Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([NH:17][C@@H:18]([CH2:27][S:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])=[CH:6]2.CCN(CC)CC.[C:45](Cl)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl>[CH3:47][C:46]([CH3:49])([CH3:48])[C:45]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([NH:17][C@@H:18]([CH2:27][S:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])=[CH:6]2)=[O:50]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cc(CO)cc([N+](=O)[O-])c3[nH]2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cc(COC(=O)C(C)(C)C)cc([N+](=O)[O-])c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,2-Dimethyl-propionic acid (R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)-amino]-3-(4-methoxy-benzylsulfanyl)-propyl ester (3.1 g, 6.01 mmol) prepared in Step A of Preparation 41 was dissolved in DCM, to which was added Et3N (1.68 mL, 12.02 mmol). Pivaloyl chloride (0.92 mL, 6.61 mmol) was added thereto, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex=1/1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]=[CH:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH3:2].ClC1C=CC=CC=1Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)CCC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 16.82 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1-methyl-indol-3-yl)-pent-2-enoic acid ethyl ester in 170 ml of tetrahydrofuran is hydrogenated for 70 minutes at 20° C. in the presence of 1.7 g of palladium/activated carbon (10%) and 0.2 g of 1,2-dichlorobenzene. The reaction mixture is then filtered and concentrated by evaporation. In this way the title compound is obtained in the form of a brownish-green resin. Rf value=0.265 (ethyl acetate/hexane 2/3).
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[N:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([CH3:27])[CH3:26])[N:24]=1>Br.O>[F:28][C:25]([C:23]1[CH:22]=[N:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[N:24]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(F)c1cnnc(N)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(F)c1cnn2ccnc2n1
Reaction time: 17 h
Yield: 17.3 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (1.20 ml, 7.73 mmol) in concentrated hydrobromic acid (0.38 ml) and water (0.38 ml) was heated at reflux for 40 min, then poured into ethanol (3 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered, washing the solid with more ethanol (3 ml). To the filtrate was added 3-amino-5-(1-fluoro-1-methylethyl)-1,2,4-triazine (1.0046 g, 6.43 mmol) and the mixture was stirred at 70–80° C. for 17 h. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 70% EtOAc/isohexane to 15% MeOH/EtOAc, then 20% EtOAc/CH2Cl2) to give 0.2000 g (17%) of the title compound as a pale yellow solid: 1H NMR (360 MHz, CDCl3) δ 1.82 (6H, d, J 22 1), 7.97 (1H, d, J 1.3), 7.99 (1H, d, J 1.2), 8.69 (1H, d, J 1.0).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>O>[C:1]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: CNCCO
Solvent: O
Product: CN(CCO)C(=O)c1ccccc1

Procedure:
Ethyl benzoate (16.0 g, 15.3 ml) was dissolved in 2-(N-methylamino)ethanol (200 ml) and the mixture heated at reflux for 17.5 hours, cooled and diluted with water (1 l). The mixture was extracted with dichloromethane (4×200 ml), and the combined dichloromethane solutions washed with brine (300 ml), dried (MgSO4) and evaporated. The title compound, an oil, was used without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-nitrobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a yellow crystalline powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][CH:3]=1.[CH2:10]([O:12]/[CH:13]=[CH:14]/B1OC(C)(C)C(C)(C)O1)[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](/[CH:11]=[CH:10]/[O:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Clc1nc(Br)ccc1I
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCO/C=C/c1ccc(Br)nc1Cl
Temperature: 73 °C

Procedure:
To a mixture of 6-bromo-2-chloro-3-iodopyridine (8.0 g, 25.1 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.98 g, 25.1 mmol), cesium carbonate (16.38 g, 50.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.052, 2.51 mmol) was added 1,4-dioxane (100 mL) and H2O (10 mL). A steady stream of N2 was bubbled through the reaction mixture for 15 minutes then the mixture was heated to 73° C. for 20 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a step gradient of 0-10-60% EtOAc/Hexanes as eluent. MS (M+H): 261.
Reaction SMILES: [C:1]1([PH:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:8]1([PH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 157 °C
Yield: 45.1 %

Procedure:
101 g (0.5 mol) of diphenylphosphine oxide and 0.5 g of aluminum chloride are mixed and heated to 157° C., the pressure being reduced simultaneously (12 mbar). Diphenylphosphine distills off through a descending condenser at a transition temperature of 144° C. The internal temperature is finally raised to 183° C. 42 g of diphenylphosphine are obtained with a purity of 99% according to 31P NMR. That corresponds to a yield of 90% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6](C2C=CC(F)=CC=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[Br:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:28]=1C=O>>[Br:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:28]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][Br:12])[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=Cc1cccc(F)c1Br
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Br

Procedure:
Methyl (4R)-4-(2-bromo-3-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 94a was prepared in analogy to compound C with procedures shown in Example 1 by using 2-bromo-3-fluorobenzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:21])([F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][N:13]=2)=[CH:8][CH:7]=1>CO>[F:21][C:4]([F:3])([F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([CH2:18][OH:19])=[CH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
NaBH4 (0.22 g, 5.82 mmol) was added to a solution of aldehyde 90 (0.776 g, 2.89 mmol) in MeOH (100 mL) at 0° C. The solution was stirred at 0° C. for 1 h, then quenched with brine and partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel (eluting with 1:1 EtOAc/hexanes) gave {2-[4-(trifluoromethoxy)phenyl]-5-pyrimidinyl}methanol (91) (0.657 g, 84%) as a white solid: mp 84-85° C.; 1H NMR [(CD3)2SO] δ 8.86 (s, 2H), 8.50 (d, J=8.9 Hz, 2H), 7.51 (d, J=8.9 Hz, 2H), 5.46 (t, J=5.5 Hz, 1H), 4.60 (d, J=5.5 Hz, 2H). APCI MS m/z 271 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[S:13][C:6]2[NH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:5]=2[CH:4]=1)#[N:2].Cl.[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18]>>[CH2:24]([C@H:16]([NH:15][C:10]([C:8]1[NH:7][C:6]2[S:13][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH:9]=1)=[O:12])[C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cc2cc(C(=O)O)[nH]c2s1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Agent: Cl
Product: N#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1

Procedure:
2-Cyano-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride were coupled according to Procedure B.
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](OCC)=[O:11])=[N:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([N:4]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][OH:11])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)nn1C(C)C
Reaction time: 2 h
Yield: 88 %

Procedure:
To ethyl 1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate (7.68 g, 39.1 mmol) in THF (50 mL) at 0° C. was added LAH (1.49 g, 39.1 mmol). The cold bath was removed, and the reaction mixture was stirred for 2 hours and quenched carefully with sodium sulfate decahydrate. The reaction mixture was filtered through Celite® and washed with Et2O (200 mL). The filtrate was concentrated under reduced pressure to give the desired product (88%).
Reaction SMILES: CN1CCNCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:18]=[C:17]([N:19]3CCN(C)CC3)[C:16]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:15]=3[O:14][C:13]=2[CH:34]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:18][C:17]#[N:19])=[C:13]([O:14][C:15]2[CH:16]=[CH:26][CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)[CH:34]=1
Reactant: CN1CCN(C2=Cc3ccc(Cl)cc3Oc3cc(C(F)(F)F)ccc32)CC1
Agent: CN1CCNCC1
Product: N#CCc1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1

Procedure:
The last-named intermediate is reacted with 1-methylpiperazine in the same manner as described in Example 14 to give the desired starting material, 1-[3-chloro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methylpiperazine, having a melting point of 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C=C(c2ccc(Cl)c(Cl)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1C=C(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)cyclopent-2-en-1-one (2 g, 8.8 mmol) in methanol (40 mL) at 0° C. was treated with CeCl3 7H2O (4.26 g, 11.4 mmol) followed portionwise by NaBH4 (0.43 g, 11.4 mmol). The reaction was warmed to room temperature. The reaction mixture was stirred for 4 h, then quenched with saturated aqueous NH4Cl and concentrated to remove methanol. The concentrate was diluted with H2O and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel chromatography using CH2Cl2/Methanol as the eluting solvent to afford 2 g (Yield 99%) of the target compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82-1.92 (m, 1 H) 2.40-2.52 (m, 1 H) 2.54-2.65 (m, 1 H) 2.79-2.91 (m, 1 H) 4.96-5.04 (m, 1 H) 6.20-6.26 (m, 1 H) 7.27-7.31 (m, 1 H) 7.37-7.42 (m, 1 H) 7.51 (d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)\[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)\[CH:11]([OH:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To 50 cc of a methanol solution containing 3.2 g of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (melting point 92°-93° C.) characterized by the NMR spectrum shown below, was added 0.5 g of sodium borohydride, while cooling in ice. The mixture was then stirred at room temperature for 3 hours and treated as in Reference Example 1 to obtain 2.6 g of the captioned compound melting at 148°-149° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C)C=O.[Cl-].[NH4+]>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
Dissolve 3,5-dimethylpyrazole (0.331 g, 3.44 mmol) in N,N-dimethylformamide (7 mL) and add sodium hydride (0.165 g, 4.13 mmol). After 10 min., cool to 0° C. and add 4-methoxybenzyl chloride (0.654 mL, 4.82 mmol) dropwise. Stir the mixture at 25° C. for 18 hr. then dilute with saturated ammonium chloride. Extract with ethyl acetate 3 times, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 40:60 hexanes:ethyl acetate), to give 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole as a colorless oil (0.682 g, 92%). MS (APCI): m/z=217 [M+H].
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13](=[S:21])NC1C=NC=CC=1>Cl>[CH2:2]1[CH:3]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:13][S:21]1
Reactant: OC[C@@H]1Cc2ccccc2CN1C(=S)Nc1cccnc1
Agent: Cl
Product: c1ccc2c(c1)CC1CSCN1C2
Yield: 113.6 %

Procedure:
(S)-3-Hydroxymethyl-N-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (13.5 g.) in 6N hydrochloric acid (300 cc.) is heated for 40 minutes at 100° C. After cooling, the solution obtained is concentrated under reduced pressure (25 mm. Hg) to 1/5 of its volume. It is rendered alkaline by adding 10N sodium hydroxide solution (200 cc.) and is then extracted with methylene chloride (3 × 150 cc.). The organic extracts are combined and then dried over magnesium sulphate. After filtering, and concentrating the filtrate to dryness under reduced pressure (25 mm. Hg), a yellow oil (11 g.) is obtained, which crystallises on addition of diisopropyl ether (150 cc.). The white crystals are filtered off, washed with diisopropyl ether (3 × 10 cc.) and then dried at 60° C., under reduced pressure (1 mm. Hg). (S)-3-Pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (9.8 g.), melting at 111° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[SH:10][CH2:11][CH2:12][OH:13].C(=O)(O)[O-].[Na+].C(Cl)Cl>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][OH:13]
Reactant: OCCS
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCCSc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,4,6-trichloropyridazine (25 g) in tetrahydrofuran (200 ml) and triethylamine (19 ml) was treated at 0° C. (ice bath cooling) with 2-mercaptoethanol (8.33 ml) over 5 minutes: After the addition was complete, the mixture was stirred at rt for 72 hours. The mixture was stirred with aqueous sodium bicarbonate solution and DCM and the solid was collected, washed with water, ether and pentane and dried in vacuo, giving (22.9 g). The combined aqueous and organic fraction was evaporated to half volume giving further solid, which was washed and dried as above (5.0 g). The total yield of solid (27.9 g; 91%) contained some bromo-analogue (5-10%) by NMR.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:32]1[C:28]([CH3:27])=[N:29][O:30][C:31]=1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Reactant: Cc1noc(C)c1B(O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1-c1c(C)noc1C
Yield: 76 %

Procedure:
By carrying out the operation analogously to example 3, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected compound is obtained in the form of a white solid with a yield of 76%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([O:34]C)=[O:33])=[CH:22][N:23](COC(=O)C(C)(C)C)[C:18]3=[N:17][CH:16]=2)=[N:3]1.[OH-].[K+]>O1CCOCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([OH:34])=[O:33])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C(F)(F)F)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(C(F)(F)F)cc21
Yield: 155.7 %

Procedure:
A mixture of methyl 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyl oxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (200 mg, 0.409 mmol) and KOH (229 mg, 4.09 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated to reflux for 4 hours. Dioxane was concentrated and the residual aqueous layer was adjusted to pH=4 with 1.0 M HCl. The precipitate was collected by filtration and dried to afford 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (230 mg, crude) as a yellow solid. LCMS: (M+H)+=362.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N:7]1([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:11]=[CH:10][CH:9]=[CH:8]1>ClCCCl>[CH:1]1([C:4]([C:8]2[N:7]([N:12]3[C:16](=[O:17])[C:15]4=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]4[C:13]3=[O:22])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCCl
Product: O=C(c1cccn1N1C(=O)c2ccccc2C1=O)C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Boron trifluoride-diethyl ether complex (10 g; 23.6×3 mM) was dissolved in 80 ml of 1,2-dichloroethane at 25° C., followed by adding dropwise cyclopropanecarbonyl chloride (7.4 g; 23.6×3 mM). After a suspension of N-(1H-pyrrol-1-yl)phthalimide (IX-1; 5 g; 23.6 mM) in 40 ml of 1,2-dichloroethane was added, the mixture was stirred at 25° C. for 18 hours. The reaction mixture was poured into ice-water and insoluble materials were removed by filtration. The 1,2-dichloroethane phase of the filtrate was separated and washed with a saturated saline solution, followed by drying with anhydrous sodium sulfate. After dried, it was concentrated and the resultant residue was purified with column chromatography on silica gel. White solid; m.p. 150°-2° C.; Yield 2.35 g (35.6%); HPLC purity 92% (254 nm) IR (KBr cm-1): 1803 1752 1647 1431 1398 1275 1236 1071 975 708 NMR(CDCl3, δ): 0.66~1.28(4H,m:cyclopropane ring CH2 --CH2) 2.16~2.5(1H,m:cyclopropane ring CH) 6.3(1H,dd,J=3,4 Hz:pyrrole ring C4) 6.9(1H,dd,J=2,3 Hz:pyrrole ring C3 or C5 ) 7.2(1H,dd,J=2,4 Hz:pyrrole ring C3 or C5 ) 7.5~8.0(4H,m:aromatic H)
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].Cl[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])=[O:15]>C(Cl)(Cl)Cl.OS([O-])(=O)=O.[K+]>[C:14](=[O:15])([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])[O:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(Cl)OCCCCCl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(OCCCCCl)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of pentafluorophenol (1 g, 5.43 mmol) and TEA (0.91 ml, 6.52 mmol) in CHCl3 (8 ml), cooled to 0° C. and under nitrogen, a solution of 4-chlorobutyl chloroformate (0.76 ml, 5.43 mmol) in CHCl3 (1 ml) was dropped into. The mixture was allowed to warm to room temperature and stirred for 480 minutes. Then it was diluted with aqueous KHSO4 (2%), the two phases were separated and the organic phase was dried and evaporated yielding 4-chlorobutyl pentafluorophenyl carbonate (1.69 g, 98%) as a colorless oil that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1F

Procedure:
Synthesized using 3,4-difluorophenylboronic acid (270 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 210 mg, 0.77 mmol, 92%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.18 (s, 2H), 6.92 (t, J=1.3 Hz, 1H), 7.13 (t, J=1.3 Hz, 1H), 7.25 (ddd, J=9.8, 8.5, 8.2 Hz, 1H), 7.49 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (s, 1H), 7.66 (dd, J=8.3, 0.6 Hz, 1H), 7.69-7.73 (m, 1H), 7.86 (ddd, J=11.4, 7.6, 2.2 Hz, 1H), 8.56 (dd, J=2.3, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 116.0 (d, J=18.2 Hz), 117.6 (d, J=17.3 Hz), 119.0, 120.2, 122.8 (dd, J=3.8, 6.7 Hz), 130.4, 130.6, 135.6 (dd, J=3.8, 5.8 Hz), 135.9, 137.3, 148.6, 150.8 (dd, J=20.2, 255.3 Hz), 151.3 (dd, J=15.4, 254.3 Hz), 155.3; MS (ESI): m/z=272.10 [M+H]+.