Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:13]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[CH3:29])=[C:12]([CH3:31])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].CO>C1COCC1>[CH3:3][C:4]1[C:13]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[CH3:29])=[C:12]([CH3:31])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
A solution of aqueous 2N NaOH (1.00 ml) is added to a stirred solution of methyl 2,4-dimethyl-3-[[2-methyl-5-(4-oxo-1-piperidyl)benzoyl]amino]benzoate (0.12 g, 304.20 μmol) in THF:MeOH (2 ml:1 ml). After 16 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with 1N HCl, and extracted with ethyl acetate. The organic layers are combined with aqueous layer and concentrated under reduced pressure. The resulting solids are dissolved in acetonitrile/H2O and lyophilized to afford the title compound as an off-white solid (58 mg, 50.12%). Mass spectrum (m/z): 381.2 (M+1).
Reaction SMILES: C1([C@H]2O[C@@H:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]CO2)C=CC=CC=1.[C:24]([O-])(O)=[O:25].[Na+].C[OH:30]>>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([O:13][CH:11]([CH2:10][OH:30])[CH2:24][OH:25])(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCO[C@@H](c3ccccc3)O2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)OC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
In 50 ml of methanol were dissolved 5.00 g of cis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane, and 5 ml of a 4N HC1-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 2 hours. To the reaction mixture were added 3.5 g of NaHCO3 powder, and the mixture was stirred for 10 minutes. Then, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The thus obtained oil was subjected to column chromatography using silica gel and eluted with ethyl acetate to obtain 3.70 g (yield: 100%) of the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1.[OH-].[Na+]>O.C(#N)C>[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH:23][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:16][CH2:15]1
Reactant: C=CC(=O)Cl
Reactant: NCCCN1CCOCC1
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C=CC(=O)NCCCN1CCOCC1
Reaction time: 3.5 h

Procedure:
In a 1 liter capacity round bottom flask equipped with a stirrer were put 90.5 g (1.0 mole) of acrylic acid chloride and 300 cc of acetonitrile and, as a polymerization inhibitor, 0.5 g of hydroquinone, and then, after the contents were cooled to 5°-10°C, 143 g (1.0 mole) of 3-morpholinopropylamine was added dropwise thereto over the course of 3.5 hours while stirring. Afterwards, the reaction mixture was stirred additionally for 2 hours at 40°-50°C. Next, a solution of 40 g of sodium hydroxide in 100 cc of water was added thereto and then the mixture was stirred for 30 minutes. After removal of the sodium chloride which separated, 152 g (77.0%) of a fraction of 144°-146°C/0.1 mmHg were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C(N(CC)CC)C.O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C1CCCNCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1nccc(N2CCCCCC2)n1
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 2,4-dichloropyrimidine (25 g) in triethylamine (47 mL) and tetrahydrofuran (300 mL) was added azepane (17 g) at 0° C. After returning to room temperature, the solution was stirred for 1 hour. Water was added to thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5→1:2) to give the title compound (7.25 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:1][O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOCc2ccccc2)CC(=O)N2CCOCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CONC(=O)CN(CC(=O)N1CCOCC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide (0.33 grams, 0.69 mmol) in methanol (35mL) was added 5% palladium on activated carbon (85 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated. The residue was chromatorgraphed on silica gel eluting with 5% methanol in methylene chloride to afford N-methoxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 65 mg (24%); 1H NMR (CD3OD): δ7.82 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.68-3.64 (m, 4H), 3.58-3.50 (m, 4H); MS (thermospray): m/z 388 (M+1), 387 (M); HRMS calculated for C16H22N3O7S (M+H): 388.1178, Found 338.1180.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:17][N:9]2[C:10]3[C:15](=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH2:20][CH2:21]1
Reactant: C=O
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc2c(c1)c(-c1ccccc1)nn2CN1CCOCC1
Yield: 51.8 %

Procedure:
3-Phenyl-5-chloroindazole (2.29 g), paraformaldehyde (0.35 g), morpholine (1.91 g) and 1N aqeous sodium hydroxide solution (1 ml) were added to 40 ml of ethanol and the mixture was allowed to react under reflux. The reaction mixture was concentrated and then the residue was dissolved in chloroform, washed with water, dried over sodium sulfate and concentrated. The residue was treated with column chromatography to obtain 1.7 g of 1-morpholinomethyl-3-phenyl-5-chloroindazole having a melting point of between 155°-156° C after recrystallization from methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:34])[NH:32][NH2:33])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[N:33][NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:34])[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(CCC(=O)C1CCCN(C(=O)OCc2ccccc2)C1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(CCC(=NNC(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)OC
Reaction time: 4 h
Yield: 94.2 %

Procedure:
The product from step 1 (16.32 g, 46.70 mmol) was dissolved in 100 mL of CH2Cl2 and treated with tert-butylcarbazate (6.48 g, 49.04 mmol) followed by para-toluensulfonic acid monohydrate (0.44 g, 2.33 mmol) and the mixture was stirred 4 h. The mixture was poured into a separatory funnel and extracted with 50 mL 2M aq. Na2CO3. The aqueous phase was extracted with 50 mL of CH2Cl2 and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified using an ISCO® instrument (Red-Sep 330, 30%-100% EtOAc hexanes) to give 20.40 g of a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 9.48 (bs, 1H), 7.40-7.28 (m, 5H), 5.04 (s, 2H), 4.32 (m, 1H), 4.05 (bd, 1H), 3.96 (bd, 1H), 3.20 (m, 6H), 2.88-2.63 (m, 2H), 2.31-2.11 (m, 1H), 1.87 (m, 1H), 1.66, (m, 1H), 1.59 (m, 1H), 1.42 (s, 9H), 1.40-1.24 (m, 5H). ES-MS m/z 463.9 [M+Na]+, HPLC RT (min) 3.67
Reaction SMILES: O[CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:3](O)=[O:4].[NH3:16].[NH2:17]N.C(O)(=O)C>O>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:2][C:3](=[O:4])[NH:16][N:17]=1
Reactant: O=C(CC(O)C(=O)O)c1ccccc1O
Reactant: N
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccccc2O)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred suspension of 2-hydroxy-4-oxo-4-(2-hydroxyphenyl)butyric acid in water was added ammonia until pH 7.0 was attained. Hydrazine was added slowly with the concurrent addition of sufficient glacial acetic acid to maintain a pH of 7.0. Steam heating was applied for 2 hours and during this time the pH of 7.0 was maintained by the addition of ammonia as necessary. The reaction mixture was allowed to cool to room temperature. The solid was filtered off, washed with water, 2-propanol and dried (MgSO4) to afford 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (85%).
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=O)=O)[CH2:3][CH2:2]1.C([NH2:20])(=O)C.B(F)(F)F.CCOCC>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:20]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C(COC(=O)C1CC1)c1ccc(Br)cc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: Brc1ccc(-c2coc(C3CC3)n2)cc1
Yield: 64.5 %

Procedure:
To a mixture of 2-(4-bromophenyl)-2-oxoethyl cyclopropane carboxylate (6.00 g, 21.19 mmol) and acetamide (6.60 g, 111.73 mmol) was added BF3/Et2O (4 ml). The mixture was heated to 140C for 2.5 h. Upon cooling, water was added, and the mixture was extracted with Et2O (4×125 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 7:3) to provide the title compound as a yellow solid (3.61 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22]4[O:25][CH:26]=[CH:27][C:21]=4[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:26]1[O:25][C:22]2[CH2:23][CH2:24][N:19]([S:16]([C:13]3[CH:12]=[CH:11][C:10](/[CH:9]=[CH:8]\[C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:15][CH:14]=3)(=[O:17])=[O:18])[CH2:20][C:21]=2[CH:27]=1)[CH3:30]
Reactant: CNC
Reactant: C=O
Reactant: O=S(=O)(c1ccc(/C=C\c2ccc(Cl)cc2)cc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)c1ccc(/C=C\c3ccc(Cl)cc3)cc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.664 g (1.660 mmol) of (Z)-5-(4-chlorostilbene-4'-sulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.22 g (2.49 mmol) of 50% aqueous dimethylamine and 0.20 g (2.49 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH3:12][C:13]1([CH3:21])[O:17]C(CCO)[CH2:15][O:14]1.FC(F)(F)S([O-])(=O)=O>C(Cl)(Cl)(Cl)Cl>[F:11][C:2]([F:10])([F:1])[S:3]([O:6][CH2:7][CH2:8][CH:9]1[CH2:15][O:14][C:13]([CH3:21])([CH3:12])[O:17]1)(=[O:4])=[O:5]
Reactant: CC1(C)OCC(CCO)O1
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OCC(CCOS(=O)(=O)C(F)(F)F)O1

Procedure:
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl trifluoromethane sulfonate was prepared in carbon tetrachloride solution and used as a dried solution in this example in the same way as 2-propen-1-yl trifluoromethanesulfonate was prepared and used in Appexamples 41 through 44, starting with 2,2dimethyl-4-(2-hydroxyethyl)1,3-dioxolane and trifluoromethanesulfonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.[C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:28](=[O:30])[CH3:29])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(N)C4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCCNC1CCCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)C1

Procedure:
The preparation is carried out analogously to FS401 starting from 94 mg (0.46 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-3-ylamine and 45 μl of bromobutyl acetate using 2 equiv. of potassium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O1CCCC1.CO.[OH-].[Li+:42]>O>[Li+:42].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([O-:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1nccc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)[O-])nccc34)no2)cc1Cl
Temperature: 80 °C
Yield: 78.6 %

Procedure:
A round bottom flask was charged with ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D8; 80 mg, 0.172 mmol), tetrahydrofuran (THF) (4.00 ml), methanol (4.00 ml), water (2 ml) and lithium hydroxide (4.11 mg, 0.172 mmol). The mixture was warmed to 80° C. for 2 h after which time the solvent was removed in vacuo and the resultant red solid triturated with diethyl ether. The resulting slurry was filtered and the solid dried in vacuo to give the title compound as a brick coloured solid (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[B:14](OCCCC)(OCCCC)OCCCC.[OH:30][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(O)(=O)C>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([B:14]2[O:37][C:34]([CH3:36])([CH3:35])[C:31]([CH3:33])([CH3:32])[O:30]2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: CC(C)(O)C(C)(C)O
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A −78° C. solution of Example 68B (3.35 g, 15 mmol) diethyl ether (100 mL) was treated dropwise with 2.5 M n-butyllithium (7.2 mL, 18 mmol), stirred for 2 hours at −78° C., treated with tributyl borate (4.14 g, 18 mmol), stirred at −78° C. for one hour and warmed to room temperature over 2 hours. The solution was treated with pinacol (2.30 g, 19.5 mmol) and acetic acid (0.9 g, 15 mmol), stirred overnight, and filtered through diatomaceous earth (Celite®). The pad was washed with diethyl ether several times and the filtrate was concentrated to a volume of 50 mL. The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 25:1 hexanes/ethyl acetate to provide 2.34 g (70%) of the desired product. MS (DCI) m/e 224 (M+H)+; 1H NMR (300 MHz, CDCl3,) δ 8.24 (d, J=5.1 Hz, 1H), 7.50 (dd, J=4.8, 2.7 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 1.36 (s, 12H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18](=[O:26])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:17])[CH2:9][CH2:8]2)(=O)C.C[O-].[Na+].Cl.CCOC(C)=O>CO.O>[CH2:20]([NH:19][C:18]([C:10]1([CH3:17])[CH2:9][CH2:8][C:7]2[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=2[CH3:27])[O:11]1)=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCNC(=O)C1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCCCCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 8 h
Yield: 108 %

Procedure:
Crude 2-(hexylcarbamoyl)-2,5,7,8-tetramethylchroman-6-yl acetate (187 mg, 0.25 mmol) in 1.25 mL MeOH was treated with 33.7 mg (0.625 mmol) NaOMe and let stir overnight. The stirred brown solution then was diluted with water (10 mL), neutralized with 2.5 M HCl (1.5 mL) and 10 mL EtOAc added. The layers were separated and the organics dried over Na2SO4 and concentrated. Flash chromatography yielded 90 mg of N-hexyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29]>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:15](=[O:24])[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:28]#[CH:27]
Reactant: C#CCBr
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccccc2)C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCN(C(=O)c1ccccc1)N(C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred suspension of N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine (1.5 g) in dimethylformamide (DMF) (20 ml) was added sodium hydride (200 mg of 60% oil dispersion) portionwise. After 15 min., propargyl bromide (0.6 g) was added to the reaction mixture dropwise and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (5×20 ml). The organic layer was then dried over magnesium sulfate and the solvent removed under vacuum to afford N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine as a yellow amorphous solid. The product, N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine, was purified by column chromatography on silica gel (solvent system:methylene chloride) to afford a 70% yield as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14]C(C=C)=[CH:12][CH:11]=3)[O:4][N:3]=1.S([O-])([O-])=[O:27].[Na+].[Na+].[C:32]([OH:36])([CH3:35])([CH3:34])C>>[OH:36][CH:32]([C:35]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:25])[C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:34][OH:27]
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C(O)CO)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
AD-mix β was dissolved in 50% aq. tert-butanol (10 mL) followed by 3-(3-methyl-isoxazol-5-yl)-4-phenyl-6-vinyl-1H-quinolin-2-one (d) (60 mg, 0.18 mmol) and the resulting mixture was stirred at room temperature overnight. Sodium sulfite (0.3 g) was added and stirring was continued until the solution cleared. The mixture was extracted with ethyl acetate (1×20 mL, 2×10 mL) and the combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (5% methanol in DCM) to give 6-(1,2-dihydroxy-ethyl)-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (e) (66 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 12.3 (s, 1H), 7.56 (dd, J=2.6, 6.9 Hz, 1H), 7.49-7.41 (m, 3H), 7.37 (d, J=8.6 Hz, 1H), 7.27-7.18 (m, 1H), 7.09-7.04 (m, 1H), 6.41 (s, 1H), 5.25-5.20 (m, 1H), 4.65 (dd, J=6.4, 7.7Hz, 1H), 4.46-4.36 (m, 1H), 2.12 (s, 3H). MS: 363.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][NH2:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C)C=O>[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23]([NH:17][CH2:16][C:14]1[O:15][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=[CH:18][C:12]=2[CH:13]=1)=[O:24]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: NCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a N,N-dimethylformamide (8 mL) solution of C-(6-benzyloxy-benzofuran-2-yl)-methylamine (400 mg, 1.58 mmol) described in Production Example 1-2-4 were added 2-amino-6-methoxymethyl-nicotinic acid (316 mg, 1.74 mmol) described in Production Example 4-1-5, triethylamine (660 μL, 4.74 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (908 mg, 2.05 mmol) at room temperature, which was stirred at room temperature for 2 hours 30 minutes. To the reaction solution was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (454 mg, 69%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:27])[CH2:26][NH:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:23]([F:27])([F:22])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(F)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=360.4 [MH+].