Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH:19]=[C:20]([F:22])[F:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.O.[F-:28].[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:15][C:16]([CH2:19][C:20]([F:28])([F:21])[F:22])=[CH:17][N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=C(F)F)s2)CC1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of 1.03 mmol 4-[5-(2,2-difluoro-vinyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in 7.5 dimethylsulphoxide and 0.3 ml water was added 7.18 mmol potassium fluoride and the mixture was heated at 120° C. for 2 h. The mixture was then diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 90%). MS (m/e): 352.3 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19](Cl)[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:26]=[S:27]1(=[O:36])[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:33]([CH:30]3[CH2:31][CH2:32][S:27](=[O:36])(=[O:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCS(=O)(=O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCS(=O)(=O)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 509.1 [M]+.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[F:15].C(Cl)Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:4][CH:2]([CH3:3])[CH3:1])=[O:11])=[CH:8][C:7]=1[F:15]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
2-Propanamine (1.2 mL, 14 mmol) was added to a mixture of 4-bromo-3-fluorobenzoic acid (2.09 g, 9.54 mmol, Alfa Aesar: Cat. #B25475) in methylene chloride (52.2 mL, 815 mmol), followed by benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (4.6 g, 10. mmol) and N,N-diisopropylethylamine (3.3 mL, 19 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-20%) to afford the desired product (2.28 g, 91.8%). LCMS (M+H)+: m/z=260.0/262.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[C:4]2[C:5]([N:28]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=3[CH:27]=1)[CH:9]=2>CO.Cl.O1CCOCC1>[CH3:1][C:2]1[N:3]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[C:4]2[C:5]([N:28]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:27]=1)[CH:9]=2
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2n1C(=O)OCC(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
A mixture of 1,1-dimethylethyl 7-(2-methyl-1-{[(2-methylpropyl)-oxy]carbonyl}-1H-imidazo[4,5-b]pyridine-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)carboxylate (1.1 g, 2.3 mmol) in methanol (6 ml) and 4 N hydrochloric acid in dioxane (12 ml) was stirred at room temperature for 1 h and then concentrated. The resulting solid was triturated with ethyl acetate to afford the hydrochloride salt of 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (0.92 g, 91% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 8.79 (d, 1H), 8.42 (d, 1H), 7.88 (d, 1H), 7.70 (dd, 1H), 7.24 (d, 1H), 4.42 (brs, 2H), 4.32 (d, 2H), 4.27 (brs, 2H), 3.50 (brs, 2H), 2.82 (s, 3H), 2.19 (m, 1H), 1.06 (d, 6H); MS (EI) for C21H24N4O3: 381 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[CH2:58][OH:59]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=2[CH2:58][OH:59])=[CH:11][C:10]1=[O:17]
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Reactant: OCc1ccc(F)cc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2CO)cc(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(2,6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (step 1) (3.0 g, 12.65 mmol) was dissolved in N,N-dimethylformamide and cooled to 0° C. Triphenylphosphine (3.98 g, 15.18 mmol) and diethyl azodicarboxylate (2.39 ml, 15.18 mmol) were added and stirred for 10 minutes. 1,2-Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was added and stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred overnight. LC-MS showed only 1 product, not a mixture of regioisomers, as expected. The reaction was added to water and extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. A Biotage silica column was done using 60% ethyl acetate/hexanes as an eluent. Desired product, with a substantial impurity was obtained. Another Biotage silica column was ran using 30% ethyl acetate/hexanes to obtain pure product. The resulting oil was triturated with diethyl ether to obtain a white solid (720 mg, 15%). 1H NMR (300 MHz, CDCl3) δ 7.51-7.39 (m, 2H), 7.26 (dd, J=9.62, 2.51 Hz, 1H), 7.13-7.01 (m, 3H), 6.03 (d, J=2.42 Hz, 1H), 5.96 (d, J=2.41 Hz, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, 1H), 2.02 (s, 3H); LC/MS, tr=2.37 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 376 (M+H). ES-HR/MS m/z 376.1181 (M+H calcd for C20H16F3NO3 requires 376.1155). Identity of the positional isomer was determined from hmbc, 2-D NMR experiments using H to C 2- and 3-bond coupling.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:14][CH2:15][CH:16]([F:18])[F:17])[CH:3]=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][C:26]([C:28]2([C:31]([F:34])([F:33])[F:32])[CH2:30][CH2:29]2)=[O:27])=[CH:22][C:21]=1[N:37]=[C:38]=S.CC(C)N=C=NC(C)C>C1COCC1>[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][C:26]([C:28]2([C:31]([F:34])([F:33])[F:32])[CH2:29][CH2:30]2)=[O:27])=[CH:22][C:21]=1[NH:37][C:38]1[NH:1][C:2]2[CH:3]=[C:4]([O:14][CH2:15][CH:16]([F:17])[F:18])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=2[N:13]=1
Reactant: CCOC(=O)c1cc(N)c(N)cc1OCC(F)F
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F

Procedure:
The sub-title compound was prepared in accordance with Example 59 (h) using ethyl 4,5-diamino-2-(2,2-difluoroethoxy)benzoate (0.466 g; 1.79 mmol; crude material from step (c)), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (0.600 g; 1.79 mmol), DIC (0.226 g; 1.79 mmol) and THF (40 mL). Yield: 0.620 g (62%).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:55](=[N:56][CH:57]=1)[N:54]=[C:53]([CH3:58])[C:52]([C:59]([NH:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]([CH3:72])([CH3:71])[CH3:70])=[CH:65][CH:64]=1)=[O:60])=[CH:51]2.C1(C(C2C=CC=CC=2)=[NH:80])C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[NH2:80][C:48]1[CH:49]=[C:50]2[C:55](=[N:56][CH:57]=1)[N:54]=[C:53]([CH3:58])[C:52]([C:59]([NH:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]([CH3:72])([CH3:71])[CH3:70])=[CH:65][CH:64]=1)=[O:60])=[CH:51]2
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1nc2ncc(Br)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc2ncc(N)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Yield: 2.6 %

Procedure:
9.2 mg (0.01 mmol) Pd2 dba3 and 19 mg (0.03 mmol) BINAP were added to a degassed mixture of 205 mg (0.5 mmol) 6-bromo-N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide, 100 ml (0.6 mmol) diphenylmethanimine and 79 mg (0.7 mmol) KOtBu in 2 ml toluene. The flask was sealed with a septa and heated at 80° C. over night. The reaction mixture was diluted with EtOAc and filtered through celite and SiO2 with EtOAc. The filtrate was concentrated and treated with THF and 1.0 M HCl for 2 h. The solution was diluted with 0.5 M Hcl and washed with EtOAc/Pet. ether 1:1. The aqueous phase was neutralized with 1 M NaOH and extracted twice with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. Flash chromatography (CH2Cl2/MeOH 10:1) gave 4.6 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([S:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(Sc2ccccc2)nc1-c1ccc(C)cc1
Yield: 46.7 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), cesium carbonate (294 mg; 0.901 mmol) and thiophenol (0.092 mL; 0.901 mmol) were placed in a 2 mL reaction tube and dissolved in tetrahydrofuran (0.6 mL). The tube was sealed and irradiated in a microwave oven at 130° C. for 30 min. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 57 mg (32%) of the title compound as a colorless oil.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=CC=C3C=2CCC(=O)N3)CCNCC1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([Cl:51])[CH:50]=1)[C:45](Cl)=[O:46]>CN(C=O)C.C(N(CC)CC)C>[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([Cl:51])[CH:50]=1)[C:45]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)[CH2:3][CH2:4]1)=[O:46]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2c(cccc2N2CCN(C(=O)c3cc(Cl)cc(Cl)c3)CC2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (3.5 g) was suspended in 40 ml DMF. After adding 960 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 5-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 2.34 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 3.0 g of 3,5-dichlorobenzoyl chloride. After completion of addition the reaction mixture was stirred for 40 minutes. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.8 g of 5-[4-(3,5-dichlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 255°-257° C., colorless needles.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.CCN(CC)CC.CN([C:23]([O:27][N:28]1N=NC2C=CC=N[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>C(Cl)Cl.CN(C=O)C>[CH3:23][O:27][N:28]([CH3:29])[C:10]([C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2cnccc2s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2cnccc2s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of thieno[3,2-c]pyridine-2-carboxylic acid (D′-1) (11.5 g, 64.2 mmol) in DCM (200 mL) and DMF (50 mL) was added Et3N (19.5 g, 26.6 mL, 192.6 mmol) followed by HATU (36.6 g, 96.3 mmol). The reaction solution was stirred at room temperature for 20 mins, and then treated with N,O-dimethylhydroxylamine hydrochloride (6.9 g, 70.6 mmol). Stirring continued overnight at room temperature. The solvent was removed. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried and concentrated. The residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 223 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(Cl)Cl.N1CCCCC1.[CH:45]([C:47]1([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:49][CH2:48]1)=O>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:45][C:47]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:48][CH2:49]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NC1(C=C(C#N)C(=O)N2CCC[C@@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Yield: 29.1 %

Procedure:
To a solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (100. mg, 0.2100 mmol) dissolved in methanol (4 mL) and DCM (4 mL) was added piperidine (0.1 mL, 0.8500 mmol) and tert-butyl N-(l-formylcyclopropyl)carbamate (58.9 mg, 0.3200 mmol). The reaction was heated to reflux for 6 hrs and then cooled and concentrated. The residue was and dissolved in ethyl acetate (50 mL) and washed with water (50 mL) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (1%-8% MeOH/DCM) to provide 39 mg (13% yield) of tert-butyl N-[1-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]cyclopropyl]carbamate.
Reaction SMILES: [CH:1]1[C:6](Cl)=[C:5]([C:8]([OH:10])=[O:9])[C:4](Cl)=[C:3](Cl)[CH:2]=1.COC1C(Cl)=CC=C(Cl)C=1C(O)=O.C1C(Cl)=C(C(O)=O)N=C(Cl)C=1.C1(N)C(Cl)=C(Cl)N=C(C(O)=O)C=1Cl.C1C(Cl)=NC(C(O)=O)=C(Cl)C=1N.C1C=C(Cl)C(C(O)=O)=C2N=CC(Cl)=CC=12.CC1C=NC2C(C(O)=O)=C(Cl)C=CC=2C=1>>[C:8]([OH:10])(=[O:9])[C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1Cl
Agent: COc1c(Cl)ccc(Cl)c1C(=O)O
Agent: Cc1cnc2c(C(=O)O)c(Cl)ccc2c1
Agent: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Product: O=C(O)c1ccccc1

Procedure:
2,3,6-TBA, dicamba, clopyralid, picloram, aminopyralid, quinclorac, and quinmerac.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+]>O>[C:13]1([NH:12][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2ncccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(Nc2ncnc3ncccc23)cc1
Yield: 26.7 %

Procedure:
4-Chloropyrido [2,3-d]pyrimidine (0.15 g, 0.91 mmol) was carefully added to a solution of aniline (0.15 g, 1.61 mmol) in water (1.5 mL). The solution was heated for 0.5 h on a steam bath, cooled, and then basified with conc. ammonium hydroxide. The crude precipitate was collected by filtration and recrystallized from 95% ethanol to give yellow crystals (0.054 g, 27%). MP 258° C.; LC-MS: 223 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:3]=1
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: Oc1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 150 °C
Reaction time: 2 h

Procedure:
3-Chloropyridin-4-ol (0.259 g), 1-fluoro-3-(trifluoromethyl)benzene (0.126 mL) and potassium carbonate (0.276 g) were suspended in N-methyl-2-pyrrolidone (1.2 mL), and the suspension was stirred at 150° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) to give the title compound (28.1 mg).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.S1C=CC2C=CC=CC1=2.C([Li])CCC.[Br:25]Br>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Br:25][C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH:2]=1
Reactant: Brc1csc2ccccc12
Reactant: BrBr
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Agent: c1ccc2sccc2c1
Product: Brc1cc2ccccc2s1

Procedure:
Starting from the commercially available 3-bromobenzo[b]thiophene (5), a synthetic route to poly(2,2′-bisbenzo[b]thiophene) (4) is outlined below in Scheme 1. 3-bromobenzo[b]thiophene (5) is alkylated to (6) using an alkyl grignard and Ni(dppp)Cl2. Benzo[b]thiophene (6) is brominated at the 2-position using n-butyllithium followed by bromine to yield (7). 2-Bromobenzo[b]thiophene (7) is homo-coupled using a liganded nickel complex reducing agent (generated from NaH, t-AmONa, Ni(OAc)2 and bipyridine) to yield 2,2′-bisbenzo[b]thiophene (2). Bromination of 2,2′-bisbenzo[b]thiophene (2) with N-bromosuccinimide or bromine water yields 5-5′-dibromo 2,2′-bisbenzo[b]thiophene (8).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:24])([F:23])[O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[C:4]([F:25])[CH:3]=1.[CH2:26]([CH:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH2:29][CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:25][C:4]1[CH:3]=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([CH:34]3[CH2:35][CH2:36][CH:31]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33]3)=[CH:42][CH:41]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([F:24])([F:23])[O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: CCCCCC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)Oc1ccc(S(F)(F)(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4ccc(S(F)(F)(F)(F)F)cc4)c(F)c3)cc2)CC1
Reaction time: 12 h
Yield: 59 %

Procedure:
Into a vessel having an inner volume of 30 ml which was equipped with a stirring apparatus, a thermometer and a reflux condenser, 0.460 g (1.00 mmol) of 4-[(4-bromo-2,6-difluorophenyl)difluoromethoxy]pentafluorosulfanylbenzene, 0.411 g (1.15 mmol) of 4-(4-n-pentylcyclohexyl)-phenylboronic acid pinacol ester, 0.070 g (0.061 mmol) of tetrakis-(triphenylphosphine)palladium, 0.425 g (2.02 mmol) of tripotassium phosphate in the powder form and 5 ml of 1,4-dioxane were placed, and the reaction was allowed to proceed at 100° C. for 12 hours with stirring. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under a reduced pressure. Then, the resulting residue was purified by the flush column chromatography (eluent: hexane), and 0.36 g (isolated yield: 59%) of 4-{[3,5-difluoro-4′-(4-n-pentylcyclohexyl)-biphenyl-4-yl]difluoromethoxy}pentafluorosulfanylbenzene was obtained as a white solid. The reaction scheme is shown in the following:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][O:7]2.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH2:31]([Sn:26]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:27][CH2:28][CH2:29][CH3:30])[C:5]1[S:1][C:2]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][O:7]3)=[N:3][CH:4]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1csc(C23CCN(CCO2)C3)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C23CCN(CCO2)C3)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of the 5-(thiazol-2-yl)-4-oxa-1-azabicyclo[3.2.1]octane (632 mg, 3.22 mmol) in tetrahydrofuran (11 mL) was added a solution of lithium diisopropylamide (7.79 mmol in 10 mL tetrahydrofuran) dropwise. The solution was stirred at −78° C. for 45 minutes, and tributyltin chloride (1.05 mL, 3.86 mmol) was added dropwise. The cold bath was removed, and the reaction allowed to warm to room temperature. The ambient reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and diethyl ether. The layers were separated, and the aqueous layer was extracted with additional diethyl ether. The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 487.4 [M+H]+.