Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:12].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:12]
Reactant: CCCc1ccc(O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1ccc(O)c(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To 38 mg (0.23 mmole) of 2-methoxy-4-propylphenol in 0.4 ml of CH2Cl2 at −78° C. and under argon was added 254 μl (0.252 mmole) of a IM BBr3 solution in CH2Cl2. The reaction mixture was stirred at −78° C. for one hour and then warmed to 0° C. The reaction was quenched by addition of 2 ml of water. The mixture was extracted three times with 5 ml of CH2Cl2, dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was flash chromatographed over silica gel using 25% ethyl acetate in hexane to furnish 30 mg of 2-hydroxy-4-propylphenol, Structure (I-6), in 86% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20]Br)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([F:33])[C:24]=1[C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20][O:32][C:31]3[C:23]([F:22])=[C:24]([C:28]([F:33])=[CH:29][CH:30]=3)[C:25]([NH2:27])=[O:26])[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: BrCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(OCc4ccccc4)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of 3-(4-benzyloxyphenyl)-5-bromomethyl-[1,2,4]thiadiazole (0.04 g, 0.11 mmol) in DMF (2 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.017 g, 0.10 mmol) and potassium carbonate (0.53 g, 0.39 mmol). The reaction mixture was stirred at 25° C. overnight under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 20 ml water and extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 40% EtOAc-Hexane) to get the desired product (0.025 g, 50%). MS ES+ (454.13).
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38](C(NC(NCCCCCCCC)=O)=O)[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][C:20]=1[F:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.[CH3:65][OH:66]>>[CH2:28]([NH:27][C:65]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:55]=[CH:56][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:58]=[CH:59][C:19]([OH:18])=[C:20]([F:60])[CH:21]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:66])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:55][CH3:56]
Reactant: CO
Reactant: CCCCCCCCNC(=O)NC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c(F)c3)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(F)c3)cc2)CC1

Procedure:
N-((4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy)-3-fluorophenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)-N′-octylurea (0.228 g, 0.271 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.126 g, 0.223 mmol).
Reaction SMILES: C[CH:2]1[O:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4](=[O:18])[O:3]1.Cl>C1(C)C=CC=CC=1.C[O-].[Na+]>[OH:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C:4]([O:3][CH3:2])=[O:18]
Reactant: CC1OC(=O)C(CC(=O)CC(=O)OC(C)(C)C)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(O)CC(=O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of tert.-butyl 4-(2-methyl-5-oxo-1,3-dioxolan-4-yl)-3-oxobutanoate (5.16 g, 20.0 mmol) in toluene (40.0 ml), sodium methoxide (1M in methanol) (20.5 was added at 0° C. over 10 minutes in an argon atmosphere and stirred at 0° C. for 30 minutes. After dropwise adding 1N hydrochloric acid (21.0 ml), the mixture was stirred at 0° C. for 10 minutes. After evaporating off the most of the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate and washed with a saturated saline and a phosphate buffer (pH 7.0). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=2:1) to give pure 1-methyl 6-tert.-butyl 2-hydroxy-4-oxoadipate (4.39 g, 17.83 mmol). Yield, 89.2 %.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][NH2:12]>C(O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:12][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: CNc1ccc([N+](=O)[O-])cn1

Procedure:
3-Nitro-6-chloropyridine (5 g, 31.5 mmol) was added to 10 ml of a 30% solution of methylamine in ethanol, followed by reaction at room temperature for 5 minutes. Then, recrystallization from chloroform-hexane gave 4.92 g of the intended product as yellow crude crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=[C:10]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[C:3]=12>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=[C:10]([C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)Cn1nc(C2=NCCN2)c2c(N)ncnc21
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cn1nc(-c2ncc[nH]2)c2c(N)ncnc21

Procedure:
As shown tert-butyl 2-(4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate can be oxidized with DMP in the presence of the solvent DMSO to obtain tert-butyl 2-(4-amino-3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1>>[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[C:12]=2[CH:11]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: COCCOCCBr
Product: COCCOCCC1(CCOCCOC)c2ccccc2-c2ccc(Br)cc21

Procedure:
2-Bromo-9,9-bis(3,6-dioxaheptyl)-fluorene was synthesized from bromo-2-(2-methoxyethoxy)ethane and 2-bromofluorene by methods described in Part A of Example 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:34]2[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]2[CH:30]([CH3:32])[CH3:31])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 140 °C
Yield: 97.5 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol), 2-isopropylbenzimidazole (92 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.06 mmol), XPhos (58 mg, 0.10 mmol) and Cs2CO3 (310 mg, 0.95 mmol) in toluene (4 mL) was purged with argon then heated at 140° C. for 45 min in a microwave reactor. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-100%) affording the title compound as an off-white solid (255 mg, 99%). LCMS (method A): RT 3.40 min [M+H]+ 545.3
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH:27]=[CH2:28])[C:5](=[O:25])[C:6]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:8]([C:9]([N:11]([CH2:15][CH:16]=[CH2:17])[CH2:12][CH:13]=[CH2:14])=[O:10])[C:7]=1[I:24])[CH:2]=[CH2:3].[C:29](Cl)(Cl)=[O:30].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:1]([N:4]([CH2:26][CH:27]=[CH2:28])[C:5](=[O:25])[C:6]1[C:20]([I:21])=[C:19]([N:22]=[C:29]=[O:30])[C:18]([I:23])=[C:8]([C:9]([N:11]([CH2:15][CH:16]=[CH2:17])[CH2:12][CH:13]=[CH2:14])=[O:10])[C:7]=1[I:24])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)C(=O)c1c(I)c(N)c(I)c(C(=O)N(CC=C)CC=C)c1I
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C=CCN(CC=C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(CC=C)CC=C)c1I
Temperature: 60 °C

Procedure:
To a solution of N,N,N′,N′-tetraallyl-5-amino-2,4,6-triiodo-isophthalamide (5 g, 7 mmol) in 1,4-dioxane (10 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (35 mL, 70 mmol) at ambient temperature. The flask was sealed and the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])C.[C:8]1([N:14]=C=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([NH:14][C:1]([NH:4][CH2:5][CH2:6][NH2:7])=[O:3])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)NCCN
Solvent: ClCCl
Product: NCCNC(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of 0.057 mole of acetylethylene diamine in 100 ml of methylene chloride at 10° C. was added dropwise 0.057 mole of phenyl isocyanate. Soon after the addition a solid precipitated. 100 ml of anhydrous ether was added to the reaction mixture and stirring was continued for another 30 minutes. The solid was recovered by filtration, dissolved in 50 ml of 15% hydrochloric acid, and the solution was heated to 80° C. for 4 hours. Removal of the aqueous acid afforded the product which had a melting point of 190.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:16]([C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]=O)=[CH:24][NH:25]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:27]=[C:26]2[C:22]([C:23](/[CH:28]=[CH:14]/[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])=[CH:24][NH:25]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3cc([N+](=O)[O-])ccc23)cc(OC)c1OC
Yield: 1.1 %

Procedure:
Substantially the same procedure as in Example 21 was repeated using 3',4',5'-trimethoxyacetophenone (1.25 g) and 6-nitroindole-3-carboxaldehyde (1.13 g) except that the obtained product was further purified by preparative HPLC, that the eluting solution was cooled, and that the precipitated crystals were collected by filtration, to give Compound 34 (26 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:40])=[C:4]([C:9]2[N:10]=[C:11]([CH:37]3[CH2:39][CH2:38]3)[N:12](COCC[Si](C)(C)C)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH3:23])[N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[C:3]([Cl:40])=[C:4]([C:9]2[N:10]=[C:11]([CH:37]3[CH2:38][CH2:39]3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH3:23])[N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)N[C@@H](C)CNc1nccc(-c2c(-c3cc(F)cc(N)c3Cl)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2-c2cc(F)cc(N)c2Cl)n1
Yield: 43 %

Procedure:
A mixture of the crude (S)-methyl 1-(4-(4-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (15.349 g), p-toluenesulfonic acid (3.64 g, 21.132 mmol) and methanol (70 mL) in a 100 mL, 3-necked round bottomed flask was heated at reflux for 1 hour. HPLC indicted completion of reaction. The reaction mixture was evaporated under vacuum and the residue was stirred with 2 N HCl (50 mL) and ethyl acetate (75 mL). The aqueous layer was separated and the organic layer was extracted once with 2 N HCl (40 mL). The combined aqueous layers were extracted once with ethyl acetate (50 mL) and then neutralized with aq NaOH (4 N). The product was extracted with 2×50 mL of ethyl acetate. The organic layer was washed once with water (40 mL), dried over MgSO4 and evaporated under vacuum to give 5.136 g (11.190 mmol) of crude (S)-methyl 1-(4-(4-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.N.[CH:11](O)=O>>[Cl:8][C:5]1[N:4]=[C:3]2[S:9][CH:11]=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)nc1S
Agent: N
Product: Clc1ccc2ncsc2n1

Procedure:
3-Amino-6-chloropyridine-2-thiol (Q-3) (16.4 g, 103 mmol) in formic acid (80 mL) was refluxed at 110° C. for 2 h. The reaction mixture was cooled and neutralized with concentrated ammonia to pH 7. A precipitate was collected by filtration as the title compound (14.5 g). MS (m/z): 171 (M+1)+.
Reaction SMILES: C([O-])(=O)C.[NH4+].C=O.[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:15][OH:16])([CH3:11])([CH3:10])[CH3:9]>O.C(O)(=O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])[CH:15]=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Yield: 68.3 %

Procedure:
A 500 ml reaction flask fitted with a mechanical stirrer, heating mantle, thermometer and water-cooled condenser was charged with 100 ml of glacial acetic acid and 17 ml of water. To the stirred solution there were added 30.8 g (0.4 mole) of ammonium acetate, 48.7 g of 37% formalin (0.60 mole formaldehyde) and 11.8 g (0.05 mole) of 3,5-ditert.butyl-4-hydroxybenzyl alcohol. The reaction flask was equipped with a take-off head to remove the methanol which is present in commercially available formalin. The mixture was refluxed (100°-2°) for 2 hours. The cooled mixture was poured on a vacuum filter and the product cake was washed with water. After drying, there was obtained 8.0 g of crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 191°-93° (68.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in analogous fashion to that described in Example 1 using (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.94 min, m/z=444.1 [M+H]+, m/z=442.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.85 (dt, J=8.62, 4.37 Hz, 1H) 2.66 (d, J=9.78 Hz, 1H) 2.98-3.07 (m, 2H) 3.16-3.25 (m, 1H) 4.18 (br. s, 1H) 4.84 (br. s, 1H) 6.95 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.50 (dd, J=7.82, 4.89 Hz, 1H) 7.80 (d, J=2.20 Hz, 1H) 7.81-7.89 (m, 3H) 7.92 (dd, J=8.68, 2.32 Hz, 1H) 8.56 (d, J=3.91 Hz, 1H) 8.65 (br. s, 1H) 10.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12](O)[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.ClCC(Cl)(Cl)Cl.P(Br)(Br)([Br:24])=O.[OH-].[Na+]>C(OCC)C>[F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([Br:24])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1O
Reactant: O=P(Br)(Br)Br
Agent: ClCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cn1nc(-c2ncc(Cl)cc2F)cc1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
20.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1-methyl-[1H]-pyrazole (Example P13) are introduced into 80 ml of tetrachloroethane. A total of 25.2 g of phosphorus oxybromide (POBr3) is added in portions to the brown suspension. The mixture is then stirred for 2 hours at an internal temperature of 130° C., after which it is cooled and, with cooling with an ice-bath, 150 ml of a 2M sodium hydroxide solution are added dropwise. After the addition of diethyl ether and separation of the phases, the organic phase is washed in succession with water, dilute hydrochloric acid and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. 19.94 g of a brown solid (crude product) are obtained, which is purified by means of digestion with 50 ml of n-hexane. 12.65 g of the desired compound are obtained in the form of a brown solid having a melting point of 110-111° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[CH:9][S:10][C:11]=1/[CH:12]=[CH:13]\[S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].Cl.C(OCC)(=O)C>C1COCC1.O>[C:5]([C:7]1[N:8]=[CH:9][S:10][C:11]=1/[CH:12]=[CH:13]\[S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 117.3 %

Procedure:
A 5 N aqueous sodium hydroxide solution (8.30 ml) was added to a suspension of 7.31 g of 4-methoxycarbonyl-5-((Z)-2-tritylthioethen-1-yl)thiazole in THF, and the mixture was stirred at 60° C. for one hr. The mixture was then cooled to room temperature, and 8.50 ml of 5 N hydrochloric acid, 100 ml of ethyl acetate, and 50 ml of water were added thereto, followed by concentration to 150 ml. Hexane (100 ml) was added to the concentrate, and the precipitated solid was collected by filtration and was washed with ethyl acetate-hexane (2:1) to give 8.30 g of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:64][C@:65]1([C:70]([NH:72][S:73]([C:76]2([CH2:79][F:80])[CH2:78][CH2:77]2)(=[O:75])=[O:74])=[O:71])[CH2:67][C@H:66]1[CH:68]=[CH2:69]>ClCCl>[F:80][CH2:79][C:76]1([S:73]([NH:72][C:70]([C@@:65]2([NH:64][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:67][C@H:66]2[CH:68]=[CH2:69])=[O:71])(=[O:74])=[O:75])[CH2:77][CH2:78]1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(CF)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(CF)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.7 g, 13.82 mmol) in dichloromethane (60 mL) was added HATU (5.78 g, 15.2 mmole) followed by DIPEA (7.13 mL, 41.4 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(1-(fluoromethyl)cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (4.34 g, 16.58 mmole) was added to the reaction mass and stirred at room temperature for 6 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (5% methanol in chloroform) to get 6.6 g (73%) of desired product as white solid. MS: MS m/z 658.3 (M++1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[NH2:17])(=[O:4])=[O:3].[F:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:26])[C:21]=2[CH:20]=1.[H-].[Na+]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:17][S:27]([C:24]1[S:23][C:22]2[CH:31]=[CH:32][C:19]([F:18])=[CH:20][C:21]=2[C:25]=1[CH3:26])(=[O:29])=[O:28])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Yield: 5.2 %

Procedure:
This compound was prepared in analogy to Example 20f starting from 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (cf. Example 20c, 0.27 g) in tetrahydrofurane (10 ml) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.265 g) with sodium hydride (0.10 g) at rt for 18 h to obtain the title compound (0.025 g) as a yellow foam. MS (ISN): 475.0 (M−H)−
Reaction SMILES: O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([O:37][CH3:38])[O:35][CH3:36])=[C:22]([N+:27]([O-])=O)[CH:23]=[N:24]2)=[CH:19][CH:18]=1>ClCCl.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([O:37][CH3:38])[O:35][CH3:36])=[C:22]([NH2:27])[CH:23]=[N:24]2)=[CH:19][CH:18]=1
Reactant: COC(CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12)OC
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: COC(CCCNc1c(N)cnc2cc(Br)ccc12)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (200 mL), sodium hydrosulfite (90.9 g, 522.3 mmol), ethyl viologen dibromide (0.64 g, 1.74 mL mmol) and potassium carbonate (95.0 g, 687 mmol) were sequentially added to a solution of (7-bromo-3-nitroquinolin-4-yl)(4,4-dimethoxybutyl)amine in dichloromethane and stirred overnight at ambient temperature. The layers were separated and the organic layer was washed sequentially with water (5×200 mL), saturated aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 59.3 g of 7-bromo-N4-(4,4-dimethoxybutyl)quinoline-3,4 diamine as a brown oil.