Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=[O:35])[C:22]1[CH:27]=[C:26]([CH2:28][CH2:29][C:30](OC)=[O:31])[CH:25]=[CH:24][C:23]=1[CH3:34].CC(C[AlH]CC(C)C)C>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=[O:35])[C:22]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][OH:31])[CH:25]=[CH:24][C:23]=1[CH3:34]
Reactant: COC(=O)CCc1ccc(C)c(C(=O)c2c(SC)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(CCCO)ccc1C
Temperature: 25 °C

Procedure:
A solution of 0.530 g (1.0 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(5-[β-methoxycarbonylethyl]-2-methylbenzoyl)-3-methylthiopyrazole in 10 mL of THF was cooled in an ice bath while 1.33 mL of a 1.5 M solution of DIBAL in THF was added. The reaction mixture was warmed to room temperature and then quenched with water. The product was extracted into EtOAc, dried and concentrated. The residues were chromatographed on silica gel using mixtures of hexane/EtOAc to elute the title product which was isolated as an amorphous foam, 174 mg (34%).
Reaction SMILES: C[O:2][C:3](=[O:5])[CH3:4].[CH2:6]([C:8]([C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:28]([CH3:35])[CH:27]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([CH3:25])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[Li+].[OH-]>O1CCOCC1>[C:3]([OH:5])(=[O:2])[CH3:4].[CH2:6]([C:8]([C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:28]([CH3:35])[CH:27]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:24])[C:20]([CH3:22])([CH3:23])[CH3:21])=[C:13]([CH3:25])[CH:12]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: COC(C)=O
Agent: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester (210 mg, 0.4 mmol) in dioxane (10 ml) is added 2N LiOH/H20 solution (10 ml) and stirred at RT overnight. The reaction is concentrated and partitioned between EtOAc/1N HCl. The organic layer is concentrated to give the title compound (180 mg, 88%).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:13]([F:14])=[C:12]2[CH:15]=[CH:16][C:7]=1[CH:8](O)[O:9][CH2:10][O:11]2.CO.O>C(OCC)C>[F:5][C:6]1[C:13]([F:14])=[C:12]2[CH:15]=[CH:16][C:7]=1[CH:8]([Br:2])[O:9][CH2:10][O:11]2
Reactant: BrP(Br)Br
Reactant: OC1OCOc2ccc1c(F)c2F
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: Fc1c2ccc(c1F)C(Br)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Phosphorus tribromide (47 g) was added to a solution of 2,3difluoromethylenedioxybenzyl alcohol (32 g) in diethyl ether at 0° C. After 0.5 hours the reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 3 hours. The reaction mixture was then cooled to 0° C., methanol was added followed by water, the mixture was extracted with diethyl ether, separated and the organic layer washed with saturated sodium bicarbonate (until neutral), dried and the solvent removed to yield the product as a pale yellow oil, (40.4 g), NMR (CDCl3): 4.50(s,2H), 7.10(m,3H).
Reaction SMILES: C([N:8]1[C:12]2=[C:13]([NH:28][S:29]([CH:32]3[CH2:34][CH2:33]3)(=[O:31])=[O:30])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(Cl)Cl>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:14]1[C:13]([NH:28][S:29]([CH:32]2[CH2:33][CH2:34]2)(=[O:31])=[O:30])=[C:12]2[NH:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[C:15]=1[CH3:18]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2
Yield: 5.9 %

Procedure:
Following the procedure set forth for the preparation of Example 2A, cyclopropanesulfonic acid [1-benzyl-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyridin-8-yl]-amide (40 mg, 0.0001 mol) in DCM (3 mL) was reacted with borontribromide (0.025 g, 0.0001 mol) to afford the crude product. Purification by column chromatography on silica gel (4% methanol in CHCl3) afforded 3 mg of the product (9.09% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]1[N:5]=[CH:6][N:7]2[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[C:11](=[O:19])[N:10]([CH3:20])[CH2:9][C:8]=12.N12CCCN=C1CCCCC2.CN(C)C=O>O>[C:3]([C:4]1[N:5]=[CH:6][N:7]2[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[C:11](=[O:19])[N:10]([CH3:20])[CH2:9][C:8]=12)#[CH:2]
Reactant: CN1Cc2c(/C=C\Cl)ncn2-c2ccc(F)cc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2

Procedure:
3.70 g (12.7 mmol) of 3-[(Z)-2-chlorovinyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 4 hours together with 2.26 ml (15.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 400 ml of water and extracted five times with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. The residue was dissolved in ethyl acetate, treated with charcoal and recrystallized from ethyl acetate. There was obtained 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-6-one of melting point 207°-208°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[C:28]([CH3:33])[N:29]=[C:30]([CH3:32])[CH:31]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(F)c(F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from commercially available 4,5-difluoro-1,2-phenylendiamine (400 mg, 2.78 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (903 mg, 2.78 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light brown solid (860 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36]CC)=[O:35])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
Diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate (0.18 g, 0.33 mmol) was suspended in ethanol (2 ml) and 0.25N NaOH (8 ml) and stirred 1.5 hours at room temperature with intermittent periods of sonication. Additional ethanol (4 ml) and warming were required to obtain a homogeneous solution. The solution was stirred 3 hours at room temperature and then adjusted to pH 3 with 1N HCl. The resulting suspension was filtered, and the white solid washed with water and dried under high vacuum to give N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamic acid (0.158 g). 1H NMR (DMSO-d5, 300 MHz) δ: 1.87-2.16 (m, 2H, glu CH2), 2.35 (t, J=7 Hz, 2H, glu CH2), 2.44 (s, 3H, CH3), 4.33-4.43 (m, 1H, glu CH), 5.43 (s, 2H, CH2O), 7.16 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 1H, Ar), 7.74 (dd, J=8,2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08 (d, J=8 Hz, 1H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, glu NH), 9.94 (s, 1H, Ar), 12.36 (br s, 2H, CO2H's), 12.59 (s, 1H, N2H). Anal. Calculated for C26H23N3O7.1/4H2O: C, 63.22; H, 4.79; N, 8.51. Found: C, 63.23; H, 4.80; N, 8.48.
Reaction SMILES: I[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[CH:15].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:6]1[N:5]=[CH:4][CH:3]=[C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(I)ccnc1OC
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1c(C#Cc2ccccc2)ccnc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 4-iodo-2-methoxynicotinate (400 mg, 1.36 mmol), ethynylbenzene (167 mg, 1.63 mmol), Pd(PPh3)2Cl2 (47 mg, 0.068 mmol), CuI (7.7 mg, 0.04 mmol) and triethylamine (400 uL) is stirred at room temperature for 20 hours. The mixture is diluted with water, made alkaline with K2CO3 and extracted with CHCl3. The organic layer is washed with brine, water and concentrated under vacuum. The title compound is purified by silica gel column chromatography using hexane/ethyl acetate as eluent. MS m/z 268.1 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[CH2:12]1[CH:17]([NH2:18])[CH2:16][CH2:15][CH:14]([OH:19])[CH2:13]1.O>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:16]1[CH:17]([N:18]2[C:3](=[O:10])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:11])[CH2:12][CH2:13][CH:14]([OH:19])[CH2:15]1
Reactant: NC1CCC(O)CC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirring solution of isobenzofuran-1,3-dione (90 g, 0.6 mol) and (1r,4r)-4-aminocyclohexanol (70 g, 0.6 mol) in toluene (250 mL) and DMF (250 mL) was stirred at 130° C. overnight. The reaction was cooled to room temperature, water was added and the product was filtered, washed with water and dried under vacuum to give the desired product as a white solid, which was used for the next step without further purification (119 g, 0.48 mol, yield: 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.84-7.79 (m, 2H), 7.72-7.68 (m, 2H), 4.18-4.10 (m, 1H), 3.80-3.73 (m, 1H), 2.40-2.29 (qd, J1=3.4 Hz, J2=130 Hz, 2H), 2.12-2.09 (dd, J=6.2 Hz, 2H), 1.78-1.74 (dd, J=6.6 Hz, 2H), 1.49-1.39 (qd, J1=3.3 Hz, J2=125 Hz, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[C:35]([O:39][CH3:40])[CH:36]=[N:37][CH:38]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:38]=[N:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cncc(OC)c1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1cncc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)c1

Procedure:
Example 23 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 5-ethynyl-3-methoxy-pyridine ( ) in the same manner as Example 15. ESI MS m/z 565 [C28H32N6O5S+H]+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH:41]([OH:43])[CH3:42]>>[OH:43][CH:41]([CH3:42])[CH2:40][NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 39.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 23 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: N[C:2]1[C:10](Cl)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4](OC)[CH:3]=1.C1N=C[N:16](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]([NH2:16])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid in freshly distilled DMF is added CDI (1 equivalent). After 1 hour at room temperature a solution of amine 35 (1 equivalent) in DMF is added. The reaction mixture is stirred at room temperature for 16 hours and concentrated in vacuo to give a residue which is treated with 15% potassium carbonate and extracted with chloroform (3×). The combined organic extracts are washed successively with water and brine and then dried over sodium sulfate. Concentration gives a solid which is purified on silica gel eluting with 7/93 MeOH(NH3)/chloroform to give the title compound 36 as a colorless solid.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]O)=[N:19][C:18]=1[NH2:26]>ClCCl>[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][F:11])=[N:19][C:18]=1[NH2:26]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)c1ccc(CCO)nc1N
Solvent: ClCCl
Product: COC(=O)c1ccc(CCF)nc1N
Yield: 7.8 %

Procedure:
A solution of (bis(2-methoxyethyl)amino)sulfur trifluoride (2.39 g, 10.8 mmol) in dichloromethane (30 mL) was cooled with a dry ice-methanol bath, and 2-amino-6-(2-hydroxyethyl)-nicotinic acid methyl ester (50 mg, 0.255 mmol) was added thereto dropwise. After dropwise addition the cold bath was immediately removed, and the solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned. The organic layer was separated, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and the title compound (4 mg, 0.020 mmol, 7.9%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH2:11][C:12](=[O:13])[O:14][C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C1Cc2ccc(Br)cc2C(=O)O1

Procedure:
To the title compound of 16A in acetonitrile (CH3CN, 60 ml) was added N,N′-dicyclohexylcarbodiimide (DCC, 5.8 g, 28.2 mmol). The reaction mixture was stirred at ambient temperature overnight. After filtration, the filtrate was evaporated to give the title compound of 16B as a yellow solid (96.32 g, 98.7% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:57][N:54]1[CH2:55][CH2:56][N:51]([CH2:50][CH2:49][CH2:48][NH:47][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]3[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[O:7])[CH:14]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:52][CH2:53]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCN(CCCN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCN2CCN(C)CC2)cc1
Yield: 16.7 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), TBTU (60 mg, 0.186 mmol), 1-(3-aminopropyl)-4-methylpiperazine (25 mg, 0.156 mmol) and DIPEA (81 μl, 0.467 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. The DMF was evaporated under vacuum and the residue dissolved in chloroform and filtered through an aminopropyl SPE (3 g). The filtrate was purified by flash chromatography on silica, eluting with DCM/ethanol/ammonia (110:8:1), which after evaporation of the solvents under vacuum gave N-(4′-([3-(4-methylpiperazin-1-yl)propylamino]carbonyl)-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (12 mg, 17%). NMR; δH [2H6]-DMSO 9.91,(1H, s), 8.55,(1H, t), 8.35,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.29,(2H, m), 2.48–2.20,(10H, m), 2.19,(3H, s), 2.13,(3H, s), 1.68,(2H, m). LCMS: retention time 2.37 min, MH+461.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[CH:15][C:14]=2[F:27])[CH2:11][C:10]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])=[N:9]1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:26])=[O:46])[CH:20]=3)=[CH:15][C:14]=2[F:27])[CH2:11][C:10]([C:28]([C:30]([F:32])([F:31])[F:33])([C:34]([F:36])([F:37])[F:35])[OH:29])=[N:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-(3-fluoro-3′-methylsulfanyl-biphenyl-4-yl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (31.0 mg, 0.06 mmol) prepared in Example 338 in dichloromethane (2.0 mL), was slowly added meta-chloroperbenzoic acid (77%, 22.8 mg, 0.12 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1, 1/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10](O)[CH2:11][C@H:12]2[CH2:17][CH2:16][Si@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9]/[CH:10]=[CH:11]/[C@H:12]2[CH2:13][CH2:14][Si@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CCCCC[Si@H]1CC[C@H](CC(O)C#Cc2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCC[Si@H]1CC[C@H](/C=C/C#Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(trans-4-pentyl-4-silacyclohexyl)-1-butyne-3-ol 8.0 g (24 mmol), p-toluenesulfonic acid monohydrate 1.6 g, and benzene 200 ml was heated under reflux to remove the water and then subjected to a conventional post-treatment. The reaction mixture thus obtained was not only a mixture of trans- and cis-isomers, with respect to the silacyclohexane ring, but also a mixture of E- and Z-isomers, with respect to the double bond. Hence, the product was separated by chromatography to give 1.2 g of the desired product of the trans-E isomer (yield 15.9%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:11][C:3]=12.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39](B(O)O)[CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O.[Cl-].[Na+].O>[F:8][C:7]1[C:2]([C:37]2[CH:36]=[C:35]([F:34])[CH:40]=[CH:39][C:38]=2[O:44][CH3:45])=[C:3]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:9]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:4]2=[N:5][CH:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1-c1c(F)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of Example 231C (2000 mg, 4.07 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (898 mg, 5.28 mmol), potassium phosphate tribasic (2589 mg, 12.20 mmol), and phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (79 mg, 0.122 mmol) in tetrahydrofuran (60 mL) and water (20 mL) was degassed and heated at 60° C. for 3 hours. The mixture was treated with water and brine and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (7:3 to 6:4) to give the title compound. MS (ESI+) m/z 582.1 (M+H)+.