Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:11]([CH2:50][OH:51])=[C:10]([Cl:52])[N:9]=1)[CH2:5][CH2:6][CH3:7].[CH3:53][S:54](Cl)(=[O:56])=[O:55].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:4]([C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:11]([CH2:50][O:51][S:54]([CH3:53])(=[O:56])=[O:55])=[C:10]([Cl:52])[N:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To a DCM (200 mL) solution of intermediate (11b) (13.6 g, 20.4 mmol), cooled to −78° C., was added methane sulfonyl chloride (6.3 mL, 81.6 mmol). The mixture was stirred at −78° C. for 15 minutes. A saturated NaHCO3 solution (100 mL) and EtOAc (500 mL) were added to the cooled mixture, which was then allowed to reach room temperature. The organic was washed an additional three times with saturated aqueous NaCl (100 mL). After drying over sodium sulfate and filtration, the removal of solvent provided intermediate (11c) as a yellow oil (15 g) which was used directly in the next step. MS m/z: [M+H+] calcd for C42H39ClN6O3S, 743.26; due to the reactive nature of intermediate (11c), only the methanol substituted product was observed upon running a mass spectrum of the sample when dissolved in methanol; methanol substituted product [M+H+]=679.6.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[CH:11]1([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:27]4[CH:26]=[C:25]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:24]=[CH:23][CH:28]=4)=[CH:3][N:4]=[C:5]3[N:10]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Brc1cnc2nc(C3CCC3)ccn12
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C4CCC4)ccn23)c1

Procedure:
3-Bromo-7-cyclobutylimidazo[1,2-a]pyrimidine was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-cyclobutylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white powder: δH (400 MHz, CDCl3) 1.90-2.55 (6H, m), 3.77 (1H, quintet, J 8), 6.83 (1H, d, J 7), 7.48-7.75 (7H, m), 7.82 (1H, dd, J 8 and 1), 7.86 (1H, s), 8.85 (1H, d, J 7); m/z (ES+) 351 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13]>C(OCC)(=O)C>[CH:12]([NH:15][C:16]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To 5-aminoindolin-2-one (50 mg, 0.34 mmol) in ethyl acetate (1 mL) was added isopropylisocyanate (0.04 mL, 0.4 mmol). The solution was stirred at rt for 16 h and the product was precipitated with ether, filtered and dried to give 46 mg, 58% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.31 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 3.90-3.83 (m, 1H), 3.51 (s, 2H), 1.77 (d, J=7.3 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:35]=[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C@@H:25]([C:32]#[C:33][CH3:34])[CH2:26][C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)=[CH:16][N:11]2[N:10]=1.[OH-].[Na+]>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:35]=[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C@@H:25]([C:32]#[C:33][CH3:34])[CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:24]=3)=[CH:16][N:11]2[N:10]=1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4c(C)cccc4C)nn3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc3nc(-c4c(C)cccc4C)nn3c2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of ethyl (3S)-3-[4-[[2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoate (0.22 g, 0.47 mmol) in EtOH (20 mL) is added 5 N NaOH (0.3 mL) and the reaction mixture is stirred at 80° C. in a microwave instrument for 30 minutes. The reaction mixture is evaporated to dryness, diluted with water, and acidified with 6 N HCl solution to pH ˜3. The precipitated solid is filtered, washed with n-pentane, and dried to give the title compound as a white solid (0.155 g, 75%). LCMS m/z 440 (M+H)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4](=[O:12])[O:5][C:6](C)([CH3:10])[O:7][C:8]=1[CH3:9]>C(O)C>[CH2:6]([O:5][C:4](=[O:12])[CH:3]([Cl:2])[C:8]([CH3:9])=[O:7])[CH3:10]
Reactant: CC1=C(Cl)C(=O)OC(C)(C)O1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cl)C(C)=O
Yield: 69.9 %

Procedure:
Sodium metal (0.3 g, 12 mmol) was added to 10 ml of ethanol, and then 5-chloro-2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.76 g, 10 mmol) was added. The reaction was stirred one hour at 20° C., during which time the sodium dissolved. The reaction partitioned between ether and saturated ammonium chloride which had been acidified to pH ~2 with HCl. Evaporation of the ethereal layer, followed by distillation afforded 1.15 g (70%) of the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[C:7]([OH:15])[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCC1CC(=O)c2c(O)cc(C=O)cc2C1
Agent: [H-]
Agent: [Na+]
Product: CCC1CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1

Procedure:
The product of Example 30 is treated with sodium hydride and benzyl bromide according to the procedure described in Example 15.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.CO[C:16](=[NH:21])[C:17]([Cl:20])([Cl:19])[Cl:18]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[NH:11][C:16]([C:17]([Cl:20])([Cl:19])[Cl:18])=[N:12][C:6]=2[CH:5]=1)=[O:13].[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[NH:11][C:16]([C:17]([Cl:18])([Cl:19])[Cl:20])=[N:21][C:6]=2[CH:5]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c(N)c(N)c1
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: COC(=O)c1cc(C)c2[nH]c(C(Cl)(Cl)Cl)nc2c1

Procedure:
7-Methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 7-Methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester was prepared by a procedure according to example 5 (i) starting from 404.0 mg (2.20 mmol) 3,4-Diamino-5-methyl-benzoic acid methyl ester and 0.39 mL (3.08 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9](=[O:12])[C:8]2[CH2:7][O:6][CH:5]([CH2:13][CH3:14])[CH2:4][C:3]1=2.C(O[CH:19]=[CH:20][CH:21]=[CH2:22])(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:13]([CH:5]1[O:6][CH2:7][C:8]2[C:9](=[O:12])[C:10]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:4]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:14]
Reactant: CCC1CC2=C(CO1)C(=O)C=CC2=O
Reactant: C=CC=COC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC1CC2=C(CO1)C(=O)c1ccccc1C2=O
Yield: 20 %

Procedure:
Following the procedure described in step 4, example 26, the starting quinone from step 3 herein (250 mg; 1.30 mmol) and 1-acetoxy-1,3-butadiene (876 μl; 7.8 mmol) were reacted in toluene (10 ml) to yield after chromatography using 2% ethyl acetate in toluene the title compound (62 mg; 20%) along with mixed fractions containing a lot of desired titled product (230 mg), M.P.: 98°-101° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1>FC(F)(F)C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([NH2:21])[CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(CCCn3cncn3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccc(CCCn3cncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopiperidine (180 mg, 0.47 mmol) obtained in Example 8(5) was dissolved in trifluoroacetic acid (5 ml) at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified using medium-pressure silica gel flash column chromatography (NH silica gel, methanol:chloroform=1:9), thereby obtaining N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-aminopiperidine (127 mg, 95%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17].[CH2:43]([O:55][CH2:56][CH:57]([CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].N1C=CC=CC=1>O1CCCC1>[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[CH:31]([C:35]([O:37][CH:57]([CH2:56][O:55][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:36])[CH:32]=[CH:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17]
Reactant: CCCCCCCCCCCCOCC(O)COCCCCCCCCCCCC
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOCC(COCCCCCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
Dicyclohexylcarbodiimide (3.96 g) was added to a stirred solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.58 g] and 2-n-dodecyloxy-1-n-dodecyloxymethylethanol (8.23 g) in a mixture of dry pyridine (60 ml) and dry tetrahydrofuran (20 ml) at 3° C., and then stirred at 0° to 5° C. for 4.75 hours and further at room temperature for an hour. The resultant mixture was poured into ice water (350 ml) and extracted with ethyl acetate (500 ml). Water (50 ml) was added to the extract and adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (100 ml×2) and an aqueous solution of sodium bicarbonate in turn, and dried over anhydrous magnesium sulfate. After evaporating the solution in vacuo, the residue was subjected to column chromatography on silica gel (266 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [6.24 g] of 2-n-dodecyloxy-1-n-dodecyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH3:21].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:3]([CH3:21])[C:4]([C:17]([O:19][CH3:20])=[O:18])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2cccc(Cl)c2)c(Br)c1C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cn(S(=O)(=O)c2cccc(Cl)c2)c(-c2ccccc2)c1C
Yield: 72.9 %

Procedure:
Methyl 5-bromo-1-[(3-chlorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate (1.0 g), phenylboronic acid (403 mg), sodium carbonate (405 mg) and tetrakis(triphenylphosphine)palladium (295 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), and the mixture was reacted in a microwave reactor (Emrys Optimizer, Personal Chemistry, 140° C., 4 min). The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-brown oil (yield 724 mg, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=2[CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
To a stirred suspension of 2-hydroxy-5-methylbenzaldehyde (5 g, 36.7 mmol) and K2CO3 (12.7 g, 91.8 mmol) in DMF (30 mL), ethyl bromoacetate (4.07 ml, 36.7 mmol) was added drop-wise. This mixture was allowed to stir for two hours under nitrogen at room temperature, and was then heated to 80° C. and stirred overnight. The reaction was quenched with H2O to form a precipitate which was collected by filtration and purified by flash chromatography (eluent 5% EtOAc in hexane) to give the title compound 25 (2.30 g, 31%). 1H-NMR (CDCl3) δ: 1.45 (t, J=7.0 Hz, 3H); 2.47 (s, 3H); 4.45 (q, J=7.0 Hz, 2H); 7.26 (m, 1H); 7.46 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 55 %

Procedure:
Methyl 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate (80.0 mg, 0.255 mmol) was dissolved in THF (0.3 mL) and MeOH (0.3 mL), then 1.0 M aq. NaOH (1.28 mL, 1.28 mmol) was added. The reaction mixture was stirred at room temperature for 50 min., then neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove all the solvents. The residue was dissolved in THF, dried, filtered and concentrated under vacuum to give the sub-title compound as a white powder (42 mg, 55%). LCMS calc. for C13H9F3NO2S (M+H)+: m/z=300.0. Found: 300.2.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([F:18])[CH:8]=1.[CH:19](N1CCOCC1)=[O:20]>C1COCC1>[Cl:6][C:7]1[C:8]([CH:19]=[O:20])=[C:9]([F:18])[C:10]([Si:14]([CH3:15])([CH3:17])[CH3:16])=[C:11]([F:13])[CH:12]=1
Reactant: O=CN1CCOCC1
Reactant: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Temperature: -70 °C
Yield: 108.2 %

Procedure:
A solution of 2.5M n-BuLi in hexanes (60 ml, 0.15 mol) was added drop-wise to a solution of (4-chloro-2,6-difluorophenyl)trimethylsilane (assumed 0.13 mol) in THF (180 mL) cooled to −70° C. under Ar. After the addition was complete, the mixture was stirred for 1 h before a solution of N-formylmorpholine (20 mL, 0.2 mol) in THF (25 mL) was added dropwise. The reaction was allowed to warm to rt with stirring and then cooled to 0° C. and quenched with H2O. Ether was added, the phases were separated, the aqueous phase was re-extracted with ether and the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (35 g) as an orange oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:18](=[O:19])[C:17]3[CH:16]=[C:15]([O:14][CH3:13])[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=3)=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc2cc(C)sc2c1
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(C)sc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a mixture of 6-methoxy-2-methylbenzo[b]thiophene (0.024 g; 0.132 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.052 g; 0.225 mmol) in 1,2-dichloroethane (1 ml) SnCl4 (0.023 ml) was added. The resulting mixture was stirred for 1 h at 40° C., quenched with H2O (1 ml), diluted to 15 ml with diethyl ether, washed with 5% NaHCO3 (5 ml), brine (10 ml), dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2; hexane/ethyl acetate 9:1) to give pure title compound (0.020 g; 41%) as a colourless crystals. 1H-NMR (CDCl3) 2.47 (s, 3H); 3.8 (s, 6H); 3.84 (s, 3H); 3.93 (s, 3H); 6.90 (dd, 1H, J=2.4, 8.89 Hz); 7.1 (s, 2H); 7.24 (d, 1H, J=2.4 Hz); 7.42 (d, 1H, J=8.89 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:45])[CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:22])=[CH:4][CH:3]=1.C[C@H:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:48]3[CH2:49][CH2:50][NH:51][CH2:52][CH2:47]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:45])[CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:22])=[CH:4][CH:3]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(CN3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (37.8 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol), acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via reversed phase HPLC using the Gilson (acidic conditions with 0.1% TFA in the solvents). The product after HPLC purification was dissolved in 3 mL of MeOH and passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 6.92 mg of the title compound (16.4%). LC-MS m/z 701 (M+H)+, 1.19 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH:37]C(=O)OC(C)(C)C)[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: N[C@@H]1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 34 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl pyrrolidin-3-ylcarbamate, 287 was obtained as an off-white solid (12.2 mg, 34%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 9.22 (s, 1H), 9.02 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.62 (dd, J=11.8, 7.2 Hz, 3H), 7.58-7.49 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 4.01-3.92 (m, 2H), 3.64-3.51 (m, 3H), 2.10 (dt, J=12.0, 5.9 Hz, 1H), 1.82-1.72 (m, 1H); ESI MS m/z=358.2 (M+1)
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22](=[O:24])[CH3:23])=[C:6]([CH3:21])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC)=[CH:12][C:11]=2[O:19][CH3:20])[C:8]=1[CH3:9])(=[O:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:22]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:8]([CH3:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:19][CH3:20])[C:6]=1[CH3:21])(=[O:24])[CH3:23]
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)ccc1-n1c(C)c(C(C)=O)c(C(C)=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of crude 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as above (90 mg, 0.3 mmol) in 5.0 mL of CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 0.9 mL, 0.9 mmol). After 1 h at 0° C., it was warmed to rt and stirred for an additional 2 h before it was quenched with saturated aq. NaHCO3 solution (5 mL). It was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with dried with MgSO4, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. This crude material was purified by automated chromatography on silica gel (using 20-50%EtOAc/hexanes gradient) to give the major product 1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as pale yellow oil: MS (ESI) 302 (M+H)+; In this reaction, small amount (˜10%) of minor product 1-[4-acetyl-1-(2,4-dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone was also isolated as clear colorless oil: MS (ESI) 288 (M+H)+.