Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7](SC)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.[CH3:53][O:54][C:55]1[CH:69]=[CH:68][C:58]([C:59]([NH:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]2)=[O:60])=[CH:57][CH:56]=1>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[CH3:53][O:54][C:55]1[CH:56]=[CH:57][C:58]([C:59]([NH:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][N:64]([C:7]3[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)[N:6]=3)[CH2:63]2)=[O:60])=[CH:68][CH:69]=1
Reactant: COc1ccc(C(=O)N[C@@H]2CCCNC2)cc1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3nnc(C(N)=O)c(Nc4ccc(C5CCNCC5)cc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (1.20 g, 5.15 mmol) in acetonitrile (40 mL) was added tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.14 g, 7.73 mmol) and then DIEA (1350 μL, 7.73 mmol). The mixture was stirred at RT for 1 hour. To the mixture was then added ammonia (7.0 N solution in methanol, 30 mL). The mixture turned cloudy in 10 min and then into a suspension. The mixture was stirred for 8 hours, and the solid was isolated by filtration. It was washed with cold acetonitrile (10 mL×2) and then washed with hexane (10 mL×3). The solid was dried in a vacuum oven to afford tert-butyl 4-(4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (490) (1.82 g, 79% yield) in high purity. Compound 490 (600 mg, 1.35 mmol) was dissolved in 20 mL NMP. To it were added dry mCPBA (77% strength, 840 mg, 3.38 mmol). The mixture was stirred at RT for 1 hour. To the mixture was added DIEA (2.10 mL, 12.1 mmol) and (R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) (550 mg, 2.03 mmol). The mixture was stirred at 70° C. for 30 min. The mixture was cooled to RT, diluted with 200 mL chloroform, washed with 1N NaOH (aq) ×2 and water, dried, concentrated in vacuo to dryness for crude (R)-tert-butyl 4-(4-(6-carbamoyl-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (491) (740 mg, 87%). It was treated with 35 mL commercial 4N HCl in dioxane at RT for 45 min. The mixture was concentrated in vacuo to dryness to afford crude (R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(piperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (492). A small amount of crude 492 was purified using reverse phase prep HPLC to isolate as HCl salt. LC-MS (ESI): m/z (M+1) 531.1. UV: λ=255 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)(=[O:31])=[O:32]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.200 g, 0.709 mmol) and 3-nitro-benzenesulfonyl chloride (0.157 g, 0.709 mmol) in 10 mL of dichloromethane, was added triethylamine (0.5 mL, 3.544 mmol). After stirring at room temperature under N2 for 16 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 20-50% ethyl acetate/hexanes to give the title compound as light yellow semi-solid (0.128 g, 39% yield). LC-MS: tR=9.5 min; m/z 468 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C(N)CN.Cl>CN(C=O)C.C(Cl)Cl>[CH2:19]([N:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@@H](Nc1ccc(F)c(Cl)c1)C(C)C
Agent: Cl
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](C(C)C)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Ethyl N-(3-chloro-4-fluorophenyl)valinate (8-1, 0.20 g, 0.74 mmol), benzylbromide (0.380 g, 2.21 mmol), and diisopropylethyleneamine (0.11 g, 0.89 mmol) were combined in DMF (0.1 mL) and stirred 18 h at 50° C. Additional benzylbromide (0.43 g, 2.5 mmol) and diisopropylethylamine (0.22 g, 1.7 mmol) were added and mixture was heated to 60° C. for 4 h and then 50° C. for 18 h. Ethylenediamine (0.266 g, 4.43 mmol) and CH2Cl2 (9 mL) were added to the mixture which stirred for 18 h at 23° C. The mixture was acidified with 1N aqueous HCl. The aqueous layer was washed with CH2Cl2 (3×). The organic layers were dried with MgSO4 and concentrated to give crude ethyl N-benzyl-N-(3-chloro-4-fluorophenyl)valinate (8-2) as a brown oil. MS 364.4 found, 364.1 (M+H+) required.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH2:8]([O:15][C:16]1[C:24]2[N:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:23]=2[C:22]2[CH:21]([CH2:30][OH:31])[CH2:20][N:19](S(C)(=O)=O)[C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C1COCC1>[CH2:8]([O:15][C:16]1[C:24]2[N:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:23]=2[C:22]2[C@H:21]([CH2:30][OH:31])[CH2:20][NH:19][C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cn(C)c2c(OCc3ccccc3)cc3c(c12)C(CO)CN3S(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cn(C)c2c(OCc3ccccc3)cc3c(c12)[C@H](CO)CN3
Reaction time: 5 h

Procedure:
To a suspension of 2b (3.3 g, 5.0 mmol) in a mixture of methanol (50 mL) and THF (30 mL) was added 5 mL of 1 M sodium methoxide in methanol. The reaction mixture was stirred for 5 hours, becoming a clear solution in approximately 30 min. Acetic acid (0.3 mL) was added to neutralize sodium methoxide, and the solution was evaporated to dryness. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel, eluting with 5% acetone in CH2Cl2, afforded 1.6 g (85%) of (1S)-2a as a white solid. This product was shown by NMR and CHN analysis to be identical with the racemic material (2a). (1R)-2a was prepared analogously from 2c.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:31])OCC(Cl)(Cl)Cl)[C:5]=1[CH3:32])(=[O:3])[CH3:2].[OH:33][CH2:34][CH2:35][NH2:36]>>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24]([NH:36][CH2:35][CH2:34][OH:33])=[O:31])[C:5]=1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reactant: NCCO
Product: CC(=O)c1c(C)c(NC(=O)NCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 66 %

Procedure:
Using 2,2,2-trichloroethyl (7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 206 and 2-hydroxyethylamine, the title compound was obtained in the same manner as in Example 143. Yield: 66%.
Reaction SMILES: S1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[N:2]1.C[N+]1([O-])CCOCC1.[S:16](=[O:20])(=O)(O)[O-:17].[Na+].C(Cl)Cl>O.CC(C)=O.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[S:16]1(=[O:20])(=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)([O-])O
Reactant: C1=CC=NSC=C1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: O=S1(=O)C=CC=CC=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a stirred solution of the thiazepine prepared in Step 8 of Example 482 (243.7 mg) in 25% H2O/acetone (8 mL) is added 4-methylmorpholine N-oxide (201.5 mg) followed by a solution of osmium tetroxide in 2-methyl-2-propanol (2.5 wt %, 30 μL). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is treated with saturated sodium bisulfate (8 mL), then poured into CH2Cl2 (50 mL). The phases are separated. The aqueous phase is extracted with CH2Cl2 (2×25 mL). The combined organic phases are washed with brine (1×25 mL), dried (MgSO4), filtered and concentrated. The residue is purified on a Biotage 40 S column using 1% CH3OH in CH2Cl2 as the eluent to afford 216.1 mg (0.47 mmol, 83%) of the thiazepine S,S-dioxide as a white solid. mp 144-146° C.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 2-hydroxy-2-methylpropanoic acid (500 mg, 4.80 mmol) in dry THF (10 ml), NaH (60% dispersion in mineral oil, 192 mg, 4.80 mmol) was added portionwise at 5° C. The resulting mixture was stirred 1 hour at RT. The solvent was removed, the residue was suspended in dry DMF (7 ml), and (bromomethyl)benzene (821 mg, 4.80 mmol) was added followed by a catalytic amount of KI. The reaction was heated under microwave irradiation at 100° C. for 3 hours. After cooling, the solvent was evaporated and the residue was partitioned between water and EtOAc; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc/petroleum ether=1/1) affording benzyl 2-hydroxy-2-methylpropanoate as a yellow liquid (773 mg, 3.98 mmol, 83% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69 %

Procedure:
By the reaction of ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate with 4-chlorobenzenesulphonyl chloride in a manner analogous to that described in Example 2, there is obtained, in a yield of 69% of theory, colorless ethyl 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy}-2-methylpropionate in the form of a viscous oil. From this there is obtained, by hydrolysis:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[CH:35].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:35]#[C:34][C:36]3[CH:37]=[CH:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (230 mg; 0.43 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (229.7 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 140 mg. HPLC-MS: m/z: 641.5 (M+H)+; Rt: 2.89 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Br[CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([O:8][CH:11]2[CH2:13][CH2:12]2)[CH:7]=1
Reactant: BrC1CC1
Reactant: Oc1cc(Br)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc(Br)cc1OC1CC1
Temperature: 150 °C
Reaction time: 47 h
Yield: 87.9 %

Procedure:
A mixture of 5-bromo-2-chlorophenol (543 mg, 2.62 mmol), bromocyclopropane (836 μl, 10.47 mmol) and caesium carbonate (1.701 g, 5.24 mmol) in N,N-dimethylacetamide (7.5 ml) was stirred for 47 h at 150° C. After 25.25 h further bromocyclopropane (836 μl, 10.47 mmol) was added. The reaction mixture was poured onto ice-water (40 ml) and set to pH=2 with aqueous HCl (1 N, 9.5 ml). This mixture was extracted with TBME (twice 50 ml). The organic layers were washed with brine (40 ml), combined and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (570 mg, 87%) as a light yellow oil. MS m/e: 248.0 [M+H]+
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C>[CH:12]1([NH:21][C:2]2[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: NC1CCc2ccccc21
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1NC1CCc2ccccc21
Yield: 95.7 %

Procedure:
A solution of 3-fluoro-4-nitropyridine-1-oxide (5.6 g) and indan-1-amine (6 g) in 100 ml ethanol was stirred at reflux for one hour and thereafter cooled and concentrated to 12 g of solid. This solid was purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give 9.2 g solid, m.p. 137°-138°. An analytical sample was obtained by recrystallizing 2.7 g from ethanol to give 2.5 g crystals, m.p. 141°-142°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[I:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([I:35])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)c(F)ccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(I)cc3)c3c(Cl)c(F)ccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Chloro-5-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole obtained in Example 34-(3) and 4-Iodobenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 548/550 (M+H). 1H-NMR (DMSO-d6) δ 3.15-3.45 (m, 4H), 3.62 (m, 2H), 4.21 (s, 2H), 4.52-4.58 (br, 1H), 5.10-5.17 (br, 1H), 5.18-5.30 (br, 2H), 5.40 (d, J=9.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 2H), 7.16 (t, J=9.3 Hz, 1H), 7.42 (s, 1H), 7.57 (dd, J=9.0, 4.0 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:23]=[O:24]>O1CCCC1>[C:25]([NH:22][C:23](=[O:24])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCNC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N(CCCCCCO[Si](C)(C)C(C)(C)C)C1CCCCC1
Reaction time: 2 h
Yield: 114 %

Procedure:
To a solution of N-(6-((tert-butyldimethylsilyl)oxy)hexyl)cyclohexanamine (330 mg, 1.05 mmol) in tetrahydrofuran (5 mL) at 0° C. was added 2-isocyanato-2-methylpropane (0.14 mL, 1.16 mmol). The mixture was stirred for 2 hours before it was quenched with methanol, and concentrated. Purification on silica gel with ethyl acetate: hexanes from 0:1 to 1:9 provided desired product as a clear oil (494.1 mg, 114%). 1H NMR (300 MHz, CDCl3): δ 4.11 (s, 1H), 3.99-3.84 (m, 1H), 3.56 (t, J=6.4 Hz, 2H), 2.92 (t, J=8.2 Hz, 2H), 1.80-0.94 (m, 18H), 0.85 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-cyano-phenylboronic acid to give 4-[6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 356(MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=[O:9].Br[CH:13]([CH2:16][CH3:17])[CH:14]=O>C1(C)C(C)=CC=CC=1>[CH2:16]([C:13]1[N:1]2[C:2]([CH:3]=[CH:4][CH:5]=[CH:6]2)=[C:7]([C:8]([OH:10])=[O:9])[CH:14]=1)[CH3:17]
Reactant: COC(=O)Cc1ccccn1
Reactant: CCC(Br)C=O
Solvent: Cc1ccccc1C
Product: CCc1cc(C(=O)O)c2ccccn12

Procedure:
A solution of methyl 2-pyridylacetate (6 ml) 2,6-lutidine (6 ml) and 2-bromobutyraldehyde (5.5 g) (P. Duhamel, L. Duhamel, J-Y. Valnot, Bull. Soc. Chim. Fr. 1973(4) 1465) in xylene (200 ml) was heated under reflux overnight, removing water by means of a Dean and Stark apparatus. The reaction mixture was cooled, washed with dilute citric acid solution and the organic phase dried (Na2SO4) and concentrated. Column chromatography (SiO2, CH2Cl2) of the residue afforded the methyl ester of the title compound (4.6 g). A solution of the ester (4.6 g) in EtOH (100 ml) and 1N NaOH (50 mL) was heated under reflux for 3h. The reaction mixture was cooled, the EtOH evaporated and the aqueous residue washed with Et2O (50 mL). Acidification of the aqueous layer afforded the title compound (3.0 g).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].CON(C)[C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31][CH3:32])[CH:26]=2)=[CH:21][CH:20]=1>>[F:5][C:3]([F:6])([C:2]([F:8])([F:7])[F:1])[C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31][CH3:32])[CH:26]=2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1ccc(-c2cccc(SC)c2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: CSc1cccc(-c2ccc(C=CC(=O)C(F)(F)C(F)(F)F)cc2)c1
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (203.5 mL, 162.8 mmol), was slowly added methyllithium/lithium bromide (1.5 M, in diethyl ether) (108.6 mL, 162.8 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of N-methoxy-N-methyl-3-(3′-methylsulfanyl-biphenyl-4-yl)-acrylamide (17.0 g, 54.3 mmol, in tetrahydrofuran 20.0 mL) prepared in Step 1 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether three times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 15.4 g of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.[Cl-].[NH4+]>ClCCl.O1CCCC1>[Br:25][C:10]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl 2-(6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate (0.90 g, 2.98 mmol) in dichloromethane (10 mL) and tetrahydrofuran (5 mL) was added N-bromosuccinimide (0.59 g, 3.38 mmol) at room temperature. After 16 h, a saturated aqueous solution of ammonium chloride (25 mL) was added and this mixture was extracted with ethyl acetate (3×60 mL). The combined extracts were washed with brine (10 mL), dried (magnesium sulfate), and evaporated. The residue was purified by chromatography (silica, 30% to 50% ethyl acetate in hexane) to give (1.1 g, 91%): 1H NMR (CDCl3) δ 7.86 (1H, d, J=8.8 z), 7.80 (1H, s), 7.37 (6H, m), 6.18 (1H, brs), 5.24 (1H, brs), 4.95 (2H, s), 4.80 (2H, m), 4.34 (1H, m), 1.26 (3H, d, J=6.8 Hz); MS (ES) m/z 404, 406 (M+).
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[CH3:11]>>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:10][CH3:11])=[O:4]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: CCO
Product: C=CCC(F)(F)C(=O)OCC

Procedure:
Analogously to Example 1, 38.5 g (0.28 mol) of 2,2-difluoro-4-pentenoic acid are esterified with ethanol. Yield: 41.3 g (89%) of a colourless oil of boiling point 55°-57° C./52 mbar, 1H-NMR (60 MHz, CDCl3): 6.1-5.0 (m, 3H); 4.30 (qa, J=7 Hz, 2H); 2.85 (d x t, J=16 Hz, 2H); 1.35 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([CH3:12])[CH:3]=1.[BrH:13].BrBr.C([O-])([O-])=O.[Na+].[Na+]>>[Br:13][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:12])=[O:11]
Reactant: Br
Reactant: CCC(=O)c1cnc(Cl)cc1C
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)ncc1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(6-Chloro-4-methyl-pyridin-3-yl)-propan-1-one (100 mg, 0.545 mmol) is dissolved in hydrobromic acid (48%) (2 ml, 17.68 mmol); to this is then added bromine (0.031 ml, 0.599 mmol) dropwise and the resulting orange solution stirred at RT. After 4 hours, further 0.2 eq (5 ul) of bromine is added and the reaction is left stirring O/N at RT. The reaction mixture is basified by careful addition of 2M Na2CO3 (5 ml) and then extracted into EtOAc (2×25 ml). The combined organic phase is washed with H2O, brine, dried (MgSO4) and evaporated to give a clear oil. The crude material is chromatographed on silica gel (20 g) eluting with (10% EtOAc/iso-hexane) to give the desired compound; MS: m/z 262.1 [M+H]+; 1H NMR (400 MHz, (CDCl3) δ 7.9 (d, 1H), 7.3 (d, 1H), 5.1 (q, 1H), 2.7 (s, 3H), 1.9 (d, 3H).