Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[S:3][C:4]([CH3:16])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(Br)sc(C)c1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)sc(C)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-bromo-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate (250 mg, 0.79 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (185 mg, 1.18 mmol, 1.50 equiv), K3PO4 (620 mg, 2.92 mmol, 3.71 equiv), Pd(PPh3)4 (73 mg, 0.06 mmol, 0.08 equiv), dioxane (20 mL). The resulting solution was stirred overnight at 90° C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). The collected fractions were combined and concentrated under vacuum. This resulted in 200 mg (69%) of ethyl 2-(4-chlorophenyl)-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:12]CC1C=CC(OC)=CC=1OC)(=[O:11])=[O:10].C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:9]([NH2:12])(=[O:10])=[O:11])[C:27]([OH:28])([CH3:29])[CH3:26]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccccc2Cl)c(OC)c1
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccccc1Cl)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
Under inert gas, 1.51 g of C-(2-chlorophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 30 ml of THF, and then, at a temperature of −78° C., 6.09 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 1.83 ml of acetone were added. After stirring for 10 minutes, the reaction solution was admixed with 2 ml of trifluoroacetic acid and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 20 ml of dichloromethane, and 3 ml of trifluoroacetic acid were added. After stirring at room temperature for 2 hours, the reaction solution was concentrated by rotary evaporation and the residue was taken up in a mixture of water and dichloromethane. The solid which precipitates out was analyzed by LCMS and 1H NMR and subsequently discarded, since no product was present. Another solid precipitated out of the filtrate, which was identified by LCMS as product-containing (512 mg). Since further product was present in both phases of the filtrate, the aqueous phase was extracted with dichloromethane, the combined organic phases were concentrated by rotary evaporation and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation (707 mg). This gave the product with a molecular weight of 263.7 g/mol (C10H14ClNO3S); MS (ESI): m/e=283 (M+H2O+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][OH:25])[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[O:37]=[C:38]=[N:39][C:40](Cl)=[O:41].C(Cl)Cl.C[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[C:40](=[O:41])[NH:39][C:38](=[O:37])[O:25]5)[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NO)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: O=C=NC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@@H]2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)o1
Reaction time: 2.25 h

Procedure:
To a solution of 2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine, 55b, (0.072 g, 0.136 mmol) in THF (2 mL) at 0° C. was added N-(oxomethylene)carbamoyl chloride (0.014 mL, 0.176 mmol). A white solid formed immediately. The slurry was shaken and sonicated to make an even suspension/slurry. Then, —CH2Cl2 (1 mL)) was added to help solvate the slurry. After 135 min, the mixture was treated with NaOMe (2 mL, 25% w/v). After 2 min, the mixture was quenched with saturated NH4Cl and acidified with 1M HCl. The mixture was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Preparative HPLC provided the desired product (25 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][N:3]=1.[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19].[F-].[Cs+]>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@@H:22]([C:23]1[CH:24]=[CH:25][C:26]([C:2]2[S:6][C:5]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][N:3]=2)=[CH:27][CH:28]=1)[OH:33])=[O:19]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1nnc(Br)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 90 °C
Yield: 7.5 %

Procedure:
To a stirred solution of tert-butyl ((5-bromo-1,3,4-thiadiazol-2-yl)methyl)-carbamate (0.878 g, 2.98 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (1.20 g, 2.71 mmol) in dimethylformamide (20 mL) is added CsF (0.818 g, 5.42 mmol) followed by CuI (0.051 g, 0.271 mmol). Resulting reaction mixture is degassed with nitrogen for 30 minutes and Pd(PPh3)4 (0.313 g, 0.271 mmol) added. The reaction mixture is heated to 90° C. for 5 hours. Reaction mixture is concentrated in vacuo to give the crude material, which is purified by column chromatography on silica gel eluting in 1% methanol in CH2Cl2 to give the title compound (100 mg): 1H-NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 4.24-4.26 (m, 1H), 4.29-4.33 (m, 0.5H), 4.41-4.45 (m, 0.5H), 4.52 (d, J=5.96 Hz, 2H), 4.57-4.61 (m, 0.5H), 4.69-4.72 (m, 0.5H), 4.93 (t, J=3.76 Hz 1H), 6.08 (d, J=4.28 Hz, 1H), 6.49 (s, 1H), 7.51 (d, J=8.24 Hz, 2H), 7.86-7.90 (m, 3H), 8.63 (d, J=8.96 Hz, 1H). LC-Ms (m/z): [M−H]=490.80.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
A mixture of 6-hydroxy-1-tetralone (50.0 g, 308 mmol), K2CO3 (64.0 g, 434 mmol) and BnBr (58.0 g, 340 mmol) in DMF (400 mL) was stirred at 25° C. for 16 hours. The mixture was diluted in water (1000 mL), extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product as a brown solid (54.0 g, yield 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[I:10]N1C(=O)CCC1=O.C(OCC)(=O)C.C(OCC)C>CN(C)C=O>[OH:9][C:5]1[CH:6]=[CH:7][C:8]([I:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(O)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A mixture of 3-methoxyphenol (600 mg, 4.83 mmol) and N-iodosuccinimide (1.09 g, 4.84 mmol) was dissolved in anhydrous N,N-dimethylformamide (25 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) and diethylether (100 mL) were added. The organic layer was washed with 1% aqueous sodium thiosulfate solution (200 mL), water (100 mL), and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (167 mg) as a colorless oil. (Yield 14%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:11][C:10]1[C:5]([CH2:3][OH:2])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1nccnc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nccnc1CO
Temperature: 9 °C
Reaction time: 3 h

Procedure:
Methyl-3-aminopyrazine-2-carboxylate (14.22 g, 93 mmol) was suspended in tetrahydrofuran (1 L) and cooled under a nitrogen atmosphere in a methanol/ice bath. Lithium aluminium hydride (100 ml, 1 M solution in diethyl ether, 100 mmol) was added at such a rate to maintain the temperature between 8-10° C. Once addition was complete the reaction was stirred at room temperature for 3 hours and then heated at reflux for 20 minutes. The reaction was then cooled to 0° C. and quenched with water (30 mL in 100 mL tetrahydrofuran) keeping the temperature below 8° C. The reaction was then stirred at room temperature for 30 minutes and then filtered. The residue was washed with hot ethyl acetate (250 mL×2) filtered. The two filtrates were combined and evaporated to dryness. This produced (3-amino-pyrazin-2-yl)methanol (7.38 g) as a pale orange solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10](N)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N.OS(O)(=O)=O>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccccc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)NC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 134.2 %

Procedure:
6.4 ml of hexamethyldisilazane (31 mmoles) were added to a refluxing mixture of 15 ml of toluene, 40 mg of saccharin (0.22 mmole) and 5.0 g of benzamide (41.3 mmoles) and the ammonia liberated was led into water by a stream of nitrogen passed over the reaction mixture. Titration with 1 N H2SO4 revealed that the calculated amount of ammonia was evolved in 15 minutes and solvent and excess hexamethyldisilazane were evaporated in vacuo to obtain 8.04 g (101%) of N-trimethylsilylbenzamide melting at 111°-115° C. The experiment was repeated without the addition of saccharin and it was found that 82% of the theoretical amount of ammonia was evolved in 15 minutes and 88% of it in 50 minutes.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[C:51]([C:56]([OH:58])=O)=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:51]1[C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:45]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:58]
Reactant: O=C(O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1
Reactant: CN(C)CCCCN
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.95 g, 2.61 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.43 g, 2.66 mmol, 1.02 eq.) and 4-dimethylaminobutylamine (0.36 g, 3.13 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[H-].[Na+].Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl-].[NH4+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ccco3)cc2c1
Reactant: BrCC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccco1)n2CC1CCCCC1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-(2-furanyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.5 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride (1.3 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 minutes, followed by addition of bromomethylcyclohexane (7.4 mg), and the reaction mixture was stirred at 15 to 30° C. for 5 hours and at 60° C. for 1 hour. The reaction solution was then poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 4.5 mg of the desired product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]1[O:28][C:27]2[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][NH2:24])=[CH:20][C:19]=2[O:18]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][C:27]3[O:28][CH2:17][O:18][C:19]=3[CH:20]=2)[N:3]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(3,4-methylenedioxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4-methylenedioxyphenethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:8]([Br:21])[CH:7]=1>O.CO>[Br:21][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]([OH:22])=[O:4]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
NaOH (48.8 g, 1.22 mol, 2.0 eq) in H2O (1.26 L) was added to a solution of 3-bromo-4-(tert-butoxycarbonylamino-methyl)-benzoic acid methyl ester (210 g, 0.61 mol, 1.0 eq) in MeOH (1.26 L). The reaction mixture was stirred at 50° C. for 2 hrs. The reaction was cooled to room temperature and concentrated to half volume. The residue was acidified to pH 5 by adding 1M HCl solution. The resulting solid was collected and dried to give the title intermediate (200 g, 99.4% yield) as white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Si:13]([O:20][CH2:21][C:22]1[S:26][CH:25]=[N:24][CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].Cl[C:28]1[N:33]=[N:32][C:31]([N:34]([CH2:42][C:43]2([C:47]3[C:52]([F:53])=[CH:51][CH:50]=[CH:49][N:48]=3)[CH2:46][CH2:45][CH2:44]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1>[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Si:13]([O:20][CH2:21][C:22]1[S:26][C:25]([C:28]2[N:33]=[N:32][C:31]([N:34]([CH2:42][C:43]3([C:47]4[C:52]([F:53])=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:46][CH2:45][CH2:44]3)[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:30][CH:29]=2)=[N:24][CH:23]=1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncs1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)s2)nn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73.9 %

Procedure:
To a stirring mixture of THF (2000 mL) and diisopropylamine (79.3 mL, 0.56 mol) at −78° C. was added n-BuLi (244 mL, 0.56 mol) dropwise. After stirring for 20 min at −78° C., a solution of 5-((t-butyldimethylsilyloxy)methyl)thiazole (110.9 g, 0.49 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than −70° C. After the addition was complete, the reaction was stirred for an additional 30 min and a solution of zinc bromide (126.6 g, 0.56 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than −65° C. The reaction was warmed to 0° C., stirred for 30 min, and added to a stirring mixture of t-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (100 g, 0.26 mol), tetrakis(triphenylphosphine)palladium(0) (56 g, 0.05 mol), and THF (2000 mL) heated to 80° C. The reaction mixture was stirred overnight at 80° C. The reaction was concentrated and then slurried in ethyl acetate and brine. The resultant solid was filtered off, and the filtrate was dried over sodium sulfate, concentrated, and purified twice by silica gel chromatography (EtOAc/hexanes) to afford 112.5 g of t-butyl 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a dark oil.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][CH2:29][C:30](OCC)=[O:31])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+].CO>C1COCC1>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)(=[O:13])=[O:14])=[C:16]([CH2:28][CH2:29][CH2:30][OH:31])[CH:17]=1
Reactant: CCOC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CCCO)c1
Temperature: 0 °C

Procedure:
A mixture of ethyl 3-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)propanoate (1.6 g, 3.2 mmol), and NaBH4 (0.48 g, 12.8 mmol) in THF (30 mL) was stirred at 0° C. Then CH3OH (1 ml) was added dropwise into the mixture and stirred at r.t. overnight. The solvent was evaporated and the residue was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC (column: YMC 150×30.0 mm, 20μ; liquid phase: [A-H2O; B-MeCN+0.1% TFA] B %: 12%-42%, 10 min) to give the title compound, which was dissolved in MeCN, acidified with aq. HCl and freeze-dried to give the product as hydrochloride salt (280 mg, yield 70%). 1H NMR (400 MHz, DMSO-d6): δ9.97 (s, 1H), 7.57-7.09 (m, 6H), 4.83 (s, 2H), 3.46-3.42 (m, 2H), 2.83-2.79 (m, 2H), 1.66-1.62 (m, 2H); ESI-MS m/z 385 (M+Na, positive); HPLC purity: 94.25% (MaxPlot 190-370 nm), 94.25% (220 nm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH2:17][CH:18]=[CH2:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:19][CH2:18][CH:17]=[CH2:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=CCC[Mg]Br
Product: C=CCCC(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-butenylmagnesium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>C(Cl)Cl>[F:28][B-:27]([F:31])([F:30])[F:29].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S+:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(CSCc2ccc(Cl)cc2)cc1
Reactant: OCc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccccc2)Cc2ccc(Cl)cc2)cc1
Yield: 80 %

Procedure:
5.66 g (20 mmol) of di-(4-chlorobenzyl) sulfide are reacted with 2.6 g (24 mmol) of benzyl alcohol and 8.13 g (50 mmol) of 54% by weight HBF4 in 20 ml of methylene chloride as described in Example 3a). 7.44 g (80% of theory) of di-(4-chlorobenzyl)-benzylsulfonium tetrafluoroborate are obtained as white crystals of melting point 123°-125° C.
Reaction SMILES: [CH:1]1([C:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:5][CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[CH2:3][CH2:2]1>C(O)C.[Ni]>[CH:1]1([CH:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(C=CC=C(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Fc1ccc(CCCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Yield: 76 %

Procedure:
Using a Parr hydrogenation apparatus, a solution of 1.7 grams (0.004 mole) of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl) -1,3-butadiene in 100 mL of absolute ethanol was hydrogenated in the presence of 0.3 gram of Raney nickel (50% in water). Upon completion of the hydrogenation, the reaction mixture was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% cyclohexane in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.2 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)butane. The nmr spectrum was consistent with the proposed structure.