Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([N:16](C(C)(C)C)[C:17]1[CH:18]=C2C(=O)OC(=O)[C:20]2=[CH:26][CH:27]=1)(C)(C)[CH3:13].C(C1C=C(C)C=C2C(OC(=O)C=12)=O)CC>>[CH2:12]([N:16]1[C:4]2[C:26](=[CH:20][CH:1]=[C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]3=2)[CH:27]=[C:17]1[CH3:18])[CH3:13]
Reactant: CC(C)(C)N(c1ccc2c(c1)C(=O)OC2=O)C(C)(C)C
Reactant: O=C1OC(=O)c2ccccc21
Agent: CCCc1cc(C)cc2c1C(=O)OC2=O
Product: CCn1c(C)cc2ccc3ccccc3c21

Procedure:
Also used as (I) are p-di-t-butylamino phthalic anhydride, p-dihexylaminophthalic anhyride, 3-propyl-5-methylphthalic anhydride, and the like.
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]([O-])=[O:21].[Na+]>C(O)(=O)C.C(O)C.O>[CH2:1]([N:8]1[C:15]([NH2:16])=[C:14]([N:20]=[O:21])[C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of 1-benzyl-3-propyl-6-amino-uracil (6.2 mmol) in 80% acetic acid (15 mL) and 30 mL of ethanol, was stirred at 40° C. while a solution of NaNO2 (9.3 mmol) in water (10 mL) was added drop wise. The reaction was stirred for 30 minutes at 40° C. and after concentration the product precipitated from the reaction mixture and was collected by filtration. (Pink solid. Yield 85%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][C:35]([O:37][CH3:38])=[O:36])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)OC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (500 mg) in tetrahydrofuran (20 ml) are added dropwise methyl chloroformate (200 mg) and triethylamine (216 mg) under ice cooling. After 1 hour, the reaction mixture is poured into ice water, and is extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methoxycarbonyloxyethylidene)acetate (546 mg). Foam. Yield: 97%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (1.0 g) in dry methylene chloride (14 ml) was added 2,6-lutidine (240 μl) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (295 μl) was added via syringe. After 15 minutes the reaction mixture was diluted with ethyl acetate, washed with 1N HCl, water, saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate. Removal of the solvent in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (293 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1N.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[I:24].[PH:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>Cl[Si](C)(C)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=1[I:24].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:20]([P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])([F:22])[F:23]
Reactant: CCO[PH](=O)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: C[Si](C)(C)Cl
Agent: FC(F)(F)c1ccc(Br)c(I)c1
Product: CCOP(=O)(OCC)C(F)(F)c1cc(C(F)(F)F)ccc1Br

Procedure:
2-Bromo-5-(trifluoromethyl)-iodobenzene was synthesized from 2-bromo-5-(trifluoromethyl)benzeneamine according to the procedure described for Example 86. Diethyl [2-bromo-5-(trifluoromethyl)phenyl]difluoromethylphosphonate was synthesized from 2-bromo-5-(trifluoromethyl)-iodobenzene according to Example 25 except that chlorotrimethylsilane (several drops) was used in place of acetic acid. Compound 87 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES−): m/z 353.0, 355.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.94 (d, J=8.2, 1H), 7.90 (s, 1H), 7.68 (d, J=8.2, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:11][CH3:12])[C:9]=1[OH:10])[C:5]#[N:6].Cl[C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.BrC1C2OC(C3C=CC(C([O-])=O)=CC=3)=NC=2C=C(C#N)C=1>>[C:5]([C:4]1[CH:7]=[C:8]([S:11][CH3:12])[C:9]2[O:10][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: CSc1cc(C#N)cc(N)c1O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(SC)c3o2)cc1

Procedure:
The title compound was prepared from 3-amino-4-hydroxy-5-(methylthio)benzonitrile and methyl 4-(chlorocarbonyl)benzoate by a procedure analogous to that described in INTERMEDIATE 1, Step C. Mass spectrum (ESI) 325.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH2:9][CH2:10][O:11]C1CCCCO1)=[O:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[OH:11][CH2:10][CH2:9][N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[C:6](=[O:7])[C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C(=O)N(CCOC2CCCCO2)c2ccccc2OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(C(=O)N(CCO)c2ccccc2OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
3-Methoxy-N-(2-methoxyphenyl)-N-(2-tetrahydropyranyloxyethyl)benzamide (501 mg, 1.30 mmol) was dissolved in methanol (4 ml) to which was subsequently added a catalytically effective amount of p-toluenesulfonic acid monohydrate and stirred for 3 hours at room temperature. The reaction solution was mixed with saturated sodium bicarbonate aqueous solution (10 ml) and extracted with ether, and then washed with water and saturated brine. The resulting organic layer was dried on anhydrous magnesium sulfate, the solvent was removed by evaporation and then the resulting colorless oily residue was purified by subjecting it to a silica gel column chromatography (ether:hexane=3:1) to obtain 340 mg (86.8%) of the title compound in the form of light yellow oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][C:18]([Br:28])=[CH:17][N:16]=2)[S:12][CH:13]=1)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[Br:28][C:18]1[CH:19]=[C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([NH:14][C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)[N:10]=2)=[N:16][CH:17]=1
Reactant: CC(=O)NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nnc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)o1
Temperature: 50 °C
Yield: 30.1 %

Procedure:
To a mixture of N′-acetyl-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.100 g, 0.210 mmol) in 5 mL acetonitrile was added POCl3 (0.0769 mL, 0.840 mmol) and the reaction was heated at 50° C. for 72 hours. The mixture was concentrated to dryness, diluted with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and purified by preparative HPLC to give the title compound (0.029 g, 30.1% yield). 1H NMR (d6 DMSO) δ 2.50 (2, 3H), 3.00 (t, J=7.4 Hz, 2H), 3.17 (t, J=7.5 Hz, 2H), 6.76 (s, 1H), 7.11 (d, J=7.6 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.2 Hz, 1H), 10-99 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c([N+](=O)[O-])c4)c3c2s1
Yield: 60 %

Procedure:
Prepared from VII and 4-amino-2-nitrophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 60%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3334, 3081, 2926, 2225, 1627, 1591, 1569, 1525, 1465, 1419, 1395, 1305, 1237, 1171, 1132, 1070, 966, 930, 834, 819; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H, J=8.7 Hz), 8.28 (m, 1H), 8.03 (m, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.61 (m, 1H), 7.15 (d, 1H, J=9.0 Hz); HRMS calcd for C16H9N6O3S (M+H+): 365.0457, found 365.0441.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18]O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:22])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1cccc2c(-c3ccc(Br)cc3)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: ClCc1cccc2c(-c3ccc(Br)cc3)nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Bromophenyl)-5-hydroxymethylisoquinoline (17 g) was dissolved in 300 ml of tetrahydrofuran, and 15 ml of phosphorus oxychloride was added. The mixture was stirred at room temperature for 1 hour. After the reaction, water was added, and the reaction mixture was neutralized with an aqueous solution of sodium hydroxide. The mixture was extracted with benzene, and dried. The solvent was distilled off. The residue was recrystallized from ether-hexane to afford 13.2 g of 1-(4-bromophenyl)-5-chloromethylisoquinoline as colorless prisms having a melting point of 115.5° to 118.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:7]1[C:2]([Cl:1])=[C:3]([C:14]#[N:15])[C:4](=[O:13])[N:5]([C@H:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[CH:6]=1
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](C)n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
To a solution of 4-chloro-1-((2S)-3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (14.6 g) in N,N-dimethylformamide (120 mL) was added N-bromosuccinimide (17.4 g), and the mixture was stirred at 50° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.2 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2].[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:1]([C:3]1[N:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2]
Reactant: CCc1[nH]c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1CC
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCn1c(CC)c(CC)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazine (step 1) (14 mg, 0.039 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (1.733 mg, 0.043 mmol). The resulting mixture was stirred at RT for 20 minutes and treated with ethyl 7-bromoheptanoate (8.44 μl, 0.043 mmol). After stirring at RT for 3 hours, the mixture was added to water and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with EtOAc (×3) and the combined organic extracts were sequentially washed with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (with trace hydrolysis acid product present);
Reaction SMILES: CN(C)C=O.CC1C=CC(S(O[CH2:17][C@@H:18]2[O:20][CH2:19]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([OH:45])=[C:40]([C:43]#[N:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:30][C:29]=1[F:48]>C(OCC)(=O)C.O>[NH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:45][CH2:17][C@H:18]4[CH2:19][O:20]4)=[C:40]([C:43]#[N:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:30][C:29]=1[F:48]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OC[C@H]1CO1
Temperature: 50 °C
Yield: 55.4 %

Procedure:
After adding dimethylformamide (8 ml), (2R)-(−)-glycidyl p-toluenesulfonate (1000 mg) and potassium carbonate (940 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (1000 mg), the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (659 mg) as light yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][CH2:9][C:10]1[C:11]([CH3:34])=[N:12][C:13]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:15]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:14]1[CH:15]=[C:10]([CH2:9][O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])[C:11]([CH3:34])=[N:12][C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C)(C)OCc1cc(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1COC(C)(C)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 200 mg of 2-[5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 2 ml THF was added a solution of 18 mg of LiOH in 2 ml water at room temperature. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 22 mg.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[CH3:10][Mg]Br>CCOCC>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])([CH3:10])[CH3:8])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)s1
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To the solution of 1-(5-bromothiophen-2-yl)ethanone (2.05 g, 10 mmol, 1 eq) in ether (20 mL) was added methylmagnesium bromide (11 mL, 11 mmol, 1.1 eq) dropwise at ice-bath. After 0.5 h, the reaction mixture was allowed to stand at room temperature for 1.5 h. Then, the reaction was quenched with saturated aqueous NH4Cl, washed with brine, dried (Na2SO4), and evaporated to afford 2-(5-bromothiophen-2-yl)propan-2-ol (1.97 g, 89%). LC-MS (m/z)=211 [M+]H+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (201 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (223 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][Si](C)(C)C>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Cl:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: CS(C)=O
Product: ClCc1ccc(OCc2ccccc2)cc1

Procedure:
A reaction and post-treatment were carried out following the conditions of Example 71 using 3 g (14 mmol) of 4-benzyloxybenzyl alcohol, 80 ml of chlorotrimethylsilane, 1.09 ml of dimethylsulfoxide, to obtain 4-benzyloxybenzyl chloride.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C@H:12]([CH3:14])[C@H:11]3[O:15][C:16](=[O:18])[NH:17][C@@H:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]2[NH:17][C:16](=[O:18])[O:15][C@H:11]12
Reactant: COc1ccc(CN2C[C@H](C)[C@H]3OC(=O)N[C@@H]3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CNC[C@H]2NC(=O)O[C@H]12
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3aR,7S,7aR)-5-(4-methoxybenzyl)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 20% palladium hydroxide on carbon (0.3 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 2 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7S,7aR)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (99%). LCMS (m/z): 157.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CSc1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.6 g, 9.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (2.5 g, 6.0 mmol) and Na2CO3 (1.9 g, 18.0 mmol) were dissolved in DME (37.5 mL) and water (7.5 mL). The mixture was purged with nitrogen for 20 minutes, treated with Pd(PPh3)4, purged with nitrogen for another 20 minutes and heated to reflux overnight. After cooling to room temperature, water (35 mL) was added and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and acetonitrile and dried overnight at 50° C., affording 2.3 g (88.5%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.70-8.57 (m, 2H), 8.55-8.42 (m, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).