Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[Li]C(CC)C.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][C:3]=1[B:27]([OH:32])[OH:28]
Reactant: CCCC1CCC(C2CCc3ccc(F)c(F)c3O2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3cc(B(O)O)c(F)c(F)c3O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7,8-difluoro-2-(4-propylcyclohexyl)chroman (3.82 g) obtained in Example 2 was dissolved in THF (38 mL). To the solution was added dropwise sec-BuLi (0.99 M solution, 15.5 mL) at −70 to −75° C. and stirred after the end of dropping at the same temperature for additional 1 hour. To the solution was added dropwise a THF solution (5 mL) of triisopropyl borate (2.15 g) at −70 to −75° C. After the end of dropping, it was stirred at the same temperature for additional 3 hours. Then temperature thereof was gradually raised to room temperature. The solution was left stirring overnight. While cooling on ice, to the reaction mixture was added 2 M hydrochloric acid and stirred at room temperature for additional 2 hours. The reaction mixture was poured to water, which was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was further washed with heptane to obtain crude 7,8-difluoro-6-dihydroxyboryl-2-(4-propylcyclohexyl)chroman. The product was used in a second step without purification.
Reaction SMILES: C[NH:2]CCO.F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:2][C:13]1[CH:14]=[CH:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ccccc1C=O
Temperature: 95 °C

Procedure:
A reactor is charged with 2-(methylamino)ethanol (134 g, 1.8 moles), 4-fluorobenzaldehyde (74.4 g, 0.6 mole), potassium carbonate (82.8 g, 0.6 mole) and dimethylsulfoxide (750 ml), and the mixture is heated at 95° C. for 72 hours. The product mixture is cooled and poured into three liters of ice water. The yellow solid that precipitates is filtered, washed with water, and dried in a vacuum oven, mp 72° C. The 4-[N-(2-hydroxyethyl)-N-methylamino]benzaldehyde product is recrystallized from water as needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Cl.O1CCOCC1>CC(O)=O.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(CN2CCOCC2)c(CN)c(=O)[nH]1
Yield: 95.3 %

Procedure:
A clear solution of 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.60 g, 2.57 mmol) in HOAc (20 mL) was treated on an H-Cube apparatus (50 psi, 60° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness, taken up in a small volume of MeOH and treated with 4 N HCl in dioxane (5 mL, 20.00 mmol). The mixture was evaporated to dryness under vacuum (began to ppt. out during evaporation), triturated with Et2O, filtered and dried under vacuum to give the product 3-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone (0.76 g, 2.450 mmol, 95% yield) as a light grey solid. 1H NMR (400 MHz, DMSO-d6) δ 6.39 (s, 1 H), 4.28 (s, 2 H), 3.99 (s, 2 H), 3.87 (br. s., 4 H), 3.27 (br. s., 4 H), 2.22 (s, 3 H). MS(ES)+m/e 238.0 [M+H]+ (weak), 221.3 [M+H]+—NH3 (strong).
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:25])[CH3:2].IC.[CH2:28]([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[N:5]([CH3:28])[C:4]1=[O:25])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Reactant: CC[C@H]1C(=O)Nc2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
(3S)-3-Ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one was treated with iodomethane according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 379 ([M+H]+).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[C:17]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)#[N:18].Cl>O>[ClH:1].[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:21][CH2:20]1)#[N:18]
Reactant: OC(CCl)COc1cccc2ccccc12
Reactant: N#CC1CCNCC1
Agent: Cl
Solvent: O
Product: N#CC1CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
4.0 Parts of 1-chloro-3-(1-naphthoxy)-2-propanol and 16.0 parts of 4-cyanopiperidine are heated in a sealed vessel for 10 hours at about 100° C. That reaction mixture is then diluted with 50 parts of water, acidified with concentrated hydrochloric acid, and extracted with 35 parts of ethyl ether. The aqueous phase is separated and made alkaline with the addition of 10 N sodium hydroxide. The resultant solid is filtered and converted to the hydrochloride salt by redissolving the solid in isopropanol and adding a solution of hydrochloric acid in isopropanol. The resulting salt is separated by filtration and crystallized from a mixture of ethanol and ethyl ether to give 3-(4-cyanopiperidino)-1-(1-naphthoxy)-2-propanol hydrochloride, identical to the product of Example 1.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH:28]([NH:31][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC(C)C)c(=O)n12
Reaction time: 0.08 h

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mole) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -16° C. during 30 minutes. After stirring for 5 minutes, 5.2 g (0.088 mol) of isopropylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 40 minutes, then the mixture is stirred for 1 hour at the same temperature and thereafter maintained under cooling by ice.
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:15]#[C:16]CO)[C:5]2[CH2:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[OH-].[Na+].C1(C)C=CC=CC=1>CCCCCC>[C:4]1([C:15]#[CH:16])[C:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:2][CH:3]=1
Reactant: Cc1cc2c(c(C#CCO)c1C)Cc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C#Cc1cccc2c1Cc1ccccc1-2
Temperature: 120 °C

Procedure:
1.74 g (7 mmol) of Dimethylhydroxymethyl-2-fluorenylacetylene and 294 mg (7.35 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 100 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 35 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 1 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The resulting crude reaction product was dissolved in 40 ml of hexane at 70° C. and then the insolubles were filtered off. The filtrate was cooled to give 2-fluorenylethyne, i.e., the desired compound as a yellow solid (1.12 g, yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7](B(O)O)=[CH:8][C:4]=2[CH:3]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1cc2cc(F)ccc2s1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4s3)c(N(C)C(C)C)nc2c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 5-fluorobenzo[b]thiophen-2-ylboronic acid (202 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (24.0 mg, 0.02 mmol) and water (3 drops) with stifling for 0.5 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 2% ethyl acetate in petroleum ether to afford methyl 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (148 mg, 88%).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:8]=1)=[O:6])C.[Li+].[OH-].Cl>C1COCC1>[F:37][C:34]([F:35])([F:36])[O:33][C:30]1[CH:31]=[CH:32][C:27]([N:9]2[C:10]3[C:15](=[CH:14][C:13]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]([C:5](=[O:6])[C:4]([OH:38])=[O:3])=[CH:8]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(=O)c1cn(-c2ccc(OC(F)(F)F)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(-c2ccc(OC(F)(F)F)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reaction time: 5 h
Yield: 60.9 %

Procedure:
To a solution of 0.142 g [1,5-bis-(4-trifluoromethoxy-phenyl)-1H-indol-3-yl]-oxo-acetic acid ethyl ester from Step 3 in 1 mL THF was added 2 ml 0.5M aqueous LiOH. The reaction was mixed using orbital shaking for 5 hr, at which time TLC indicated that the reaction was complete. The solution was acidified by the dropwise addition of 2N aqueous HCl and extracted with dichloromethane. The organic phase was dried by filtration through a ChemElute column (Varian Inc., Palo Alto, Calif.) and the solvent was evaporated to afford 82 mg [1,5-Bis-(4-trifluoromethoxy-phenyl)-1H-indol-3-yl]-oxo-acetic acid as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.13 (s, 1H), 8.64 (s, 1H), 7.70 (d, J=6.6 Hz, 2H), 7.57–7.68 (m, 3H), 7.46–7.56 (m, 3H), 7.33 (d, J=8 Hz, 2H), MS: m/z (ESI) 508.2 (M−H);
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]2[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]2[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl
Yield: 74.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (0.377 g, 0.620 mmol) prepared in Example 87a, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (0.212 g, 75%) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:26]=[CH:27][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:4][CH:5]=2)[S:11][C:12]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cn2ccnc2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Compound 59 (448 mg, 1.00 mmol) was dissolved in DMF (4 mL), imidazole (204 mg, 3.00 mmol) was added thereto, followed by stirring at 65° C. for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) to afford the entitled Compound 60 (348 mg, 80%).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1>C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cccc(Br)c1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine is converted to the free base (4.9 g.; 0.05 mole) in benzene in the usual manner. Then 9.9 g. (0.05 mole) of m-bromophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added. The reaction mixture is stirred at room temperature for 11/2 hours and the solvent then evaporated in vacuo to give a solid redisue of 1-(3-bromophenyl)-3 -(1-methyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 138°-149° C.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>O1CCCC1>[F:13][CH:2]([F:1])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)F)[nH]c1=O
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(C(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolution of 200 mg (1.1 mmol) of 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in 25 ml of tetrahydrofuran and addition of 206 mg (1.3 mmol) of N,N-carbonyldiimidazole, the mixture was stirred initially at room temperature for 30 min and then under reflux for 30 min. A solution of 66 mg (1.1 mmol) of isopropylamine in 5 ml of tetrahydrofuran was then added dropwise, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness, the residue was then taken up in ethyl acetate and the mixture was washed with 2N hydrochloric acid and water, dried and concentrated. Purification by column chromatography gave 150 mg (61% of theory) of a colorless powder.
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:6]([CH3:13])(=[O:12])[O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:5])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH:4]([P:6]([CH3:13])(=[O:12])[O:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:5]
Reactant: CC(C)COP(C)(=O)C(C)CC#N
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)C(C)CCN

Procedure:
A solution of 29.8 g of isobutyl P-(3-cyanoprop-2-yl)-P-methyl-phosphinate in 200 ml of ethanol is added to 310.0 g of an 8% solution of ammonia in ethanol. To this are added 20 ml of Raney nickel slurry, and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is distilled under reduced pressure to give isobutyl P-(4-aminobut-2-yl)-P-methyl-phosphinate, b.p. 100°/0.1 mbar, 31P-NMR spectrum: δ=+58.9 and +58.4 ppm (CDCl3).
Reaction SMILES: CCO.[CH3:4][O:5][C:6]([C:8]1[C:9]([OH:27])=[C:10]2[C:15](=[CH:16][N:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:25])[C:12](Br)=[CH:11]2)=[O:7].C([O-])(=O)C.[Na+]>[Pd].CCOC(C)=O>[CH3:4][O:5][C:6]([C:8]1[C:9]([OH:27])=[C:10]2[C:15](=[CH:16][N:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:25])[CH2:12][CH2:11]2)=[O:7]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Reaction time: 16 h
Yield: 62.4 %

Procedure:
A flask was charged with EtOH (10 mL) and 10% palladium on carbon (200 mg). A solution of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (150 mg, 0.39 mmol) in EtOAc (40 mL) and sodium acetate (47 mg, 0.58 mmol) were added, and the resulting mixture was stirred under H2 atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 76 mg of the title compound as a white solid. MS: (+) m/z 325.11 (M+1).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.27-7.17 (m, 2 H), 7.09-7.04 (m, 1 H), 6.96-6.91 (m, 1 H), 6.89-6.81 (m, 3 H), 6.28 (dd, J=3.5, 10.9 Hz, 1 H), 5.62-5.43 (m, 3 H), 4.33-4.25 (m, 2 H), 3.78 (d, J=1.2 Hz, 3 H), 2.96-2.80 (m, 2 H), 2.78 (s, 3 H), 2.15-2.03 (m, 2 H), 1.02-0.91 (s, 9 H); LC/MS (m/z) ES+=515.38 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25](=[O:28])[CH2:26][CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:26][CH3:27]
Reactant: Br[Mg]c1ccccc1OCc1ccccc1
Reactant: CCC(=O)c1cc(C)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1cc(C)ccc1C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 100 ml. of a 1.5 molar solution of 2-benzyloxyphenyl magnesium bromide in tetrahydrofurane a solution of 24.3 g. of 2',5'-dimethyl-propiophenone in 50 ml. of dry tetrahydrofurane is added under moderate reflux. The reaction mixture is stirred under slight boiling for 30 minutes, cooled and poured onto a saturated solution of ammonium chloride in ice water. Tetrahydrofurane is distilled off under reduced pressure, and the residue is extracted with benzene. The benzene phase is washed to neutral with water, and dried over anhydrous sodium sulfate. The benzene is evaporated in vacuo and the residue is fractionated to yield 43.9 g. of the named compound, boiling at 160°-162° C./1.33 Pa.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH3:11].[C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: Cc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 78 %

Procedure:
N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, as described in Example 2, from 5-amino-4-methyl-3-triflouromethylisoxazole and 4-biphenylsulfonyl chloride in 78% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a white solid, m.p. 139-140° C.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8][C:9]([CH3:24])([O:11][C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([C:21](O)=[O:22])[CH2:17][CH2:16]1)=[O:13])[CH3:10].[NH3:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:9]([O:11][C:12](=[O:13])[NH:14][C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21](=[O:22])[NH2:25])[CH2:17][CH2:16]1)([CH3:24])([CH3:10])[CH3:8]
Reactant: N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)CC1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Pivaloyl chloride (0.36 ml, 2.96 mmol) was added to a solution of cis-4-[[(1,1-dimethylethoxy)carbonyl]amino]-cyclohexanecarboxylic acid (600 mg, 2.47 mmol) in CHCl3 (10 ml), triethylamine (0.7 ml) at 0° C. and stirred for 1 h. Then aqueous ammonia was added to the reaction mixture and stirred for 1 h. After completion of reaction, the reaction mixture was diluted with CHCl3 (2×25 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, the crude compound was washed with hexane (2×6 ml) and dried to afford 500 mg (91.8%) of cis-tert-butyl-4-carbamoylcyclohexylcarbamate as white color solid.