Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(C2CCCNC2)c1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
3-[3-(4-Trifluoromethoxy-benzenesulfonylamino)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (340 mg, 0.66 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. Aqueous NaHCO3 solution (10 ml) was added and extracted twice with ethyl acetate (25 ml). The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the pure product (250 mg, 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([CH2:27][CH3:28])([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:17][CH3:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([CH3:26])[CH:20]=3)([CH2:27][CH3:28])[CH2:17][CH3:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1oc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1oc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2c1C
Yield: 94 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (4.04 g, 10.6 mmol) and 1-bromopinacolone (2.66 g, 14.9 mmol) and K2CO3 (2.91 g, 21.2 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (4.77 g, 94%).
Reaction SMILES: [K].[C:2]([CH:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH2:25]>Cl>[C:5]([C:4]1[C:2]([NH2:3])=[N:25][N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:20])([F:22])[F:21])=[CH:16][C:15]=2[Cl:23])[C:10]=1[NH2:11])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C#N)C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [K]
Product: CCOC(=O)c1c(N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 38.4 %

Procedure:
Ethyl dicyanoacetate potassium salt (35.2 g) was added to a stirred suspension of 2,6-dichloro-4-trifluoromethylphenylhydrazine (49 g) in hydrochloric acid (0.9 M; 220 ml) and the mixture was stirred and boiled under reflux for 18 h, then cooled to precipitate a solid which was filtered off, triturated with diethyl ether (250 ml) and dried to give an off-white solid which was recrystallized from ethyl acetate-hexane to give 4-carboethoxy-3,5-diamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (29.2 g), m.p. 196°-197° C., in the form of an off-white solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[N:39]=[CH:38][C:37]([C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:25][CH2:26]2)=[O:20])=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccc(Cl)nc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 6-chloro-pyridin-3-yl-boronic acid to give the title compound as light yellow gum. MS: 534.3 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O-:4])[CH2:2][CH3:3].[Na+].[Na].C(O)CC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[N:13]=1>CCOC(C)=O>[Br:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:4][CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: CCC[O-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CCCOc1cccc(Br)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a sodium propan-1-olate solution, prepared by addition of sodium (36 mg, 1.58 mmol) to propanol (1 mL), was added 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 2 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 189 mg of Intermediate 161.1 as a colorless oil. LCMS (2 min gradient) RT=1.82 min, 216.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].C1COCC1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[S:13]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccccc1C(N)=O
Solvent: C1CCOC1
Product: COc1ccccc1C(N)=S
Yield: 185.7 %

Procedure:
Combine 2-methoxy benzamide (10.0 g, 66.2 mmol) with phosphorus pentasulfide (10.1 g, 22.7 mmol) and THF (200 mmol) in a sealed vessel and stir for 30 minutes at room temperature. Sonicate the mixture for 1 hour and then allow the mixture to stand at room temperature. Decant the THF solution from the solids and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to give 2-methoxy-thiobenzamide (7.05 g, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[CH3:13][O:12][C:11]1[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(OC)c(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
Methyl 3-bromo-4-(methyloxy)benzoate (245 mg, 1 mmol, commercially available) was dissolved in DME: 2N Na2CO3 (2:1, 18 ml) and then phenyl boronic acid (244 mg) and tetrakistriphenylphosphine palladium(0) (58 mg) were added. The reaction was heated to 80° C. and then left to cool over the weekend. Added EtOAc and water, the organics were separated, dried and evaporated to give a black gum. Purification by flash chromatography afforded the title compound (194 mg) as a gum. δH (d6-DMSO, 400 MHz) 3.83 (3H, s), 3.85 (3H, s), 7.24 (1H, d), 7.33-7.50 (5H, m), 7.83 (1H, d), 7.97 (1H, dd). MS (ES): C15H14O3 requires 242; found 243 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CCCCCC>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 50.0 g of acetophenone and 150 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 8 hours. The mixture was allowed to cool to room temperature, then the solvent was removed in vacuo to give a crystalline residue. The residue was treated with 400 ml of hexane then filtered. The material on the filter was washed with hexane to give 47.8 g of the desired product as yellow crystals, mp 88°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(F)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 53.7 %

Procedure:
N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-fluoro benzohydrazide was prepared using 4-fluorobenzoic hydrazide (4.4 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.0 mmol, 1.0 equiv.) as described previously in the preparation of intermediate 5a. The crude golden yellow solid was recrystallized using hot methylene chloride to provide the desired product as a light yellow solid (870 mg, 54% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.85 (br. s., 1H), 9.5 (br. s., 1H), 8.02 (dd, J=5.4, 8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d, J=6.8 Hz, 1H), 4.70 (br. s., 1H), 4.24 (m, 1H), 4.12 (dd, J=4.9, 7.3 Hz, 1H), 2.35 (s, 3H), 1.38 (d, J=6.3 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18ClFN4O3 [M]+ 404.82, found 405.4; TLC Rf=0.38, 100% EtOAc, vanillin stain.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:19]1)=[O:17])[CH3:14].[CH:34](=[O:36])[CH3:35]>O1CCCC1>[CH2:13]([O:15][C:16]([C:18]1([CH:34]([OH:36])[CH3:35])[CH2:22][CH2:21][CH:20]([O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:31]([CH3:32])[CH3:33])[CH:28]([CH3:30])[CH3:29])[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(C)O)CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.4 mL, 31.285 mmol) in anhydrous tetrahydrofuran (60 mL) was treated with n-butyllithium (2.5 M in hexanes, 11.7 mL, 29.329 mmol). After stirring at −78° C. for 30 min, the reaction mixture was treated with a solution of 3-triisopropylsilanyloxy-cyclopentanecarboxylic acid ethyl ester (6.15 g, 19.553 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring at −78° C. for 40 min, the reaction mixture was treated with neat acetaldehyde (3.3 mL, 58.659 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 50 min then quenched at 0° C. with a saturated solution of ammonium chloride (100 mL). The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (6.61 g, 94%) as a light yellow oil and as a complex mixture of diastereoisomers.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=[S:34])[CH2:28][CH2:27]1>CC(C)=O>[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([S:34][CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:35])[CH2:28][CH2:27]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: OC(=S)CN1CCOCC1
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
21-Bromo-5α-pregnane-3,11,20-trione (1.04 g.) was refluxed in dry acetone (100 ml) with morpholino thioacetic acid (600 mg) for 15 minutes. The reaction mixture was concentrated, partitioned between ethyl acetate, water, pH 8, the organic layer was washed, dried (MgSO4) and evaporated to an off white solid (1.26g.)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C@H:18]3CC[C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].N[C@H:29]1CC[C@H](C(OC)=O)C[CH2:30]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:17]3[CH2:30][CH2:29][CH:20]([CH2:21][C:24]([O:26][CH3:27])=[O:25])[CH2:19][CH2:18]3)=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)C2CCN(c3ccc(C#N)cc3)CC2)CC1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Product: COC(=O)CC1CCN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)CC1

Procedure:
1-(4-cyanophenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-piperidine Using methyl trans-4-amino-cyclohexanecarboxylate. Melting point: 230°-232° C.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O1CCCC1.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>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(Ethoxycarbonyl)phenylzinc iodide in tetrahydrofuran (0.5M, 2 mL, 1 mmol) was added to a solution of 2-bromopyridine (0.16 g, 1 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.05 mmol) in tetrahydrofuran (5 mL) and stirred at RT for 3 h. The reaction was quenched with saturated ammonium chloride and extracted three times with ethyl acetate. The combined organic phase was dried (MgSO4), concentrated in vacuo, and the residue chromatographed (silica gel, 10% ethyl acetate/hexane) to give the title compound as a yellow solid (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:16]([N:19]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:20]2[CH:21]=[CH:22][C:23]3[N:24]([CH2:33][CH3:34])[C:25]4[C:30]([C:31]=3[CH:32]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:18])=[O:17])[CH:5]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[CH3:43][Si:44]([C:47]#[CH:48])([CH3:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:19]([S:16]([C:4]1[CH:5]=[C:6]([C:48]#[C:47][Si:44]([CH3:46])([CH3:45])[CH3:43])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:17])=[O:18])[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH2:33][CH3:34])[C:25]3[C:30]([C:31]=2[CH:32]=1)=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH3:41])([CH3:40])[CH3:42]
Reactant: C#C[Si](C)(C)C
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
320 mg tert-butyl [(3-chloro-5-trifluoromethylsulphonyloxy-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 4 ml dimethylformamide. 20 mg copper-1-iodide, 40 mg bis-triphenylphosphine-palladium-dichloride and 210 μl trimethylsilylacetylene are added under argon. Then the mixture is heated to 60° C. for 6 hours and then stirred overnight at ambient temperature. The mixture is then divided between saturated potassium carbonate solution and ethyl acetate. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: OB(O)c1cccc(F)c1
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxyphenol (1.4 g, 0.0071 mol), 3-fluorobenzeneboronic acid (500 mg, 0.004 mol), TEA (3.0 mL, 0.021 mol), cupric acetate (1.0 g, 0.0057 mol) and DCM (40 mL, 0.6 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.71 (s, 3H), 6.52 (dt, J=10.36, 2.40 Hz, 1H), 6.57-6.69 (m, 2H), 6.81 (d, J=8.34 Hz, 1H), 6.99 (dd, J=8.34, 2.27 Hz, 1H), 7.04 (d, J=2.27 Hz, 1H), 7.13 (td, J=8.34, 6.82 Hz, 1H).
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=O)C.[N+:11]([CH2:14][C:15]([NH2:17])=[O:16])([O-:13])=[O:12].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH:8]1([C:6]2[NH:17][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1
Reactant: CN(C)C=CC(=O)C1CC1
Reactant: NC(=O)C[N+](=O)[O-]
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Product: O=c1[nH]c(C2CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of crude β-N,N-dimethylaminoethenylcyclopropyl ketone (17-2; 12 g, <86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100 ml) and piperidine (72 ml)] was stirred at room temperature overnight. Following dilution with water (20 ml), the yellow precipitate was isolated via filtration and drying in vacuo to yield the title compound 17-3: 1H NMR (CDCl3) δ 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H), 6.02 (br d, J=8.0 Hz, 1 H), 8.41 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]4[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=4)[N:18]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[N:40]1([CH2:45][C:46]2([CH2:49][NH2:50])[CH2:48][CH2:47]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.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>C(Cl)Cl>[N:40]1([CH2:45][C:46]2([CH2:49][NH:50][C:34]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:19]4[N:20]=[C:21]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])[N:22]=[C:17]([NH:16][C:13]5([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:39])=[CH:12][CH:11]=6)[CH2:15][CH2:14]5)[N:18]=4)=[CH:38][CH:37]=3)=[O:35])[CH2:48][CH2:47]2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)O)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Reactant: NCC1(CN2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Yield: 65 %

Procedure:
4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (330 mg, 0.603 mmol), (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanamine (112 mg, 0.723 mmol), HATU (344 mg, 0.904 mmol), and Hunig's Base (0.526 mL, 3.01 mmol) were stirred in DCM (Volume: 5 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc then 5% DCM/MeOH to give ethyl 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetate (268 mg). LC-MS (Condition A), MS m/z (M++H) 684.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[CH:22][CH:21]=1>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:30][CH:29]=3)[CH2:26]2)[N:3]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Fc1cccc(Br)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3cccc(Br)n3)C2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
To 2-bromo-6-fluoropyridine (150.0 mg, 0.852 mmol) in 2-propanol (3.00 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.445 mL, 2.56 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (174 mg, 0.852 mmol). The resulting reaction mixture was stirred at RT for 3.5 h, then heated to 70° C. for 24 h, cooled to RT and concentrated. Purification of the crude product using MPLC (5 g cartridge, 12 g column, 0 to 60% EtOAc-hexanes) gave 2-bromo-6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (211.4 mg).
Reaction SMILES: [O:1]([CH3:13])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>N1C=CC=CC=1>[Br:34][CH:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: BrC(Br)(Br)Br
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](C(O)Br)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
To a 0° C. solution of methyl α-D-glucopyranoside (3.9 g, 20 mmol) in 125 mL of anhydrous pyridine was added triphenylphosphine (10.5 g, 40 mmol) followed by carbon tetrabromide (9.9 g, 30 mmol). The reaction was stirred at 0° C. for 10 minutes then warmed to 65° C. for 4 hours. The reaction was quenched with 20 mL of methanol and concentrated to a crude residue, a portion of which was purified by column chromatography eluting from silica gel with a gradient of 0 to 15% methanol in dichloromethane to give 1.1 g of an off-white solid (64%). 1H NMR (400 MHz, d6-DMSO) δ 3.00-3.06 (m, 1H), 3.16-3.23 (m, 1H), 3.30 (s, 3H), 3.30-3.41 (m, H), 3.47-3.57 (m, 2H), 3.73-3.76 (dd, J=1.6, 10.3 Hz, 1H), 4.56-4.57 (d, J=3.6 Hz, 1H), 4.82-4.83 (d, J=6.4 Hz, 1H), 4.90-4.91 (d, J=5.0 Hz, 1H), 5.21-5.23 (d, J=5.9 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) δ 35.2, 55.0, 71.0, 71.9, 72.3, 73.0, 99.9.
Reaction SMILES: I[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:12](C1C=CC=CC=1N)#[CH:13]>>[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[CH:13])(=[O:4])[CH3:2]
Reactant: C#Cc1ccccc1N
Reactant: O=C(CI)Nc1ccccc1
Product: C#Cc1ccccc1NC(C)=O

Procedure:
The N-acetyl-2-ethynylaniline was prepared from 2-iodoacetanilide by Sonogashira coupling and using the same method as the synthesis of 2-ethynyl aniline. Afforded light brown solid 45% yield.