Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[NH3:36]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:36])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:28][CH2:29]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C3CC3)c2)cc1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C3CC3)c2)cc1
Temperature: 100 °C
Reaction time: 47 h
Yield: 27.6 %

Procedure:
A 20-mL vial was charged with ethyl 2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetate (0.090 g, 0.23 mmol), dioxane (1 mL) and methanol (3 mL). To this solution was added NH3 (6.0 mL, 7N in methanol, 42.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 47 h. The crude reaction mixture was concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetamide (0.024 g, 27%) as a colorless oil. MW=377.87. 1H NMR (CDCl3, 500 MHz) δ 7.94-7.91 (m, 1H), 7.81-7.76 (m, 1H), 7.36-7.31 (m, 2H), 7.30-7.26 (m, 2H), 7.21-7.17 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.02 (s, 1H), 5.45 (br s, 2H), 3.58 (s, 2H), 1.99-1.93 (m, 1H), 1.13-1.08 (m, 2H), 0.97-0.92 (m, 2H); ESI MS m/z 378 [M+H]+. Treatment with 1.25M HCl (0.103 mL, 0.130 mol) in methanol afforded the title compound (0.022 g, 84%) as an off-white solid. MW=414.33. M.p. 104-106° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.48 (br s, 1H), 8.78 (br s, 1H), 7.92 (d, J=1.0 Hz, 1H), 7.84-7.76 (m, 1H), 7.52 (br s, 2H), 7.45 (s, 1H), 7.30-7.25 (m, 2H), 7.25-7.16 (m, 2H), 7.11 (s, 1H), 6.87 (s, 1H), 6.74 (s, 1H), 3.36 (s, 2H), 2.15-2.02 (m, 1H), 1.10-0.90 (m, 4H); ESI MS m/z 378 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11].O>CO>[CH3:1][O:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(CCCCCBr)N1CCCc2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCCCC(=O)N1CCCc2ccccc21

Procedure:
Sodium methoxide (0.8 g) was added to a solution of 1-(6-bromohexanoyl)-1,2,3,4-tetrahydroquinoline (2.1 g) in methanol (50 ml). The mixture was refluxed for 8 hours, then poured into water and extracted with ether. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with 98:2 methylene chloride:methanol, so as to obtain the product 1-(6-methoxyhexanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [BH4-].[Na+].O.C(=O)(O)[O-].[Na+].[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]=[C:17]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH:17]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc2c(c1)C(c1ccc(C(F)(F)F)cc1)=NCC2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)C(c1ccc(C(F)(F)F)cc1)NCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (0.6 g, 2.1 mmol) in methanol (10 mL) from step 2 was cooled to 0° C. and sodium borohydride (0.2 g, 6.2 mmol) was added in small portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with ethyl acetate (10 mL) and concentrated to yield a light-yellow residue which was dissolved in ethyl acetate (40 mL), water (10 mL), and saturated sodium bicarbonate (20 mL). After stirring for 15 min, it was transferred to a separatory funnel, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale-yellow solid. MS (ESI pos. ion) m/z: 296 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cccnc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1-c1ccc(CBr)cc1

Procedure:
A mixture of 2-cyano-3-(4-tolyl)pyridine (940 mg, 4.84 mmol), N-bromosuccinimide (1.03 mg, 5.81 mmol), and dibenzoylperoxide (117 mg, 0.48 mmol) in CCl4 (70 mL) was heated to reflux to 2 h. The mixture was cooled then filtered through 50 g of silica gel eluting with CH2Cl2. The product was purified further by flash chromatography (20% EtOAc/hexanes) to give the above titled compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH2:14][CH2:15][O:16][CH3:17]>C([O-])([O-])=O.[Na+].[Na+].CCOCC>[CH3:8][C:3]1[CH:4]=[CH:14][C:15]2[O:16][C:17]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])=[CH:10][C:11]=2[CH:2]=1
Reactant: COCCOC
Reactant: COC(=O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)c1ccccc1-c1cc2cc(C)ccc2o1
Temperature: 25 °C

Procedure:
A solution of methyl 2-bromobenzoate (11.70 g), Intermediate 1 (12.75 g) and tetrakistriphenylphosphine palladium (0) (0.5 g) in DME (300 ml) and 2N Na2CO3 (60 ml) was heated to reflux with vigorous stirring under nitrogen. After 1.5 h a further 500 mg of catalyst was added and stirring at reflux under nitrogen continued. After about 5 h the reaction was cooled to room temperature and diluted with ether (300 ml). The organic layer was separated and washed with water (3×100 ml) and dried. Filtration and evaporation gave a yellow oily suspension (19.27 g) which was purified by chromatography eluting with System A (1:9) to give a yellow oil (11.06 g). This was further purified by Kugelrohr distillation to give the title compound (4.31 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[CH2:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][CH2:27][N:26]([CH3:32])[CH3:25])[CH3:31])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CNCCCN(C)C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCCN(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N1,N1,N3-trimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (br. s., 2H) 2.43 (s, 3H) 2.68-2.95 (m, 7H) 3.00 (s, 3H) 3.13 (br. s., 1H) 3.23-3.61 (m, 2H) 7.60-7.89 (m, 3H) 7.99-8.82 (m, 4H) 9.53 (br. s., 1H) 12.69-13.62 (m, 1H). ESI-MS m/z [M+H]+ 419.3.
Reaction SMILES: F[C:2]1[N:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:8][C:5]1[N:4]=[N:3][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:23])([F:24])[F:9])[CH:12]=3)[CH2:22][CH2:21]2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Fc1ccc(F)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 2.7 parts of 3,6-difluoropyridazine, 4.6 parts of 1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 60° C. The reaction mixture was poured into water. The product was filtered off, washed with water and crystallized from 2-propanol, yielding 3 parts (46%) of 3-fluoro-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp. 131.5° C. (compound 24).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([Li])(CC)C.C1CCCCC1.C(O[B:44]1[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]1)(C)C>C1COCC1>[CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[C:27]([B:44]6[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]6)=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3ccccc34)cc21
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3c(B5OC(C)(C)C(C)(C)O5)cccc34)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Into a solution of 4-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan (11.55 g, 32.0 mmol) and THF (200 ml), a solution of sec-butyllithium 1.4 M in cyclohexane (30.9 ml, 43.3 mmol) at −78° C. was slowly added. The resulting mixture was stirred at −78° C. for 2 hours before adding 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.81 ml, 48.1 mmol) by syringe. The reaction solution was allowed to gradually warm to room temperature and stirred for 14 h. The reaction was quenched with methanol (MeOH) and the solvent was removed in vacuo. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulfate, then filtered, before the solvent was evaporated. The crude product was purified by column chromatography on silica gel with a heptane/DCM/EtOAc (75/20/5 to 40/50/10, v/v/v) eluent and recrystallization from toluene yielded 2-(6-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 g, 84%) as a white solid.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:14]1[N:15]=[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[C:35](=[O:36])[NH:34][CH2:33][CH2:32][N:31]3[CH2:37][CH3:38])=[CH:26][CH:25]=2)[C:17](=[O:22])[N:18]([CH2:20]C)[CH:19]=1.[F:39][C:40]1[C:45]([NH:46][C:47]([C:49]2[S:53][C:52]3[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=3[CH:50]=2)=[O:48])=[C:44]([CH3:58])[C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:41]=1>O>[CH2:37]([N:31]1[CH2:32][CH2:33][NH:34][C:35](=[O:36])[CH:30]1[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:16]2[C:17](=[O:22])[N:18]([CH3:20])[CH:19]=[C:14]([C:43]3[C:44]([CH3:58])=[C:45]([NH:46][C:47]([C:49]4[S:53][C:52]5[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=5[CH:50]=4)=[O:48])[C:40]([F:39])=[CH:41][CH:42]=3)[N:15]=2)=[CH:29][CH:28]=1)[CH3:38]
Reactant: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(CC)c2=O)cc1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2c(s1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(-c3ccc(F)c(NC(=O)c4cc5c(s4)CCCC5)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (13 mL), water (3 mL) and sodium carbonate (417 mg, 3.93 mmol). After bubbling nitrogen through the resulting mixture for 15 min, 34 (150 mg, 0.370 mmol), N-(6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide. (192 mg, 0.460 mmol and tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.065 mmol) were added, and the reaction mixture then heated at reflux for 5 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with diethyl ether (10 mL). The resulting solid was dissolved in methylene chloride/methanol (10:1), absorbed onto silica gel and purified by flash chromatography to afford 35 in 41% yield (93 mg) as a yellow solid: mp 179-180° C.; 1H NMR (500 MHz, CDCl3) δ 8.31 (bs, 1H), 7.79 (d, 2H, J=8.5 Hz), 7.39 (m, 3H), 7.33 (m, 1H), 7.22 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.68 (s, 1H), 5.80 (d, 1H, J=3.5 Hz), 3.99 (s, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.36 (m, 1H), 3.11 (m, 1H), 2.82 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.59 (m, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 1.85 (m, 4H), 0.99 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 615.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[Br:11].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O.Cl>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH3:19])[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(O)ccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound of example 152 (6.5 g, 28.1 mmol) was dissolved in dry 1,4-dioxane (50 mL) under dry N2 atmosphere. To this solution, NaH (50%, 3.37 g, 70.20 mmol) was added in portions at 25° C. and the mixture was stirred for 10 min. Dimethyl sulfate (4 mL, 5.31 g, 40.48 mmol) was added and the reaction mixture was stirred at 50° C. for 1 h. It was poured into ice water, acidified using 6N HCl and extracted using EtOAc (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4), concentrated and purified using a silica gel column and 5% EtOAc in petroleum ether (60-80° C.) as eluant to obtain the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([O:29][CH3:30])[C:15]([CH3:31])=[C:14]2[C:10]=1[C:11](=[O:32])[O:12][CH2:13]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([O:29][CH3:30])[C:15]([CH3:31])=[C:14]2[C:10]=1[C:11](=[O:32])[O:12][CH2:13]2
Reactant: COC(=O)C(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(C)C/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 0 °C

Procedure:
To methyl (E) 6-(4-tert -butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate (0.8 g) in tetrahydrofuran (5 ml) was added 1N tetra-n-butylammonium fluoride in tetrahydrofuran (4 ml). After 10 minutes the solution was diluted with ice water and extracted with ethyl acetate. The extract was dried and evaporated to give methyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:41](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:40][CH3:41])([C:36]([F:39])([F:37])[F:38])[C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)N(CCc2ccc(Cl)c(Cl)c2)Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2[nH]ccc2c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cc(C)cc3cc[nH]c23)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
20 mg of 5-methyl-1H-indole-7-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-amide (0.03 mmol) were dissolved in 5 ml DMF and potassium carbonate (9 mg, 0.07 mmol) and methyl iodide (3 μl, 0.05 mmol) were added. The reaction mixture was stirred over night at rt, then saturated ammonium chloride solution was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtrated and concentrated. The remaining residue was purified by silica gel filtration (hexane/EtOAc 1:1). This gave 20 mg (98%) of the title compound as a white foam. MS (ISP) 617.2 (M+H)+.
Reaction SMILES: O[CH:2]([C:6]1[C:7]([O:12][CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH:4]=[CH2:5].[Cl:14]CCl.S(Cl)(Cl)=O>>[Cl:14][CH:2]([C:6]1[C:7]([O:12][CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: ClCCl
Reactant: C=CCC(O)c1cccnc1OC
Solvent: O=S(Cl)Cl
Product: C=CCC(Cl)c1cccnc1OC
Yield: 93.8 %

Procedure:
56.5 g (0.32 mol) of the compound from Example I are stirred in 400 ml of anhydrous dichloromethane containing 277 ml (3.8 mol) of thionyl chloride overnight at 20°-30° C. Subsequently, dichloromethane and unreacted thionyl chloride are removed in a water pump vacuum at 20°-30° C. The residue is partitioned between dichloromethane and aqueous saturated sodium bicarbonate solution. The organic phase is separated off, dried and evaporated in vacuo. 59.3 g of the crude title compound are obtained as an oil.
Reaction SMILES: CO[C:3]1[C:7](OC)=[CH:6][S:5][CH:4]=1.[CH3:10][C@@H:11]([OH:15])[C@@H:12]([OH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:10][CH:11]1[O:15][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:14][CH:12]1[CH3:13]
Reactant: C[C@H](O)[C@@H](C)O
Reactant: COc1cscc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1Oc2cscc2OC1C
Yield: 21.5 %

Procedure:
A solution of 3,4-dimethoxythiophene (7.2 g, 50 mmol), meso-2,3-butanediol (5.4 g, 60 mmol), and p-toluenesulphonic acid (0.2 g) in toluene (100 ml) was heated at 100° C. under a continuous argon flow for 24 h. The reaction mixture was then poured into methylene chloride (200 mL) and the organic phase washed with a 1M aqueous solution of sodium hydrogen carbonate and brine, dried with anhydrous magnesium sulphate and concentrated. This resulted in a mixture of cis and trans product that could be separated by column chromatography, yielding pure cis (2.8 g, 16%) and trans (1.83 g, 11%) 2,3-dimethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine.
Reaction SMILES: [C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31]Br)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na+].[I-].[F:36][C:37]1[C:43]([F:44])=[CH:42][C:41]([F:45])=[C:40]([F:46])[C:38]=1[O-:39].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][O:39][C:38]1[C:40]([F:46])=[C:41]([F:45])[CH:42]=[C:43]([F:44])[C:37]=1[F:36])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [O-]c1c(F)c(F)cc(F)c1F
Reactant: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N-[(carbobenzyloxycarbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (3.36 g, 6.73 mmol) in acetone (20 ml) was added dry NaI (0.20 g, 1.35 mmol) and potassium (2,3,5,6-tetrafluoro)-phenoxide (1.37 g, 6.73 mmol) at room temperature and stirred for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The resultant solid was triturated with ether to provide the titled product as a white solid (3.53 g, 6.04 mmol, 89%). MS C28 H32N2O7, [M+Na]+ =607, [M−H]− =583.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)[C:3](=O)[CH3:4].[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:19][C:18]([NH2:20])=[N:17][C:3]=2[CH3:4])=[CH:7][C:8]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CC(=O)C(Br)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
1-bromo-1-(4-chloro-3-methanesulfonyl-phenyl)-propan-2-one (480 mg 1.5 mmol) and thiourea (114 mg 1.5 mmol) were combined in ethanol (12 ml) and heated to 70° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the solid product was collected by filtration and dried under vacuum to yield 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine as an off-white solid (375 mg). 1H NMR (400 MHz DMSO-d6) δ 9.4 (br s, 2H), 8.0 (d, 1H), 7.9 (d, 1H), 7.8 (dd, 1H), 3.4 (s, 3H), 2.3 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]COCC[Si](C)(C)C)=[C:20]([O:33][CH3:34])[CH:19]=3)=[O:16])=[N:9]2)=[CH:4][CH:3]=1.CS([Cl:39])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:39][CH2:13][C:11]1[C:10]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:33][CH3:34])[CH:19]=2)=[O:16])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CO)ccc1OCOCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CCl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
To a mixture of 1-(4-chlorophenyl)-4-(hydroxymethyl)-N-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazole-3-carboxamide (2.11 g, 4.19 mmol) in CH2Cl2 (40 mL) at room temperature under Ar was added methanesulfonyl chloride (0.424 mL, 5.44 mmol) and triethylamine. (1.20 mL, 8.61 mmol). The resulting solution was stirred at room temperature for 1.5 h. Solvent was evaporated. The crude product was diluted with EtOAc (150 mL), washed with H2O (30 mL). The organic layer was separated, dried over MgSO4 and concentrated to give a crude product which was further purified by ISCO automated chromatography (110 g, Hexane/EtOAc, 100:0 to 50:50 gradient) to give the products as beige solid (0.721 g, 44% yield). SEM group was deprotected during the process. LCMS (ES): m/z 392.0 [M+H]+.