O)C>[NH2:3][C:4]1[N:8]([CH2:9][CH2:10][O:11][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[N:7]=[C:6]([OH:12])[C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2c(O)nn(CCO)c2N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(O)nn(CCO[Si](C)(C)C(C)(C)C)c2N)cc1
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 44.3 %

Procedure:
Sodium hydride (0.35 g, 60% suspension in mineral oil) was added in one portion to a stirred solution of 5-amino-1-(2-hydroxyethyl)-4-(4-methylphenyl)-1-H-pyrazol-3-ol(1.0 g) (Preparation 32) in anhydrous N,N-dimethylacetamide (20 ml) under a nitrogen atmosphere at room temperature. The initial effervescence observed subsided after 2-3 minutes and an orange/brown mixture resulted. After a further 7 minutes, tert-butyldimethylsilyl chloride (0.65 g) was added to the mixture in one portion and the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride (50 ml) was added to the reaction mixture and the resulting aqueous medium was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water (40 ml), brine (40 ml) then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/hexane to give the title compound as a white solid (0.66 g).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15](=[O:28])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=1.Cl.CO.C(=O)([O-])O.[Na+].CCCCCC.C(OCC)(=O)C>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:15](=[O:28])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COCOc1ccc(CCC(=O)c2ccc(OCOC)cc2OCOC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: O=C(CCc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
Then, 4.44 g of the so-obtained 1-[2,4-bis(methoxymethoxy)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone was dissolved in methanol, and 38 ml of a hydrochloric acid/methanol reagent was added to the solution and the mixture was stirred at 60° C. for 30 minutes. After the reaction, the reaction liquid was poured into ice water, neutralized with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate, and the organic layer was washed with water, dried with sodium sulfate and concentrated under a reduced pressure to obtain a reaction mixture The reaction mixture was subjected to the column chromatography [69 g of 270-400 mesh Kieselgel 60; 0.5 kg/cm2 ; eluting solvent=hexane/ethyl acetate (1/1)] to obtain 2.55 g (yield=86.7%) of 1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)-1-propanone.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1)=[O:1]
Reactant: OCc1ccc(CCc2cccc3cncn23)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(CCc2cccc3cncn23)cc1

Procedure:
5-[p-(Hydroxymethyl)phenethyl]imidazo[1,5-a]pyridine (2.52 g) is refluxed in 100 ml of methylene chloride with 25.2 g of activated manganese dioxide for 24 hours. The mixture is filtered and evaporated to yield 5-(p-formylphenethyl)imidazo[1,5-a]pyridine.