Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH:16]([CH3:18])[CH3:17])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)C(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid (2,4 g) and 4-nitrophenol (1.63 g) in 15 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.02 g) and the mixture was stirred at room temperature for 18 hours. Crystallization of the crude product from 2-propanol-hexane yielded 2.85 g of (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid 4-nitrophenyl ester, mp 95°-96.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:33]=[N:32][CH:31]=[C:30]([N:34]3[CH:46]=[CH:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[C:27]=2[CH:28]=[O:29])=[CH:3]1.[BH4-].[Na+]>CO>[OH:29][CH2:28][C:27]1[C:26]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:25][O:24][CH2:23]5)[CH2:20][CH2:21]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:33][N:32]=[CH:31][C:30]=1[N:34]1[CH:46]=[CH:45][N:37]2[C:38]3[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=3[CH:44]=[C:36]2[C:35]1=[O:47]
Reactant: Cn1cc(-c2cncc(-n3ccn4c5c(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cncc(-n3ccn4c5c(cc4c3=O)CCCC5)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a suspension of 126b (76 mg, 0.12 mmol) at 0° C. in methanol (4 mL) was added sodium borohydride (20 mg, 0.7 mmol) and the mixture was stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 126 (28 mg, 37%). LCMS: [M+H]+ 635. 1H NMR (500 MHz, DMSO) δ 8.61 (d, J=2.5, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.43 (s, 1H), 7.86 (d, J=3.0, 1H), 7.38-7.36 (m, 2H), 7.27-7.22 (m, 2H), 6.82-6.78 (m, 2H), 5.18-5.11 (m, 1H), 4.55 (t, J=6.0, 2H), 4.45 (t, J=6.0, 2H), 4.41-4.29 (m, 2H), 3.60 (s, 3H), 3.44-3.42 (m, 1H), 3.06 (t, J=4.5, 4H), 2.75-2.73 (m, 2H), 2.62-2.60 (m, 2H), 2.38 (t, J=4.5, 4H), 1.86-1.75 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:8][C:7](=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O.C(N(CCC)CCC)CC>>[C:1]([C:5]1([Cl:24])[NH:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Agent: CCCN(CCC)CCC
Product: CC(C)(C)C1(Cl)C=CN=C(c2ccccc2C(F)(F)F)N1
Temperature: 115 °C
Yield: 65.5 %

Procedure:
A solution of 6-tert-butyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (0.47 g, 1.59 mmol) in phosphorous oxychloride (1.65 mL, 15.9 mmol) was treated with tri-n-propylamine (0.61 mL, 3.17 mmol) and heated at 110-120° C. for 1 hour. The solvent was removed by evaporation then azeotroped three times with toluene. The residue was taken up in ethyl acetate, washed sequentially with 1 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (1:9)] provided the title compound (0.33 g, 66% yield) as a yellow oil.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][NH2:20].O.ClCCl>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:20][CH3:19])=[N:7][CH:6]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: COc1ccc2sc(-c3ccc(F)nc3)nc2c1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1
Temperature: 100 °C

Procedure:
To 2-(6-fluoropyridin-3-yl)-5-methoxy-1,3-benzothiazole (59.2 mg, 0.227 mmol) was added methylamine in ethanol (8 M, 2 mL) and the reaction mixture was heated in a microwave oven at 100° C. for 5 min. Water and dichloromethane were added and the layers separated. The aqueous phase was extracted with dichloromethane (3×). The combined organic phases were washed with water, dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by column chromatography (heptane/EtOAc 60:40 to 50:50) to give the title compound (39 mg) as a pale yellow solid. 1H NMR δ ppm 8.68 (d, 1 H) 7.98 (dd, 1 H) 7.91 (d, 1 H) 7.50 (d, 1 H) 7.27 (q, 1 H) 7.01 (dd, 1 H) 6.59 (d, 1 H) 3.85 (s, 3 H) 2.86 (d, 3 H); MS m/z (M+H) 272.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O>CC(N(C)C)=O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: CCC(=O)Cl
Reactant: N#Cc1cc(Cl)ccc1N
Agent: CN(C)c1ccccn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(=O)Nc1ccc(Cl)cc1C#N
Reaction time: 8 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (5.0 g) and dimethylaminopyridine (0.12 g) in dimethylacetamide (25 ml) was added propionyl chloride (3.4 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and diisopropyl ether to give N-(4-chloro-2-cyanophenyl)propanamide (5.7 g).
Reaction SMILES: COC(N1[C:9](=[O:10])[CH:8]=[CH:7][C:6]1=[O:11])=O.[CH2:12]([S:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].S(=O)(=O)(O)O>O.C1COCC1.C(Cl)(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH2:12]([S:19][CH2:20][C@@H:21]([N:22]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]1=[O:11])[C:23]([OH:25])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)[C@@H](CSCc1ccccc1)N1C(=O)C=CC1=O
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
According to the method of O. Keller and J. Rudinger (Helv. Chim. Acta., 58, 531 (1975)), 6.2 g (40 mmols) of N-methoxycarbonylmaleimide was added at 0° C. to a solution of 8.44 g (40 mmols)of S-benzyl-L-cysteine in a mixture of 200 ml of saturated aqueous solution of sodium hydrogen carbonate and 100 ml of THF. The mixture was stirred for 10 minutes and then diluted with 300 ml of water and 150 ml of THF. The reaction mixture was stirred at room temperature for 30 minutes and subsequently at 40° C. for 30 minutes, neutralized with concentrated sulfuric acid and thereafter concentrated to about 200 ml in a vacuum. The concentrate was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous sodium sulfate (Na2SO4) and concentrated to give a white solid. The product was subjected to silica gel chromatography (90:10:5 chloroform-ethyl acetate-acetic acid to 40:60:5 chloroform-ethyl acetate-acetic acid), giving 2.29 g of (2S)-3-benzylthio-2-maleimidopropionic acid. M.p.: 86°-87° C.
Reaction SMILES: O=[C:2]1O[C:6]2[C:8]3[C:13]([CH2:14][C:5]=2[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]1[C:20]#[N:21])=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+]>C1COCC1>[N:15]1([C:4]2[C:5]3[CH2:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:6]=3[C:6]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH2:14][C:2]=3[C:3]=2[C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCCC2)c2c(oc1=O)-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c2c(c3c(c1N1CCCC1)Cc1ccccc1-3)-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(pyrrolidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (278 mg), indanone-2 (132 mg) and NaH (42 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water aid subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 206-208° C.; 1H NMR (300 MHz, CDCl3) δ 2.03-2.11 (m, 4H, 2CH2), 3.85-3.92 (m, 4H, 2CH2), 4.07 (s, 2H, CH2), 4.11 (s, 2H, CH2), 729-7.35 (m, 1H, ArH), 7.38-7.52 (m, 3H, ArH), 7.58-7.62 (m, 2H, ArH), 8.34 (d, J=7.8 Hz; 1H, ArH), 8.55 (d, J=7.68 Hz, 1H, ArH); IR (KBr) 2213 cm−1 (CN); MS (ESI) 349 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:30](=[O:34])[C:31]([NH2:33])=[O:32])=[C:9]([CH2:28][CH3:29])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:33][C:31](=[O:32])[C:30]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]=1[CH2:28][CH3:29])=[O:34]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 59.3 %

Procedure:
A mixture of 600 mg (1.3 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 8 mL of 1N NaOH and 20 mL of MeOH was heated to maintain reflux for 0.67 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl and extracted with EtOAc. The EtOAc solution was dried (MgSO4) and evaporated and the residue crystallized from MeOH to give 352 mg (59% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid, mp, 211-214° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]1[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:31][CH2:32][OH:33].ClCCl.CO>C(#N)C>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:31][CH2:32][OH:33])[CH:11]([CH3:15])[CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCBr
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CCN1CCO
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a solution of N,N-dibenzyl-2-methylpiperidin-4-amine (Intermediate 217, 880 mg, 3.0 mmol) in acetonitrile (6 mL) was added triethylamine (0.85 ml, 6.0 mmol) and 2-bromoethanol (0.32 mL, 4.5 mmol). The reaction is stirred at 70° C. at 300 watts in the microwave for 20 minutes. Acetonitrile was removed under reduced pressure, the residue was taken up in dichloromethane (100 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) and the aqueous phase was back extracted three times with dichloromethane (3×70 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness under reduced pressure. Chromatography of the residue on silica gel with dichloromethane/methanol (10:1) gave 660 mg (65% yield) of the product as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14]C2C=C(C(F)(F)F)C=C([N+]([O-])=O)C=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CC(O)=O>Br>[N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cc(C(F)(F)F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Yield: 100.3 %

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)phenyl ether (20.0 g, 0.090 mol) in HBr (74.7 mL, 1.38 mmol) and HOAc (279.8 mL, 4.92 mol) was heated at reflux until reaction was judged to be complete by LCMS. The reaction was concentrated to tan solid to yield the desired product (18.7 g, 96% yield). LCMS: (FA) ES− 206.2 (M−1).
Reaction SMILES: C([NH:4][CH:5]1[CH:12]2[C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][C:15]=3[C:6]1([CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)(=O)C>C(O)C.Cl>[NH2:4][CH:5]1[CH:12]2[C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[C:6]1([CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CC(=O)NC1C2CCCCCC1(C)c1cc(OC(C)=O)ccc1C2=O
Agent: Cl
Solvent: CCO
Product: CC12CCCCCC(C(=O)c3ccc(O)cc31)C2N
Yield: 65 %

Procedure:
13-Acetylamino-6,7,8,9,10,11-hexahydro-3-acetoxy-5-methyl-5,11-methanobenzocyclodecen-12(5H)-one (3 g., 0.008 mole) was refluxed with 10 mL of 20% hydrochloric acid in the presence of a few drops of ethanol for 24 hours. The reaction mixture was boiled with 0.5 g. of charcoal, filtered and the solvent was evaporated under reduced pressure. The remaining solid was recrystallized from acetone-ethanol (5:1) to afford 1.5 g. (65% yield) of the title compound as a hydrochloride dihydrate, mp 256°-258° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]2[NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([OH:20])[CH:3]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cc(Cl)cc(O)c21
Yield: 1.4 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 492 mg of 5-aminoquinolin-2(1H)-one. 20 mg of the title compound is obtained by reaction of 300 mg of the imine with 3.2 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[N:17]=1.[O:27]1[CH2:32][CH2:31][CH2:30][O:29][CH:28]1[C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1>COC(C)(C)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[O:27]1[CH2:32][CH2:31][CH2:30][O:29][CH:28]1[C:33]1[CH:34]=[CH:35][C:36]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[N:14]=[N:15][N:16]([C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[N:17]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2Cl)n1
Reactant: Br[Mg]c1ccc(C2OCCCO2)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C3OCCCO3)cc2)n1
Temperature: 0 °C

Procedure:
In another flask, dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) (0.022 g; 0.04 mmol) is suspended in tert-butyl methyl ether (3 mL) and cooled to about 0° C. before a 0.5 M solution of zinc chloride in tetrahydrofuran (0.40 mL; 0.20 mmol) and a solution of 5-(2-chloro-phenyl)-2-(1-methyl-1-phenyl-ethyl )-2H-tetrazole (1.20 g; 4.0 mmol) in tert-butyl methyl ether (1.2 mL) are added. To the vigorously stirred resulting suspension is added at about 0° C. 9.6 mL of the above 0.5 M 4-([1,3]dioxan-2-yl)phenylmagnesium bromide solution (4.8 mmol) over one hour. The resulting dark brown solution is allowed to warm up and further stirred at room temperature for 20 hours. The mixture is cooled to about 0° C., quenched with 10 mL of a 3.8% solution of ammonium chloride in water and diluted with ethyl acetate (25 mL). The aqueous phase is separated and extracted with ethyl acetate (25 mL). The combined organic phases are washed with a 0.5 M solution of sodium hydroxide in water (10 mL) and with a 10% solution of sodium chloride in water (10 mL). The combined organic phases are evaporated in vacuo. A solution of the resulting pale green solid in a small amount of ethyl acetate is filtered and evaporated. The resulting pale green solid is purified by column chromatography on silica gel eluting with a 1:10 mixture of tert-butyl methyl ether and toluene to afford 5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-2-(1-methyl-1-phenyl-ethyl)-2H-tetrazole as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][O:13]C(=O)[N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[C:18]([C:35]([F:38])([F:37])[F:36])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42](B(O)O)[CH:41]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[OH:13][CH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]3)=[C:18]([C:35]([F:38])([F:37])[F:36])[CH:17]=1)=[CH:3][C:2]([C:42]1[CH:41]=[N:40][C:49]3[C:44]([CH:43]=1)=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:11][CH:10]=2
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(Cl)cc5c43)cc2C(F)(F)F)CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a solution of tert-butyl 4-(4-(9-chloro-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (56 mg, 0.1 mmol) and quinolin-3-ylboronic acid (25 mg, 0.15 mmol) in 1,4-dioxane (1 mL) at room temperature was added bischloroditriphenyl phosphine palladium (4 mg, 0.005 mmol), tert-butyl Xphos (4 mg, 0.01 mmol), and Na2CO3(0.3 mL, 0.3 mmol). The resultant solution was heated to 100° C. for 4 h and then allowed to cool to room temperature, filtered through celite, and washed with EtOAc (3×10 mL). After removal of solvent in vacuo, the residue was purified by flash column chromatography to afford the title compound (35 mg, 55%) . LC-MS: (M+H)=630.30
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8].O1CCCC1.O.[OH-].[Li+]>O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([CH:4]([CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:25])=[O:2])[C:12](=[O:24])[CH:13]=1
Reactant: COC(=O)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid methyl ester (1.02 g, 2.70 mmol) in a 1:1 solution of tetrahydrofuran:water (30 mL) was treated with lithium hydroxide monohydrate (270 mg, 5.40 mmol). The mixture was stirred for 2 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran, diluted with water and the pH adjusted to pH=5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid (766 mg, 78%) as a cream colored solid: HR-ES-MS m/z calculated for C15H13NO4ClF3 [M+H]+ 364.0558, observed 364.0557.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].[OH-].[Na+].[BrH:18]>O>[Br:18][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc2ncccc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
5-Aminoquinoline (5 g, 34.7 mmol) is dissolved in HBr 48% (15 mL) and water (15 mL) and then cooled to 0° C. A solution of NaNO2 (2.5 g, 36.2 mmol) in water (15 mL) is added over about 10 minutes. The mixture is stirred for about 30 minutes at 0° C. and then at r.t. for about 1.5 hours. The mixture is transferred to an addition funnel and 75° C. solution of CuBr is added over 30 minutes. The mixture is stirred for about 30 minutes and then allowed to cool to r.t., which is then stirred for another 2 hours. The mixture is cooled to 0° C. and adjusted to pH of about 14 with 5N NaOH. The solution is filtered, and the solids are washed with DCM. The aqueous layer is extracted with DCM (2×200 mL), and the organic fractions are combined and concentrated. The residue is chromatographed on silica gel to give about 1.6 g of 5-bromoquinoline (22%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:20]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:19][C:13]=3[C:14]=2[C:15]([O:17]C)=[O:16])=[CH:6][CH:5]=1>CCO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:20]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:19][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Excess NaOH (10 mL, 1N aq) was added to a stirring solution of methyl 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylate (3.0 g, 6.89 mmol) in EtOH (34 mL) and THF (34 mL). It was allowed to stir at 60° C. overnight. The mixture was then heated to 67° C. and allowed to stir for 4 more hours. The mixture was concentrated then diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (2.7 g, 96%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31-1.38 (m, 6 H) 2.99 (s, 3 H) 4.63-4.73 (m, 1 H) 7.32-7.41 (m, 2 H) 8.00-8.08 (m, 2 H) 8.88 (s, 2 H) 13.05 (s, 1 H). LC-MS retention time: 1.03 min; m/z (MH−): 406. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.