Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:4][C:3]1[CH:13]=[CH:12][CH:11]=[C:1]2[C:2]=1[CH:14]=[CH:7][CH:8]=[C:9]2[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: [Li]CCCC
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1cccc2c(-c3ccccc3C#N)cccc12
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 114 %

Procedure:
The title D compound (1.99 g, 9.00 mmol) was dissolved in 10 mL of freshly distilled tetrahydrofuran, cooled to -78° C. and n-butyllithium (2.23M in hexane, 4.24 mL, 9.45 mmol) was added dropwise over 10 minutes. Upon complete addition the reaction was cloudy, bright yellow. After stirring 40 minutes, zinc chloride (1.0M in ether, 9.45 mL, 9.45 mmol) was added and the reaction mixture turned to clear pale yellow. The reaction was stirred 30 minutes, then the cold bath was removed and the reaction stirred an additional 30 minutes before 2-bromobenzonitrile (1.64 g, 9.45 mmol) and tetrakis(triphenylphosphine)palladium(O) (520 mg, 0.45 mmol) were added. After stirring 22 hours at 55° C., the reaction mixture was adsorbed on 10 g of silica gel and purified by flash chromatography (170 g silica gel; 30% toluene, hexane) to yield 1.31 g (60%) of the product as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:9]([N:11]1[C:15]2[N:16]=[CH:17][C:18]([C:27]3[O:31][N:30]=[C:29]([CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:28]=3)=[C:19]([NH:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14]=2[CH:13]=[N:12]1)[CH3:10].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:9]([N:11]1[C:15]2[N:16]=[CH:17][C:18]([C:27]3[O:31][N:30]=[C:29]([CH2:32][CH:33]4[CH2:38][CH2:37][N:36]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:35][CH2:34]4)[N:28]=3)=[C:19]([NH:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:14]=2[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)CC(=O)Cl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(=O)CC(C)C)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Isovaleryl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 1 g) and the cartridge was eluted sequentially with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 176. LCMS showed MH+=496, TRET=3.17 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][C:15]=2[I:17])[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[Mg]Br>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[CH:14][C:15]=2[I:17])[C:9]([OH:10])([C:26]2[CH:25]=[CH:24][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[C:7]1=[O:8])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(C(F)(F)F)ccc(I)c21
Reactant: Br[Mg]c1ccc2ccccc2c1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(C(F)(F)F)ccc(I)c21
Yield: 53 %

Procedure:
The title compound (103 mg, 53%) was prepared from 1-(2-diethylaminoethyl)-7-iodo-4-trifluoromethylisatin (152 mg, 0.345 mmol) and 2-naphthylmagnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].C([Mg]Cl)(C)C.[Mg].BrC(Br)C.[S:16]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17]1.[Cl-].[NH4+]>O1CCCC1>[S:16]1[CH:20]=[CH:19][C:18]([CH:21]([OH:22])[CH2:2][CH2:3][CH2:4][OH:5])=[CH:17]1
Reactant: O=Cc1ccsc1
Reactant: OCCCCl
Agent: CC(Br)Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCCCC(O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
3-Chloropropanol (6.77 ml, 81 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and the solution cooled to 0° C. i-Propyl magnesium chloride, 2M solution, (40.5 ml, 81 mmol) was added dropwise, keeping the temperature at 0° C. When the addition was complete the reaction was allowed to warm to room temperature. Magnesium (2.96 g, 122 mmol) was added in one portion, followed by dibromoethane (0.1 ml). The reaction was heated and gently refluxed for 3 h, adding more dibromoethane (0.1 ml) at 1 and 2 h. The reaction was cooled and left to stand overnight. The resultant Grignard solution was titrated and had a concentration of 0.4M. The Grignard reagent prepared above (30 ml, 12 mmol) was syringed into a nitrogen flushed 3-necked flask, cooled to 0° C. and treated dropwise with 3-thiophene carboxaldehyde (1.12 g, 10 mmol) in tetrahydrofuran (10 ml). The reaction was allowed to warm to room temperature slowly and then stirred for a further 18 h. Saturated aqueous ammonium chloride (20 ml) was added and the mixture extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with water (20 ml), dried (magnesium sulphate) and evaporated to afford the title compound as a colourless oil (1.52 g, 88%).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(S(N)(=O)=O)c1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(OC)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-methoxybenzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B describe hereinabove. Yield (27%); 1H NMR (d6-DMSO) δ 12.18 (br s, 1H), 7.53-7.07 (m, 17H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 3.78 (s, 3H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 522 (M−H−).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].Cl[C:32]1C(C)=NOC=1N(COC)S(C1C=C(C)SC=1C(Cl)=O)(=O)=O>>[C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][C:17]([CH3:32])=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:21])=[O:22])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1cc(C)sc1C(=O)Cl
Product: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sc(C)cc1S(=O)(=O)Nc1onc(C)c1Cl

Procedure:
N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid chloride was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylic acid chloride.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH:30]1[C:42]2[NH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.Br[C:44]1[CH:61]=[CH:60][C:59]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=1.CC(C)([O-])C.[Na+]>CC1C=CC=CC=1C.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]>[CH:45]1[C:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:59]=2[CH:60]=[CH:61][C:44]=1[N:41]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:42]1=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc2c3ccccc3c3ccccc3c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)c1ccccc1c1cc(-n3c4ccccc4c4ccccc43)ccc21
Yield: 56 %

Procedure:
To a stirred solution of Pd2(dba)3 (0.52 g, 0.57 mmol) in o-xylene (140 mL), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.94 g, 2.3 mmol) was added and degassed with nitrogen for 15 minutes. Carbazole (5.33 g, 31.9 mmol) and 2-bromotriphenylene (7.0 g, 22.7 mmol), sodium tert-butoxide (6.57 g, 68.3 mmol) were added and degassed with nitrogen for another 15 minutes. The reaction was refluxed for 2 days. The reaction mixture was filtered through silica, washed with DCM and dried under vacuum. Silica gel chromatography with 10% DCM/hexane, yielded 4.98 g of a while solid (56%) as the product.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16](Br)[C:11]=2[O:10][C:9]=1[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]=[C:31]([C:16]2[C:11]3[O:10][C:9]([C:19]#[N:20])=[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[CH:13]=[C:14]([CH3:18])[CH:15]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc(Br)c2oc(C#N)c(Cc3ccccc3)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Temperature: 80 °C

Procedure:
To a flask was added 3-benzyl-7-bromo-5-methyl-benzofuran-2-carbonitrile (0.13 gm, 0.40 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.161 gm, 0.52 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (0.020 gm, 0.0245 mmol), and potassium carbonate (0.124 gm, 0.9 mmol). Dimethylfomamide was added via syringe and the mixture evacuated and refilled with nitrogen, then heated for 16 hours at 80° C. The mixture was concentrated under vacuum, water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude 4-(3-benzyl-2-cyano-5-methyl-benzofuran-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a residue that was used directly in the next step without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>O1CCCC1>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:20]([C:17]3([CH3:16])[CH2:19][CH2:18]3)=[O:21])=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC1(C(=O)Cl)CC1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2(C)CC2)cc1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 150 ml of absolute tetrahydrofuran by stirring and heating to 60° C. 4.2 g (35.4 millimoles) of 1-methylcyclopropanecarboxylic acid chloride are added dropwise to the above solution at 60° C., and the reaction mixture is then stirred for 7 hours at the reflux temperature. The product is filtered off at 10° C., washed with water and recrystallized twice from dimethylformamide/water. 5.5 g (65% of theory) of 4,5-dihydro-5-methyl-6-[p-(1-methylcyclopropylcarbonylamino)-phenyl]-3(2H)-pyridazinone are obtained as almost colorless crystals, of melting point 235°-237° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1Br.[Cu][C:21]#[N:22].C([O-])(O)=O.[Na+].CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1[C:21]#[N:22]
Reactant: N#C[Cu]
Reactant: CSc1ncc2c(N)c(Br)c(=O)n(C3CCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(N)c(C#N)c(=O)n(C3CCC3)c2n1
Temperature: 220 °C
Yield: 67.3 %

Procedure:
To a solution of 5-amino-6-bromo-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.15 mmol) in 0.5 mL NMP was added copper(I) cyanide (56 mg, 0.63 mmol). The resulting mixture was heated at 220° C. in a microwave reactor for 20 min. After cooling, the reaction mixture was treated with a mixture of NaHCO3 (sat'd, aq) and EtOAc. The mixture was filtered and the collected solid then mixed with NH4OH (15%, aq). The aqueous mixture was extracted with EtOAc and then combined organic layers and evaporated under reduced pressure. The crude residue was purified by preparative TLC (DCM/MeOH, 93/7) to give 29 mg of 5-amino-6-cyano-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:15]#[N:16])[C:11]([NH:13][CH3:14])=[O:12].[Cl-:17].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[ClH:17].[NH2:16][C:15]1[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:8]=[N:9][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)C(C#N)=NNc1ccccc1Br
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-[(2-bromophenyl)-hydrazono]-N-methyl-2-cyanoacetamide (2.00 g, 7.12 mmol), aluminum chloride (3.46 g, 25.97 mmol), and anhydrous toluene (68 mL). The reaction was gently refluxed for 45 minutes, cooled to room temperature, and slowly treated with 2N HCl (68 mL). A precipitate formed. The mixture was heated to 90° C. for 10 minutes, cooled to room temperature, and filtered. The solids were dried under high vacuum at 50° C. to afford the title compound (2.02 g, 90%). 1H NMR (300.132 MHz, DMSO) δ 9.08 (d, J=4.7 Hz, 1H), 8.56 (dd, J=8.4, 0.8 Hz, 1H), 8.28 (dd, J=7.6, 0.7 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 2.89 (d, J=4.7 Hz, 3H). MS APCI, m/z=281/283 (M+H). HPLC 1.61 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([S:41](Cl)(=[O:43])=[O:42])=[N:39][CH:40]=1>C(Cl)Cl.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][S:41]([C:38]4[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][N:39]=4)(=[O:43])=[O:42])[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NS(=O)(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of tert-butyl((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16i-B, 0.059 g, 0.16 mmol) in DCM (1.5 mL) at 0° C. were added triethylamine (0.070 mL, 0.50 mmol) and 5-chloropyridine-2-sulfonyl chloride (0.034 g, 0.16 mmol). The reaction mixture was allowed to warm up to room temperature over a period of 2 h and then diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (10% to 50% EtOAc in heptane) to give the title compound (0.061 g, 0.11 mmol, 70% yield) as a colorless oil. MS m/z=547.0 [M+H]+. Calculated for C22H22ClF3N4O5S 546.1.
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:15][N:14]=1.[NH4+].[Cl-]>C1COCC1.O.C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([C:19](=[O:21])[CH2:20][C:4](=[O:9])[C:5]([F:6])([F:7])[F:8])[CH:16]=[CH:15][N:14]=1
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccnc(Cl)c1
Reaction time: 16 h

Procedure:
Trifluoro-acetic acid ethyl ester (0.30 mL, 2.49 mmol) is added carefully into sodium hydride (60% in mineral oil, 100 mg, 2.49 mmol) suspended in dry THF (2.0 mL) at room temperature. Then 1-(2-chloro-pyridin-4-yl)-ethanone (200 mg, 1.25 mmol) is added into the reaction mixture followed by the addition of ethanol (0.12 mL). The reaction mixture is stirred for 16 hrs and saturated NH4Cl solution (3.0 mL) is added along with 25 mL of water. The mixture is then extracted with EtOAc (3×25 mL). The organic layers are combined and concentrated to give the crude product which is used without purification.
Reaction SMILES: [Na].Cl.[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1.C([O:23][C:24](=[O:34])[C:25](Br)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])C>CO>[C:27]1([C:25]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:4]([CH3:3])[CH2:5][CH2:6]3)=[CH:19][CH:18]=2)([CH3:26])[C:24]([OH:34])=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCC(c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1CCC(c2ccc(OC(C)(C(=O)O)c3ccccc3)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 4.6 g. of sodium in 140 ml. of methanol is combined with 27.55 g. of 1-methyl-4-(4-hydroxyphenyl)-1,2,3,4-tetrahydroquinoline hydrochloride. The mixture is agitated for 30 minutes at 20°, and then 25.7 g. of 2-bromo-2-phenylpropionic acid ethyl ester is added dropwise thereto and the mixture is refluxed thereafter for 4 hours. After concentrating the mixture by evaporation, the residue is combined with water and extracted with chloroform. From the organic phase, the ethyl ester of 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionic acid is obtained as a yellow oil; nD20 = 1.5738.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:46]3[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Temperature: 160 °C
Yield: 56.6 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (39 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. To the fraction, conc. HCl (3 ml) and methanol (3 ml) were added and the residue was evaporated after 24 h. The residue was purified by HPLC to give the titled compound as a white solid (24 mg, 43%). 1HNMR (DMSO-d6) 400 MHz δ: 8.53 (s, 1H), 8.25 (s, 1H), 8.07 (dd, J=4.9, 1.4 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.92 (dd, J=7.7, 1.4 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.33 (td, J=7.7, 1.7 Hz, 1H), 7.27 (d, J=7.4 Hz, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.10 (t, J=8.0 Hz), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 6.73 (dd, J=8.0, 4.6 Hz, 1H), 6.39 (d, J=8.6 Hz, 1H), 5.97 (s, 2H), 2.45-2.38 (m, 2H), 2.23-2.15 (m, 2H), 2.09-2.00 (m, 1H), 1.75-1.66 (m, 1H); LCMS: 472 [M+H].
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17].[N+]([O-])(O)=O.CC1C=C(C)[N:26]([C:30](N)=[NH:31])N=1>O1CCOCC1.O.C(N(CC)C(C)C)(C)C>[NH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[C:30]([NH2:31])=[NH:26]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: NCCCCC/C=C/C(=O)O
Solvent: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: N=C(N)NCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A suspension of 21 g (77.4 mmoles) of (10) and 31.1 g (155 mmoles) 3,5-dimethylpyrazole-1carboxamidine nitrate in 50 mL dioxane, 2 mL water and 47.2 mL N,N-diisopropylethylamine was warmed on a steam bath until a clear solution was obtained. After stirring 20 h at room temperature, the solid was filtered and washed well with water to provide 13 g of crude title compound (11).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][CH:11]([F:36])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33](O)=[O:34])[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[CH3:37][C:38]1[C:42]([S:43]([NH2:46])(=[O:45])=[O:44])=[C:41]([CH3:47])[O:40][N:39]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:10][CH:11]([F:36])[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]([NH:46][S:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:47])(=[O:44])=[O:45])=[O:34])[O:30][C:31]=3[CH3:32])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C)c1S(=O)(=O)NC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.7 %

Procedure:
Diisopropylethylamine (60 μl, 0.339 mmoles) and a solution of 4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (171) (50 mg, 0.103 mmoles) in N,N-dimethylformamide (1.0 ml) were added to a stirred solution of 3,5-dimethyl-isoxazole-4-sulphonic acid amide (55 mg, 0.308 mmoles) in N,N-dimethylformamide (5.0 ml). A solution of O—(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.124 mmoles) in N,N-dimethylformamide (1.0 ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 174(2 mg) as a solid. LC/MS System D; Rt=10.35 mins, m/z (ES+)=532 (M+H for C25H23F2N3O6S).