Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[K+]>CO.O.O.CO>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:17][C:18]1=[O:19]
Reactant: [N-]=C=O
Reactant: COC(=O)CNCC(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.41 g (12.27 mmol) of the compound from Example 231A in 14 ml methanol/water (7:3) is added dropwise to a solution of 995 mg (12.27 mmol) of potassium isocyanate in 11 ml methanol/water (7:3). This is stirred for 1 hr at RT. The thick suspension is diluted with 7.4 ml water and 39 ml methanol to facilitate stirring, then heated under reflux for 1 hr and then left to stand overnight at RT. After cooling to 0° C., the precipitate is filtered off, washed with ice-cold water and dried overnight in the drying cabinet at 60° C. 2.84 g (76% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:19](=[O:20])[CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: ClCCOc1ccccc1
Product: O=C(Cc1ccccc1Cl)c1ccc(OCCCl)cc1

Procedure:
1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanoe is prepared according to the method described in the example 4a using 2-chloroethoxybenzene and 2-chlorophenylacetic acid as starting materials.
Reaction SMILES: Cl.[F:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([N:15]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:29]3)=[N:14][C:5]=2[CH:4]=1
Reactant: COCCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccc(F)cc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3sc(C)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
Combine 7-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (270 mg, 0.95 mmol), (S)-2-(3-methoxy-propyl)-piperazine (330 mg, 2 mmol) in a mixture of toluene and dimethylsulfoxide (1:2) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-7-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (320 mg, 0.82 mmol): mass spectrum (APCI): m/z=389.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][C:28]=2[O:29][CH3:30])/[C:13](=[O:22])[NH:14]3)=[CH:6][CH:5]=1.[Cl-].[NH4+]>O.CO.[Zn]>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][C:28]=2[O:29][CH3:30])/[C:13](=[O:22])[NH:14]3)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2c([N+](=O)[O-])ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2c(N)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Yield: 46.7 %

Procedure:
Using Method L above, (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-5-nitro-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (85 mg, 0.22 mmol) (from Example 45 supra) was reduced with zinc (130 mg, 1.97 mmol) and ammonium chloride (25.8 mg, 0.48 mmol) in 10% water in methanol (10 mL) at reflux for 2 h to yield (Z)-4-[5-amino-2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (yield: 40 mg, 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>CC(C)=O>[CH3:18][S:19]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)(=[O:21])=[O:20]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1C(=O)N2C(=NC1(C)C)N(S(C)(=O)=O)c1ccccc12

Procedure:
The general procedure of Example 17 was employed to prepare the title compound by reaction of 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, methanesulfonyl chloride and triethylamine in acetone solution. The title compound was isolated and purified by liquid chromatography giving a solid, mp 147° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][CH2:20][C:21]2[C:22]([NH:31][CH:32]([CH3:34])[CH3:33])=[CH:23][C:24]([N:27]([O:29][CH3:30])[CH3:28])=[N:25][CH:26]=2)=[C:12]([CH3:35])[CH:11]=1.CCN(CC)CC>O1CCOCC1>[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N:19]2[CH2:20][C:21]3[CH:26]=[N:25][C:24]([N:27]([O:29][CH3:30])[CH3:28])=[CH:23][C:22]=3[N:31]([CH:32]([CH3:33])[CH3:34])[C:4]2=[O:3])=[C:12]([CH3:35])[CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CON(C)c1cc(NC(C)C)c(CNc2cc([N+](=O)[O-])c(F)cc2C)cn1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CON(C)c1cc2c(cn1)CN(c1cc([N+](=O)[O-])c(F)cc1C)C(=O)N2C(C)C
Yield: 70.2 %

Procedure:
Using the procedure of Example A4 step 3, diphosgene (1.3 g, 6.4 mmol), 5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine (2.0 g, 5.3 mmol) and Et3N (2.2 g, 21.2 mmol) were reacted in dioxane to give 3-(4-fluoro-2-methyl-5-nitrophenyl)-1-isopropyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (1.5 g, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J=7.2 Hz, 1 H), 7.94 (s, 1 H), 7.55 (d, J=12.4 Hz, 1 H), 6.68 (s, 1 H), 4.77 (d, J=13.6 Hz, 1 H), 4.45-4.37 (m, 2 H), 3.71 (s, 3 H), 3.13 (s, 3 H), 2.14 (s, 3 H), 1.46 (t, J=6.4 Hz, 6H).
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:12]1[CH2:26][CH:13]1[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>ClC1C=CC=CC=1Cl>[OH:12][CH:13]([CH2:26][NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: NC1CCCc2ccccc21
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1CC(O)CNC1CCCc2ccccc21
Temperature: 150 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthylamine (99 mg, 0.68 mmol) in o-dichlorobenzene (1 ml) was added N-(2,3-epoxypropyl)phthalimide (137 mg, 0.68 mmol), and the mixture was stirred at 150° C. for 4 h. The reaction mixture was chromatographed on silica gel (eluting with 0.5% methanol/chloroform) to afford N-[2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (108 mg, 47%): MS(ES+) m/e 351 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.66 (m, 2H), 7.36 (m, 1H), 7.10 (m, 2H), 7.02 (m, 1H), 6.77 (br, 1H), 5.09 (m, 1H), 3.98 (m, 1H), 3.86-3.63 (m, 3H), 2.95-2.60 (m, 4H), 1.91-1.66 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:17]1([C:21]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1>>[N:17]1([C:21]([C:23]2[N:24]=[CH:25][C:26]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:27][CH:28]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1

Procedure:
The preparations of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]3[C:12]([CH2:13][NH:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]3[C:12]([CH2:13][N:14]([CH3:30])[CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Reaction time: 18 h
Yield: 64.1 %

Procedure:
Formaldehyde (37% w/v aqueous, 0.1 ml, 1.2 mmol) was added to a solution of the amine of example 12 (100 mg, 0.26 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (111 mg, 0.53 mmol) was added, and the reaction mixture was stirred for a further 18 hours. The mixture was partitioned between 2N aqueous sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was evaporated under reduced pressure and purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant to afford the title compound as a brown foam (66 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4][N:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>[Pd].CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: CC1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CNCCN1C(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
A mixture of 85 parts of (1,1-dimethylethyl) 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 55 parts (94.6%) of (1,1-dimethylethyl) 2-methyl-1-piperazinecarboxylate as a residue (int. 42).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH2:19]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCN(c2ccc(OC)cc2)CC1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl N-(4-methoxyphenyl)-isonipecotate (2.63 g, 10 mmol) in dichloromethane (100 mL) was added a solution of 2 M boron tribromide in dichloromethane (20 mL, 40 mmol), and the resulting solution was stirred for 0.5 hours at room temperature. The resulting reaction solution was poured into ice water, then an aqueous solution of 1 M sodium hydroxide (110 mL) was added to the solution. After stirring, the resulting solution was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to thereby yield 2.43 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccnc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccnc3)c2cc1OC
Yield: 19.8 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 112.9 mg (1.2 mmol) of 3-amino-pyridine to give 60.6 mg (19.8%) of the product as an orange solid, m.p. 231-233° C., mass (electrospray, m/e): M+H 306.8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:24])[C:9](=[O:23])[C:10]([C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([O:21]C)[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:3]=1.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:24])[C:9](=[O:23])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:21])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:3]=1
Reactant: COc1cc(OC)cc(C(C)(C)C(=O)N(C)c2cnc(Cl)cc2-c2ccccc2C)c1
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(O)cc(O)c1
Reaction time: 15 h
Yield: 95.1 %

Procedure:
To a solution of 2.8 g (6.4 mmol) N-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide in 70 ml CH2Cl2 19 ml (19 mmol) BBr3 (1 M in CH2Cl2) were added at 0° C. The reaction mixture was allowed to reach ambient temperature and stirred for 15 h After addition of 50 ml water the mixture was extracted with three portions of dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/methanol) to give 2.5 g (95%) of the title compound as a white foam.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][C@@H:10]2[O:9][C@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:23]2[O:24][C:25](=[O:27])[CH3:26])=[CH:31][CH:30]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Yield: 100.5 %

Procedure:
To a solution of galactose pentaacetate (3.30 g, 8.50 mmol) and 4-hydroxy-thiophenol (1.40 g, 11.1 mmol) in 50 mL of methylene chloride at -78° C. is added boron trifluoride diethyl ether complex (2.10 mL, 17.1 mmol ). The solution is allowed to warm slowly to 0° C. and then stirred for an additional hour at 0° C. The mixture is poured into saturated aqueous NaHCO3 (200 mL) and extracted with CH2Cl2 (2×150 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (50% EtOAc/hexane) to give 3.90 g (99%) of 1-deoxy-1-(4-hydroxyphenylthio)-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 78 as a white solid: Rf 0.3 (50% EtOAc/hexane); 1H NMR (CDCl3, 300 MHz) δ 7.42 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 5.78 (br s, 1H), 5.39 (d, J=2.56 Hz, 1H, H-4), 5.15 (t, J=9.9 Hz, 1H, H-2), 5.00 (dd, J=3.3, 9.9 Hz, 1H, H-3), 4.56 (d, J=9.9 Hz, 1H, H-1), 4.19 (dd, J=6.6, 11.0 Hz, 1H), 4.09 (dd, J=6.6, 11.0 Hz, 1H), 3.89 (t, J=6.6 Hz, 1H, H-5), 2.12 (s, 3H, OAc), 2.09 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.97 (s, 3H, OAc).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:6][S:7][CH2:8][CH:9]([CH3:24])[C:10](=[O:23])[CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]\[CH2:15][CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][OH:20])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:6][S:7][CH2:8][CH:9]([CH3:24])[C:10](=[O:23])[CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]\[CH2:15][CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][O:20][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H](CSCC(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO)NC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](CSCC(C)C(=O)CC/C(C)=C\CC/C(C)=C\COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.5 g of methyl N-acetyl-3-[[(6Z,10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]alaninate dissolved in 15 mil of methylene chloride is treated at 0° with 39 ml of pyridine and 30 ml of acetic anhydride. The solution is stirred at room temperature for 20 hours. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The crude product is chromatographed on silica gel with ether-methanol 50:1. There is obtained methyl N-acetyl-3-[[(6Z,10Z)-12-acetoxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]alaninate which exhibits the following absorption bands in the IR spectrum: 1738 cm-1, 1713 cm-1, 1664 cm-1, 1438 cm-1, 1412 cm-1, 1236 cm-1, 1117 cm-1.
Reaction SMILES: [OH-].[Na+].C([C:11]1[S:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:13](=[O:23])[CH:12]=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([N:14]2[C:13](=[O:23])[CH:12]=[CH:11][S:15]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(-n2sc(C(=O)c3ccccc3)cc2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(-n2sccc2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
Aqueous sodium hydroxide (4 mL, 10%) was added to the solution of 5-benzoyl-2-p-tolylisothiazol-3-one 29 (203 mg, 0.678 mmol) in benzene (9 mL), and the mixture was stirred for 3 d at room temperature. The reaction mixture was added water (20 mL) and extracted with ethyl acetate. The combined organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) and gave the compound 30 (77 mg, 59%). 1H-1-NMR (CDCl3, 300 MHz) δ 2.38 (s, 3H), 6.32 (d, J=6.6 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 8.14 (d, J=6.6 Hz, 1H). HRMS: calculated for C10H10NOS (M+H)+192.0483. Found 192.0494.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C3C=CC(C(F)(F)F)=CC=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1CC(O)=O)=[O:5])C.Cl[C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][N:42]=1>>[CH3:1][O:3][C:4]([C:7]1[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:9]2[C:14]([C:6]=1[C:4]([O:3][CH3:1])=[O:5])=[CH:13][C:12]([O:15][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][N:42]=1)=[CH:11][CH:10]=2)=[O:5]
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12

Procedure:
The title compound was prepared in accordance with step (c) Example 38 from 5-hydroxy-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid dimethyl ester (150 mg, 0.39 mmol, see (b) Example 12) and 2-chloro-5-nitropyridin (75 mg, 0.47 mmol). Yield 169 mg (86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1)[NH2:5].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].[N-]=C=O>C(Cl)Cl>[CH2:18]([NH:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[C:2]([F:1])[CH:3]=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Agent: [N-]=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 35 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
To a stirred solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.5 g, 6.33 mmol) in DCM (30 ml) was added ethyl isocyanate (1503 μL, 19 mmol). Reaction mixture was stirred at 35° C. for 20 hours. Additional isocyanate was added and reaction mixture left for sufficient time to ensure reaction completion. The crude reaction mixture was then partitioned between water and DCM. The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by flash chromatography using 0-60% ethyl acetate/petroleum ether 40-60 to yield a yellow solid (1.054 g, 3.42 mmol, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OC1CCOCC1
Yield: 66.9 %

Procedure:
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (3 g, 15 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-bromo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2.86 g, 67%).
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH2:5]1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH2:5]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCC[C@H](C(N)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCC[C@H](C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
In a 25 mL pear-shaped flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-carbamoyl-cyclohexyl)-amide (72 mg, 0.124 mmol) was combined with pyridine (412 μl) to give a off-white solution. The reaction mixture was cooled at 0° C. and trifluoroacetic anhydride (0.71 M in pyridine, 26 μl, 0.18 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 30 min and then concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 27 mg (39%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-cyano-cyclohexyl)-amide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.14 (s, 1H), 8.66 (s, 1H), 8.40 (d, J=8.7 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 8.01 (d, J=1.0 Hz, 1H), 7.38 (dd, J=8.7, 1.0 Hz, 1H), 5.73 (s, 2H), 4.18 (s, 3H), 4.09-4.28 (m, 1H), 3.59 (t, J=7.9 Hz, 2H), 3.41-3.60 (br. s., 1H), 2.24 (app. d, J=12.5 Hz, 1H), 2.07 (app. d, J=12.1 Hz, 1H), 1.59-1.91 (m, 5H), 1.39-1.59 (m, 1H), 0.86 (t, J=7.9 Hz, 2H), −0.08 (s, 9H).