Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[N:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-Phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine (2.5 g, 9.9 mmol), and N,N-diisopropylethylamine (8.6 mL, 50 mmol) in dichloromethane (8 mL) at 0° C. was added dropwise isobutyryl chloride (1.04 mL, 9.9 mmol); the mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water and extracted with dichloromethane (3×). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to a dark sticky solid. The residue was purified by flash chromatography (eluting with ethyl acetate/hexanes 3:1) to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(O)C>[N+:36](=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:6])=[N-:37]
Reactant: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of O-acetoacetyl-N-trifluoroacetyl-L-serine (232 mg) and triethylamine (0.41 ml) in ethanol (7 ml) was added p-toluenesulfonyl azide (193 mg) at 0° C. The mixture was stirred for an hour at 0° C. and for 4 hours at room temperature. The solvent was distilled off in vacuo and the residue was diluted with chloroform and washed successively with aqueous acetic acid, water and brine. After drying over sodium sulfate, the chloroform extract was filtered and concentrated. The residue was flash chromatographed on silica gel (10 g) eluting successively with chloroform and a 1:9 mixture of methanol and chloroform to give O-(2-diazo-1,3-dioxobutyl)-N-trifloroacetyl-L-serine (193 mg).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])[C:3]([OH:5])=[O:4].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]S.CO.O[O:30][S:31]([O-:33])=O.[K+]>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:9]1([C:7](=[O:8])[CH2:6][CH:2]([CH2:1][S:31]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[C:16]([F:15])([F:25])[F:26])(=[O:33])=[O:30])[C:3]([OH:5])=[O:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: O=S([O-])OO
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Reactant: FC(F)(F)c1ccccc1CS
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1C(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of 2-methylene-4-morpholin-4-yl-4-oxo-butyric acid (2 g, 10.03 mmol), in DMF (5 mL), 2-trifluoromethylbenzyl mercaptan (1.93 g, 10.03 mmol) and DMAP (122 mg, 1.0 mmol) was stirred at ambient temperature for 16 hours. Methanol (200 mL) and a saturated aqueous solution of Oxone® (20 g, 32.5 mmol) were added with continued stirring for 2 hours. Methanol was removed under vacuum and the aqueous residue was diluted with 200 mL of water. The crystallized product was filtered, washed with water, and dried under vacuum to yield 4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyric acid (0.95 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Cl[CH2:9][CH:10]=O.C([O-])(O)=O.[Na+]>C(O)CCC>[Br:1][C:2]1[S:6][C:5]2=[N:7][CH:9]=[CH:10][N:4]2[N:3]=1
Reactant: O=CCCl
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Brc1nn2ccnc2s1
Temperature: 120 °C

Procedure:
20 g of 5-bromo-[1,3,4]thiadiazol-2-ylamine were dissolved in 60 ml of n-butanol. 15 ml of chloroacetaldehyde (55% in water) were added to the solution. The mixture was heated for 3 h at 120° C. After cooling the reaction mixture was poured into a NaHCO3 solution. The mixture was extracted three times with ethylacetate and the organic phase dried with sodium sulphate and evaporated. The resulting material was purified via silica-gel column chromatography using a petroleum ether-ethylacetate gradient. 2.9 g yellow crystals of the desired product were obtained.
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O.CO.[Pd]>[C:26]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(C#N)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% Palladium-on-carbon (0.3 g) was added to a solution of 2,2-diphenyl-5-[N-(4-cyanophenethyl)-N-methylamino]pentanamide (0.3 g-see Example 13) in 5% formic acid in methanol (21 ml). The mixture was stirred at room temperature under nitrogen for 1 hour, then filtered and the filtrate concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give an oil which crystallised on standing. The solid was triturated with ether to give the title compound as buff crystals, yield 0.1 g, m.p. 139°-142°.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Cl:40][C:41]1[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][C:42]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:47][C:45]2[CH:44]=[CH:43][C:42]([C:48]3[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=3)=[C:41]([Cl:40])[CH:46]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (2.7 g, 12.7 mmol) was added to a DCE solution (22 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as in Example 6, (2.3 g, 6.3 mmol), 2,4′-dichloro-[1,1′-biphenyl]-4-amine (1.7 g, 7.0 mmol), and AcOH (1.5 mL, 25.4 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1([F:13])C(=O)[N:5]2C(C)(C)[O:7][CH2:8][C@H:4]2[CH2:3]1.Cl.[O:15]1CCOC[CH2:16]1.[CH3:21][OH:22]>>[NH2:5][C@@H:4]([CH2:8][OH:7])[CH2:3][C:2]([F:13])([F:1])[C:21]([O:15][CH3:16])=[O:22]
Reactant: CC1(C)OC[C@H]2CC(F)(F)C(=O)N21
Reactant: C1COCCO1
Reactant: CO
Agent: Cl
Product: COC(=O)C(F)(F)C[C@@H](N)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice-cooled solution consisting of (R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 6, 1.28 g, 6.70 mmol) in methanol (20 mL) was added dropwise 4N HCl in dioxane (3.0 mL, 12 mmol) and stirred at room temperature for 16 hours. The resulting mixture was concentrated and the product concentrate used without purification; TLC Rf 0.60 (solvent system 93:7 v/v dichloromethane-methanol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]=[CH:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([OH:14])=[O:13].[C:15]([O-])([O-])=O.[K+].[K+].CI.Cl>CN(C=O)C>[CH3:1][C@H:2]1[CH2:11][CH:10]=[CH:9][C:4]2([CH2:5][CH2:6][CH2:7][CH2:8]2)[C@@H:3]1[C:12]([O:14][CH3:15])=[O:13].[CH3:1][C@H:2]1[CH2:11][CH:10]=[CH:9][C:4]2([CH2:5][CH2:6][CH2:7][CH2:8]2)[C@H:3]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC1CC=CC2(CCCC2)C1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@@H](C)CC=CC12CCCC2
Product: COC(=O)[C@H]1[C@@H](C)CC=CC12CCCC2
Reaction time: 0.5 h
Yield: 10 %
Yield: 35 %

Procedure:
At 5° C., a solution of 7-methylspiro[4.5]dec-9-ene-6-carboxylic acid (1.4 g, 7.2 mmol) in DMF was treated with K2CO3 (1.1 g, 7.9 mmol). The resulting mixture was stirred for 30 min., treated with methyl iodide (0.67 ml, 10.8 mmol), stirred at 20° C. for 2 h, poured into cold 2N aqueous HCl (20 ml), and extracted twice with hexane (70 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (170 g SiO2, pentane/diethyl ether 80:1) of the crude product (1.4 g) gave rel-(6R,7S)-methyl 7-methylspiro[4.5]dec-9-ene-6-carboxylate (0.15 g, 10%) and rel-(6S,7S)-methyl 7-methylspiro[4.5]dec-9-ene-6-carboxylate (0.53 g, 35%).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:35][CH:34]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][N:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2ccncn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060 g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield: 0.035 g (57.37%). 1H NMR (400 MHz, CD3OD): δ 9.00 (d, J=1.2 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 7.98-7.90 (m and dd, 3H), 7.85 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.51-7.49 (two overlapping d, 2H), 7.35-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.84-1.81 (m, 2H), 1.52-1.49 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −76.94 (TFA), −112.22, −122.76 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27]C)=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1.[OH-].[Li+:47]>O1CCCC1.CO.O>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:24][C:25]([O-:27])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43].[Li+:47]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)[O-])n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I6) (0.360 g, 0.572 mmol) in tetrahydrofuran (17 mL), methanol (3 mL) and water (5 mL) was added lithium hydroxide (0.042 g, 1.77 mmol) and the resulting mixture was stirred at room temperature for 20 hours. The reaction volatiles were evaporated in vacuo and the resulting residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (20 mL), dried (magnesium sulfate), filtered, evaporated in vacuo and dried to give the title compound (I7) (0.356 g, 100%) as a yellow foam; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 2.96-3.06 (m, 8H) 3.56-3.62 (m, 6H), 3.77 (s, 3H), 6.47-6.51 (m, 2H), 7.00-7.11 (m, 2H), 8.00 (brs, 2H) and 8.43 (s, 1H). LCMS Method B: rt 9.00 min; m/z 616.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>CS(C)=O.[Cu]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4.36 g of 4-methyl-phenol in 70 ml of dry dimethylsulfoxide under nitrogen with stirring is added 9.0 g of potassium t-butoxide. After stirring for 15 minutes, 0.1 g of copper metal is added followed by 10.0 g of 4-iodobenzoic acid. The reactants are stirred under nitrogen while heating at 210° C. for 18 hours. The cooled reaction mixture is extracted with chloroform (2×900 ml) and the remaining water acidified with 2N HCl (pH=3) with ice bath cooling, to give 8.1 g of the desired product. MS(M+H=229.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12]N[CH2:10][CH2:9]1.Br[C:28]1[N:33]=[C:32]2[C:34]([C:47]3[CH:48]=[C:49]4[C:53](=[CH:54][CH:55]=3)[NH:52][CH:51]=[CH:50]4)=[CH:35][N:36](S(C3C=CC(C)=CC=3)(=O)=O)[C:31]2=[N:30][CH:29]=1.BrC1C=C2C(C3C=C4C(=CC=3)NC=C4)=CN(S(C3C=CC(C)=CC=3)(=O)=[O:76])C2=NC=1>>[NH:52]1[C:53]2[C:49](=[CH:48][C:47]([C:34]3[C:32]4=[N:33][C:28]([C:16]5[CH:15]=[CH:14][C:4]([O:5][CH2:6][CH2:7][N:8]6[CH2:9][CH2:10][O:76][CH2:12][CH2:13]6)=[C:3]([O:2][CH3:1])[CH:17]=5)=[CH:29][N:30]=[C:31]4[NH:36][CH:35]=3)=[CH:55][CH:54]=2)[CH:50]=[CH:51]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCCN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3nc(Br)cnc32)cc1
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3n2)ccc1OCCN1CCOCC1

Procedure:
Compound AZ was prepared by a method analogous to that described in Example 36 by substituting 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine for 1-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine and 2-bromo-7-(1H-indol-5-yl)-5-tosyl-5H-pyrrolo[3,2-b]pyrazine for intermediate B. HPLC retention time: 1.59 minutes. MS ESI (m/z): 470.4 (M+H)+, calc. 469.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[C:3](=[O:14])O1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC>[C:16]1([N:15]2[CH2:1][C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[CH:5][C:4]=3[C:3]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OCc2c1cnc1ccccc21
Reactant: Nc1ccccc1
Solvent: CCCCCC
Product: O=C1c2cnc3ccccc3c2CN1c1ccccc1
Temperature: 25 °C

Procedure:
A mixture Furo[3,4-c]quinolin-3(1H)-one (100 mg) and aniline (2 mL) was heated at 180° C. for 5 min. After cooling to room temperature the mixture was slowly diluted with hexane and the resulting product was collected and washed with hexane to afford 2-Phenyl-pyrrolo[3,4-c]quinolin-3(1H)-one.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16](=[O:18])[CH3:17])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O>[C:16]([C:7]1[N:8]([CH3:15])[C:9](=[O:14])[C:10]([CH3:13])=[C:11]([Cl:12])[C:6]=1[C:4]([OH:5])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(C(=O)O)c(Cl)c(C)c(=O)n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent) in THF:water (4:1) is added 1 M aqueous LiOH solution (2.05 equivalents). After 30 minutes, the reaction mixture is acidified to pH 1 with 1 N HCl solution and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give the desired product which is used directly without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH2:13]=O>O>[ClH:12].[Cl:12][CH2:13][C:6]1[CH:7]=[CH:8][C:9]([OH:11])=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: C=O
Reactant: Oc1cccc2cccnc12
Agent: Cl
Solvent: O
Product: Oc1ccc(CCl)c2cccnc12
Reaction time: 2 h

Procedure:
A mixture of 14.6 g (0.1 mol) of 8-quinolinol, 16 mL of 32% HCl in water, and 16 mL (0.1 mL) of 37% formaldehyde in water at 0° C. was treated with hydrogen chloride gas for 6 h. The solution was allowed to stand at room temperature for 2 h without stirring. The yellow solid obtained was collected on a filter, washed with 90% alcohol and dried under vacuum to give 5-chloromethyl-8-quinolinol hydrochloride A (19.0 g, 98%): 1H NMR (250 MHz, CDCl3, δ) 5.32 (s, 2H), 7.53 (m, 1H), 7.85 (m, 2H), 8.12 (m, 1H), 9.12 (m, 1H), 9.28 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13]([O:15][CH2:16][CH2:17]O)[CH3:14]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:14][CH2:13][O:15][CH2:16][CH3:17])=[O:8])=[CH:3][C:2]=1[C:10]([O:12][CH2:17][CH2:16][O:15][CH2:13][CH3:14])=[O:11]
Reactant: CCOCCO
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Product: CCOCCOC(=O)c1ccnc(C(=O)OCCOCC)c1

Procedure:
As described in Example 26, 10 g of pyridine-2,4-dicarboxylic acid are reacted with ethylene glycol monoethyl ether via the acid chloride. The reaction mixture is worked up analogously to Example 26. The product is obtained as an oil. Yield 7.2 g
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[S:20](Cl)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].CCOC(C)=O>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)=[CH:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: Oc1ccc(-c2nnco2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1ccc(-c2nnco2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
A solution of 4-(1,3,4-oxadiazol-2-yl)phenol (1.05 g, 6.48 mmol) and triethylamine (1.82 mL, 13.0 mmol) in CH2Cl2 (12 mL) was cooled to 0° C. and treated with triflic chloride (0.83 mL, 7.77 mmol). The resultant orange-colored reaction was stirred 30 min at 0° C. and 30 min at RT. The reaction was poured into EtOAc (50 mL), washed with water (20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4) and concentrated in vacuo to provide 4-(1,3,4-Oxadiazol-2-yl)phenyl trifluoromethanesulfonate (1.94 g, 102% yield) as a beige-colored solid. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1 H), 8.22 (d, J=8.6 Hz, 2 H), 7.78 (d, J=8.6 Hz, 2 H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:21]([NH:25][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CN
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(NCC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.45 g, 1.54 mmole) and isobutylamine (0.11 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil (0.53g, 98%). No further purification was performed. LCMS m/z 344.00 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=[O:4].C1COCC1.CO.O.[OH-].[Li+]>O>[CH3:36][C:35]([CH3:37])([CH3:38])[C:34]#[C:33][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:24]([CH:26]2[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)c1ccc(Oc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1CCC(C(=O)N(c2ccc(Oc3ccccn3)cc2)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Temperature: 60 °C
Yield: 70 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-phenyl]-amino}-thiophene-2-carboxylic acid methyl ester (174 mg, 0.33 mmol) in a 3:2:1 mixture of THF:MeOH:water (5 mL) was treated with lithium hydroxide monohydrate (0.69 g, 1.65 mmol) and heated to 60° C. for 1 hour. The organic volatiles were evaporated under reduced pressure and the crude material was purified by reverse-phase HPLC to afford the title compound in 70% yield. MS (m/z): 517.0 [M+H]−; HPLC retention time: 4.90 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).