Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].B(F)(F)F.CCOCC.[CH3:20][C:21]1([CH:27]=[CH2:28])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>O1CCOCC1.CCOCC>[CH3:20][C:21]1([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:27][CH2:28][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[CH3:9])[O:10]1
Reactant: C=CC1(C)CCC(=O)O1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluant ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane to afford a white crystalline product in a yield of 40%. M.P.: 148-149° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:3]1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([NH:27][C:28]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:18])([CH3:1])[CH2:3]1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC1(C)CN(c2ccccc2N)c2ccccc21
Solvent: ClCCl
Product: CC1(C)CN(c2ccccc2NC(=S)NC(=O)c2ccccc2)c2ccccc21
Yield: 112.7 %

Procedure:
To a solution of 2e (40 mg, 0.168 mmol) in CH2Cl2 was added benzoyl isothiocyanate (30 mg, 0.189 mmol). The reaction mixture was kept at reflux for 2.5 h. The reaction mixture was filtered through a cake of Celite® and washed the cake with CH2Cl2. The solvent was evaporated under reduced pressure. The desired product was purified by column chromatography using 0 to 80% EtOAc in hexane over 60 min as eluting gradient to afford 2f (76 mg, 99%) as a powder. MS (ES) m/z 402 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])(=O)C.[Na+].[CH2:15]([O:17][C:18](=[O:30])[C:19](=[N:28]O)[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].ClCCl>C(O)(=O)C.[Zn]>[CH3:5][C:3]1[NH:28][C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:30])=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]=1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A mixture of ethyl acetoacetate (72.5 g, 0.56 mol), zinc dust (98 g, 1.51 mol) and anhydrous sodium acetate (102 g, 1.21 mol) in glacial acetic acid (110 mL) was heated to 60° C. Ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (110 g, 0.5 mol) was added as a solution (some precipitation on standing) in glacial acetic acid (550 mL) in 3 portions with vigorous stirring over a period of 1 h. The temperature increased to 90° C. during the addition and the reaction was then maintained at 60-75° C. for 3 h. Additional zinc dust (49 g, 0.75 mol) was added over 15 min, again causing a temperature rise, and then the reaction mixture was then stirred at 60 to 75° C. for 1 h. After cooling to room temperature the mixture was filtered and the filtrate was evaporated in vacuo to give a residue which was azeotroped with toluene (2×200 mL) to remove residual acetic acid. Water (2 L) and ethyl acetate (300 mL) were added to the residue and the mixture was stirred until two clear phases were obtained. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×200 mL). The combined organic phases were washed successively with water (2×250 mL), saturated bicarbonate solution (2×250 mL), water (2×100 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and then concentrated to give a gummy residue. A mixture of dichloromethane and petroleum ether (175 mL; 1:6) was added to the solid and it was stirred for 15 min. The resulting free-flowing solid was filtered off and washed with chilled petroleum ether (100 mL) to afford diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85 g, 57%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](O)(=[O:16])[CH2:12][C:13](O)=[O:14].O=P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[NH:6][C:13](=[O:14])[CH:12]=[C:11]2[OH:16]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(N)ccc1Br
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2[nH]c(=O)cc(O)c2cc1Br
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
To a mixture of 4-bromo-3-methoxyaniline (10 g, 49.5 mmol) and malonic acid (5.15 g, 49.5 mmol) was added POCl3 (5.07 ml, 54.4 mmol) with thorough mixing, and it was then heated to 105° C. After 5 minutes, the reaction began to bubble vigorously, and eventually formed a hard foam and heating was continued for 1 hour. After cooling, water (200 mL) was added, and the mixture was stirred for 30 minutes. The solid was filtered off and washed with water. To the solid was added 2N NaOH (300 mL) and stirring was continued overnight. The remaining solid was filtered off, and EtOH (5 mL) was then added to the filtrate and the basic layer acidified with concentrated HCl to pH 2. The resulting solid was then filtered off, washed with water. The solid was then transferred to a flask and the remaining water was removed by azeotroping with EtOH (200 mL×2). The solid was then further dried under high vacuum for 15 h to yield 8.75 g of the title compound as an off-white solid. LRMS ESI+ (M+H)+ Calcd 270.2 Found 272.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[O:8])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22](N(C)C)OC(C)(C)C)[CH3:21]>O1CCOCC1>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:15][C:14]1[NH:13][C:12](=[O:16])[CH:11]=[CH:10][C:9]=1[C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(=O)[nH]c2C=CN(C)C)cc1
Reaction time: 0.5 h

Procedure:
A mixture containing 50 g of 5-(4-methoxybenzoyl)-6-methyl-2(1H)-pyridinone, 400 ml of p-dioxane and 40 ml of bis(dimethyamino)-t-butoxymethane was refluxed with stirring for 5 and 1/2 hours. The reaction mixture was allowed to cool and the separated crystalline product was collected, washed with ethanol and dried in a vacuum oven at 80°-85° C., to yield 65.8 g of 6-[2-(dimethylamino)ethenyl]-5-(4-methoxybenzoyl)-2(1H)-pyridinone, m.p. 216°-218° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH:2]=[CH2:3].[C@@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:23][C@@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH:2]=[CH2:3]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: C=CCOc1cccc(C=O)c1
Product: C=CCOc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 58A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]#[N:25])=[N:14]1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19]([C:20]([F:23])([F:21])[F:22])=[O:34])[C:15]([C:24]#[N:25])=[N:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 15 g (35.5 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole in 125 ml of dichloromethane at room temperature was added a solution of m-chloroperbenzoic acid (8.76 g, 70%, 35.5 mmol) in 375 ml of dichloromethane. The resulting solution was stirred at room temperature for 17 hr. It was then concentrated and triturated with ethyl acetate and heptane(1:2). Upon filtration a solid was obtained. This solid was dissolved in ethyl acetate and stirred with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried (magnesium sulfate) and concentrated. Upon chromatographic purification via silica gel column, a solid (5.7 g, 13.01 mol, 37%) was obtained as the desired product, mp 185-187d.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1NC(=O)C.[F:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.ClN(Cl)CC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:27])[CH:3]=1)[CH2:8][NH:9][C:10]([NH:11][C:12](=[O:25])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:32])[CH:21]=2)[NH:16][CH:15]=1)=[NH:26]
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: ClN(Cl)Cc1ccccc1
Product: N=C(NCc1cc(Cl)cc(Cl)c1)NC(=O)Cc1c[nH]c2ccc(F)cc12

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-fluoro-1H-indol-3-yl)acetic acid in step 4 (A) and dichlorobenzyl amine in step 4 (B), the title compound was prepared. MS (ESI) (M+H)+=393.24. 1H-NMR (500 MHz, CDCl3) δ 7.53 (s, 1 H), 7.08 (d, 1 H), 6.87 (bs, 3 H), 6.84 (bs, 4 H), 6.42 (m, 1 H), 4.38 (s, 2 H), 4.12 (s, 2 H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:21][CH3:22])=[O:5])C.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=[C:24]=[O:25]>>[CH2:17]([N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[N:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[C:24]1=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCCCNc1c(C(=O)OCC)cnc2c(OC)cccc12
Product: CCCCn1c(=O)n(-c2cccc(C)c2)c(=O)c2cnc3c(OC)cccc3c21
Yield: 43.7 %

Procedure:
1-Butyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (17 mg) was prepared from 4-butylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 390 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-])=O)=[C:14]([CH:16]=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]=O>[CH2:23]([O:22][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:14]1[CH:15]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:11]=[CH:12][C:13]=1[NH2:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)CCC=Cc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 108 %

Procedure:
A solution of ethyl 5-(5-tert-butoxycarbonylaminomethyl-2-nitrophenyl)pent-4-enoate (560 mg, 1.48 mmol) in ethyl acetate (20 mL) was hydrogenated over platinum oxide (100 mg) under atmospheric pressure of hydrogen at room temperature for 2.5 h. The mixture was passed through celite and the filtrate was concentrated to give 560 mg of the title compound (100%).
Reaction SMILES: C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.ClC(Cl)C.[Cl:20][C:21]1[C:26]([NH:27][C:28]2[N:33]=[C:32]([N:34]([CH:44]3[CH2:46][CH2:45]3)CC3C=CC(OC)=CC=3)[C:31]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]3[N:29]=2)=[CH:25][C:24]([C:52]#[N:53])=[CH:23][C:22]=1[N:54]1[CH2:59][CH2:58][CH:57]2[N:60]([C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:62][CH:56]2[CH2:55]1>>[Cl:20][C:21]1[C:26]([NH:27][C:28]2[N:33]=[C:32]([NH:34][CH:44]3[CH2:45][CH2:46]3)[C:31]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]3[N:29]=2)=[CH:25][C:24]([C:52]#[N:53])=[CH:23][C:22]=1[N:54]1[CH2:59][CH2:58][CH:57]2[N:60]([C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:62][CH:56]2[CH2:55]1
Reactant: COC(=O)N1CCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)N1CCC2CN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Anisole (0.027 ml, 0.244 mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) were added to methyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (28 mg, 0.0429 mmol) and the resulting solution was stirred at room temperature over the weekend. Solvent was evaporated in vacuo and the residue was dissolved in acetonitrile and neutralized with 2N ammonia in methanol. Desired product precipitated and was collected by filtration, methyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (17.2 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](F)=[C:26]([CH:29]=1)[C:27]#[N:28].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(#N)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: COc1ccc(CNc2ncnc3c2CNCC3)cn1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CNc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1
Yield: 44.5 %

Procedure:
A mixture of N-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (440 mg, 1.6 mmol), 5-chloro-2-fluorobenzonitrile (630 mg, 4.0 mmol), N,N-diisopropylethylamine (560 uL, 3.2 mmol), and acetonitrile (4.0 mL) was subjected to microwave irradiation at 180° C. for 4 h. After that an additional 5-chloro-2-fluorobenzonitrile (400 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After cooling, the mixture was treated with aq. NaHCO3 and EtOAc (100 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (EtOAc: 100%) and the obtained solid was washed with ether to yield an off-white solid (290 mg, 44%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([O:40]CC)=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([OH:40])=[O:39])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a stirred solution of ethyl 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylate (5 g, 9 mmol) in ethanol (150 mL) was added 1.5 M KOH solution (9 mL, 13.5 mmol, 1.5 eq). After stirring for 3 hours at room temperature, 2 M HCl solution (7.5 mL) was added and the suspension taken up in ethyl acetate was washed with brine. After drying and removal of the solvent, the residue was rinsed with a small volume of acetone and filtered off, to give after drying, the title compound (4.1 g, 86% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:13][CH2:12][CH2:11][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1ccncc1C
Reactant: BrCCCc1ccccc1
Product: Cc1cnccc1C(C)CCCc1ccccc1
Yield: 38.7 %

Procedure:
1.83 g (15.1 mmol) of 3-methyl 4-ethylpyridine and 3.0 g (15.1 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.40 g of the desired compound (yield: 38.8%).
Reaction SMILES: BrC1N=C(/C(=N\[S@@](C(C)(C)C)=O)/C(F)F)C(F)=C([Si](CC)(CC)CC)C=1.[Cl-].C(OC(=O)C[Zn+])(C)(C)C.C(OCC)C.[Br:42][C:43]1[N:48]=[C:47]([C@@:49]([NH:61][S@@:62]([C:64]([CH3:67])([CH3:66])[CH3:65])=[O:63])([CH:58]([F:60])[F:59])[CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:46]([F:68])=[C:45]([Si:69]([CH2:74][CH3:75])([CH2:72][CH3:73])[CH2:70][CH3:71])[CH:44]=1>C([O-])(O)=O.[Na+].C1COCC1>[Br:42][C:43]1[N:48]=[C:47]([C@:49]([NH:61][S@@:62]([C:64]([CH3:65])([CH3:67])[CH3:66])=[O:63])([CH:58]([F:60])[F:59])[CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:46]([F:68])=[C:45]([Si:69]([CH2:74][CH3:75])([CH2:70][CH3:71])[CH2:72][CH3:73])[CH:44]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@@](CC(=O)OC(C)(C)C)(N[S@](=O)C(C)(C)C)C(F)F)c1F
Agent: CC(C)(C)OC(=O)C[Zn+]
Agent: CC[Si](CC)(CC)c1cc(Br)nc(/C(=N\[S@](=O)C(C)(C)C)C(F)F)c1F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](CC(=O)OC(C)(C)C)(N[S@](=O)C(C)(C)C)C(F)F)c1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To a 25 mL round-bottomed flask was added (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (0.48 g, 1.018 mmol) and THF (4 mL). The mixture was cooled to 0° C. and 2-tert-butoxy-2-oxoethylzinc chloride 0.5 m in diethyl ether (5.09 mL, 2.55 mmol) was added dropwise over 10 min. After the addition the reaction mixture was stirred at 0° C. to rt for 4 h. The reaction mixture was diluted with sat NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide a 4:1 mixture of (R)-tert-butyl 3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate and (5)-tert-butyl 3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (0.428 g, 0.728 mmol, 71.5% yield) as light-yellow oil. MS m/z=587, 589 M+, Calculated for C23H38BrF3N2O3SSi: 587.61. Used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: N#Cc1cccc(CBr)n1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ccccc3c2=O)cc1C
Yield: 41.5 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.341 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one, 80.6 mg (0.409 mmol) of 6-bromomethyl-pyridine-2-carbonitrile, 16.4 mg (0.409 mmol, 60% dispersion in oil), and 3.5 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 58 mg of 6-[3-(4-Methoxy-3-methyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridine-2-carbonitrile. LC-MSD, m/z for C25H19N3O3 [M+H]: 410.14 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.3 min.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:21].[Na+]>CC(C)=O>[I:21][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [I-]
Reactant: CCOC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 40.5 g. (0.1 moles) of ethyl α-bromo-2'-chloro-4-biphenylylacetate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-2'-chloro-4-biphenylylacetate.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].Cl[C:33]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[F:31][C:2]([F:30])([F:1])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:33]3[CH:42]=[C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cc(-c4ccccc4)c4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 21 from 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-chloro-4-phenyl-quinoline.