Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:31])[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:31])[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
43 mg (0.09 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 2.2C) were hydrolysed with TFA according to General Method 2. Yield: 20 mg (purity 89%, 48% of theory)
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:22])[C:16](=[O:21])C(O)(C)C)[N:13]([C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:24])[C:12]1=[O:30])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I(O)(=O)(=O)=[O:32]>CO>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:30])[N:13]([C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:24])[C@@H:14]1[C@@H:15]([CH3:22])[C:16]([OH:32])=[O:21])[CH3:10])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)C(C)(C)O
Reactant: [O-][I+3]([O-])([O-])O
Solvent: CO
Product: CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(ethoxalyl)-4-[(1R)-3-hydroxy-1,3-dimethyl-2-oxobutyl]-2-azetidinone (50 mg) in methanol (2 ml) was added 0.54M aqueous periodic acid solution (1.0 ml). After stirring at room temperature for 5 hours, the solvent was removed in vacuo and the residue was extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated to afford (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-1-(ethoxalyl)-4-oxoazetidin-2-yl]propionic acid (93 mg). To a solution of the compound obtained above in diethyl ether (2 ml) was added a solution of diazomethane in diethyl ether at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel (1 g) eluting with a mixture of ethyl acetate and hexane (1:5, V/V) to give methyl (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-1-(ethoxalyl)-4-oxoazetidin-2-yl]propionate (24 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:35][CH:34]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and 4-phenoxybenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenoxybenzamide as a white powder, m.p. 90.5-91.5° C. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (t, J=5.7 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.45-7.40 (m, 3H), 7.21 (m, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 6.61 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.25 (m,2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 451.2008 (451.2008 calcd for C27H25N5O2).
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH2:29]>>[OH:1][CH:2]([CH2:27][NH:29][CH3:28])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2ccc3ccccc3c2)c2ccc(OCC3CO3)cc2O1
Reactant: CN
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccc2ccccc2c1

Procedure:
Reaction of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(2-naphthyl)chroman with methylamine, by an analogous method to that described in Example 2 gave 7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-4-(2-naphthyl)chroman isolated as its hydrochloride salt m.p. 183°-188°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si](C=[N+]=[N-])(C)C.B(F)(F)F>CO.C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ncccc1O
Agent: FB(F)F
Solvent: CO
Solvent: c1ccccc1
Product: COc1cccnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-3-hydroxypyridine (Aldrich, 200 mg) in 20% methanol/benzene (4 mL) was treated with trimethylsilyldiazomethane (1.8 mL, 2.0 M), boron trifluoride diethyletherate (0.026 mL) and stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the crude oil was purified by medium pressure liquid chromatography on a 21×300 mm silica column eluted with 50% ethyl acetate/lmethylene chloride to give the title compound (50 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:16])[CH2:12][CH2:11][N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+].C(Cl)Cl>Cl.O>[CH2:13]([N:10]1[CH2:11][CH2:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][NH2:17])=[CH:3][CH:4]=2)([CH3:16])[C:9]1=[O:15])[CH3:14]
Reactant: O=N[O-]
Reactant: CCN1CCC(C)(c2ccc(N)cc2)C1=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCN1CCC(C)(c2ccc(NN)cc2)C1=O
Reaction time: 0.75 h

Procedure:
A solution of 676 mg (3.1 mmol) of (±)-3-(4-aminophenyl)-1-ethyl-3-methylpyrrolidin-2-one (from Step 3) in 3.1 mL of concentrated hydrochloric acid was then stirred at about −5° C. in an ice-acetone bath as a solution of 222 mg (3.2 mmol) of sodium nitrite in 1.25 mL of water was added dropwise over about 15 minutes. Stirring was continued at −10° to −5° C. for 45 minutes. The mixture was kept cold and added gradually to a solution of 3.50 g (15.5 mmol) of stannous chloride dihydrate in 2.5 mL of concentrated hydrochloric acid stirred under nitrogen at <0° C. in an ice-acetone bath. After completion of the addition, stirring was continued in the cooling bath for about 30 minutes, and then the mixture was partitioned between 25 mL of ethyl acetate and 4 mL of water. The aqueous layer was washed with an additional 10 mL of ethyl acetate. The combined ethyl acetate fractions were treated cautiously with 25 mL of saturated aqueous sodium carbonate solution, resulting in heavy precipitation and some gas evolution. After dilution with additional ethyl acetate and water, the mixture was filtered. The filtrate was transferred to a separatory funnel, and the ethyl acetate layer was washed with saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature to yield 396 mg (55%) of a viscous, yellow oil; primarily one spot by TLC in 95:5 CH2Cl2. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][C:13]=1[CH2:22][O:23][CH3:24])[CH3:5]>C1COCC1.O>[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]=1[CH2:22][O:23][CH3:24])[CH3:5]
Reactant: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
Lithium hydroxide monohydrate (5.31 g, 127 mmol) was added portion-wise into a solution of methyl 2′-ethyl-2-(methoxymethyl)-1,1′-biphenyl-4-carboxylate (12.0 g, 42.2 mmol) in THF (150 mL) and water (30 mL). The resulting mixture was stirred at RT for 12 hours. The reaction mixture was concentrated under reduced pressure. The resulting aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. The organic layers were washed with water and brine, combined and dried (Na2SO4). The solvents were removed under reduced pressure to afford the title compound as a white solid (9.0 g, 80%). HPLC (Method A), Rt 4.2 min (purity: 96.7%). UPLC/MS, M−(ESI): 269.2. 1H NMR (DMSO-d6, 400 MHz) δ 12.9 (1H, bs), 8.08 (1H, s), 7.89 (1H, d), 7.35 (2H, m), 7.23 (2H, m), 7.04 (1H, d), 4.09 (2H, m), 3.17 (3H, s), 2.34 (1H, m), 2.22 (1H, m), 0.94 (3H, t).
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:19](=[N:25]/O)/[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:19]\[C:20]2[O:24][CH:23]=[CH:22][CH:21]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Reactant: O/N=C\c1ccco1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 60 °C
Reaction time: 15 h
Yield: 40.5 %

Procedure:
In 450 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 131 g (0.5 mol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 66.5 g (0.6 mol) of (Z)-furfuraldoxime, and the solution was stirred at 60° C. for 15 hours. The solvent was evaporated under reduced pressure, and the residual oily material was poured into 3 l of ice-cooled water, and crystals precipitated were collected by filtration. The crystals were washed with water (500 ml×2), dried under reduced pressure and recrystallized from ethanol and then from ethyl acetate-hexane (7:3) to yield 63.5 g of ethyl 5-fluoro-6-(Z)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5carboxylate. m.p. 152°-153° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Cl)s1

Procedure:
50.4 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 475.0 ([M+H]+)
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([OH:33])[CH2:14][N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22]3)(=[O:18])=[O:17])[CH2:2]1.CO[CH:44](OC)[N:45]([CH3:47])[CH3:46]>C(Cl)(Cl)Cl>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([OH:33])[CH2:14][N:15]([S:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[C:22]3=[CH:44][N:45]([CH3:47])[CH3:46])(=[O:18])=[O:17])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:2]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Yield: 74.7 %

Procedure:
A solution of {1-benzyl-2-hydroxy-3-[isobutyl-(2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 20 (59 mg, 0.1 mmol) and N,N-dimethylformamide dimethylacetal (27 ul, 0.2 mmol) in 1 ml of chloroform was refluxed for 1 h, cooled, and concentrated in vacuo. The residue was chromatographed on silica gel, (methanol:ethyl acetate 3:97) to obtain {1-benzyl-3-[(3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 21 (48 mg, 75%). TLC: Rf 0.09 (ethyl acetate). MS m/z 643 (MH)+. 1H NMR (CDCl3) consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([F:15])=[CH:7][CH:6]=2.O.[C:29](OC(=O)C)(=O)[CH3:30]>S(=O)(=O)(O)O>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]([C:3]2[C:2]3[N:1]=[C:29]([CH3:30])[O:13][C:12](=[O:14])[C:11]=3[C:10]3[CH:9]=[C:8]([F:15])[CH:7]=[CH:6][C:5]=3[N:4]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc2c(-c3ccc(-c4ccccc4)cc3)nc3ccc(F)cc3c2c(=O)o1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4 g of 3-amino-2-[1,1'-biphenyl]-4-yl-6-fluoro-4-quinolinecarboxylic acid in 30 ml of acetic anhydride was added 10 drops of concentrated sulfuric acid. The mixture was heated at 90° C. for 2 hours, then cooled and poured into 200 ml of water. This solution was stirred at 20° C. for 30 minutes, then the resulting solid was collected and washed with water. The residue was dissolved in 150 ml of dichloromethane and washed with 100 ml of saturated aqueous sodium bicarbonate. The organic layer was separated, dried and the volatiles removed in vacuo. The residue was dissolved in a small amount of dichloromethane and passed through a short pad of hydrous magnesium silicate, eluting with dichloromethane:hexane 1:1). The solids which were obtained were recrystallized from dichloromethane/hexane, giving 4.1 g of the desired intermediate as yellow crystals, mp 188°-189° C.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][C:14]1[S:15][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=2)=[CH:17][N:18]=1>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:19][C:16]2[S:15][C:14]([NH:13][C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])=[N:18][CH:17]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Di-t-butylcarbonate (4.36 g, 20 mmol) was added to a stirred solution of 2-amino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.33 g, 5 mmol) and 4-N,N-dimethylaminopyridine (62 mg, 0.5 mmol) in THF (120 mL). The solution was stirred at rt. for 6 h and concentrated. The residue was purified using flash column chromatography on silica gel. Elution with 10% EtOAc in hexanes followed by 25% EtOAc in hexanes afforded a mixture of the titled compound and the corresponding bis(tert-butoxycarbonyl)amino adduct (1.8 g) as an oil.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH3:6][C:7]1([CH3:15])[C:12](=O)[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8]1.C([BH3-])#[N:17].[Na+]>CO>[NH2:17][CH:12]1[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8][C:7]1([CH3:15])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CC1CNCC(C)(C)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CNCC(C)(C)C1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 3,3,5-trimethyl-4-piperidone (0.8 g, 5.67 mmol) in methanol (20 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.25 g, 3.96 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer, was basified with 1 M sodium hydroxide solution (pH 10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-3,3,5-trimethylpiperidine. Yield 0.45 g (54%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[CH3:23]C1C=C(C=CC=1)C(Cl)=O>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[C:17]([CH3:23])[CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)c1

Procedure:
This compound was prepared analogously to Intermediate A by replacing benzoyl chloride (step 2) with 3-methylbenzoyl chloride (commercial).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[C:9]([CH3:10])=[CH:14][N:15]([CH3:16])[CH3:17])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)c1ccc(Cl)cc1
Product: CC(=CN(C)C)C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 50.0 g of p-chloropropiophenone and 200 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 28 hours. The reaction mixture was evaporated in vacuo to give a yellow oil. The oil was then subjected to Kugelrohr distillation. The residual oil from the distillation was collected and triturated with hexane to provide crystals. The solid was collected by filtration and gave 21.5 g of 4'-chloro-3-dimethylamino-2-methylacrylophenone as yellow crystals, m.p. 45°-47° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:44]>>[Cl:44][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCCl)cc1

Procedure:
To tert-butyl 2-{2-[4-(2-hydroxyethyl)phenoxy]ethoxy}ethylcarbamate (0.56 g, 1.7 mmol) dissolved in 10 ml carbon tetrachloride was added triphenylphosphine bound on styrene (861 mg, 2.6 mmol of about 3 mmol/g resin). The reaction mixture was heated to reflux for 2 hours. After the required time the reaction was cooled and filtered. After drying a quantitative yield of product was isolated. 1H NMR (CDCl3) δ 7.11 (d, 2H, Ar), 6.86 (d, 2H, Ar), 4.95 (bs, exchangeable, NH), 4.08 (dd, CH2—O), 3.79 (dd, CH2—O), 3.65 (t, CH2—Cl), 3.59 (t, CH2—O), 3.32 (bm, CH2—NH), 2.99 (t, CH2—Ar), 1.70 (bs, exchangeable, OH) 1.42 (s, 9H, CH3). Mass spectrum, m/e Calcd for C17H27ClNO4+: 344.16 (100%), 346.16 (32%). Found: 344.57, 346.55.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C.P(=O)(O)(O)O>O>[CH2:7]1[CH2:8][C:9](=[O:11])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6]1
Reactant: O=C(O)CCCc1cccs1
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1CCCc2sccc21
Yield: 88.9 %

Procedure:
4-(2-Thienyl)butyric acid (28.42 g, 167 mmol) was placed in a round bottom flask with acetic anhydride (30 mL) and phosphoric acid (0.6 mL), and heated to reflux for 3.2 hours. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (22.60 g) which was vacuum distilled (1 mm Hg, 107°-115° C.) to give a white solid (13.08 g, 51%): mp 34°-40° C.); 1H NMR (CDCl3) 300 MHz 7.29 (d, J=5.2 Hz, 1H), 6.99 (d, J=5.2 Hz, 1H, 2.95 (t, J=6.0 Hz, 2H), 2.47(m, 2H), 2.13(m, 2H). M+H=153.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]2=[O:18])=[N:7][CH:8]=1.Cl.N1C=CC=CC=1>ClCCl>[OH:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14]2=[O:15])=[N:7][CH:8]=1
Reactant: COc1cnc(N2C(=O)CC(C)(C)CC2=O)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(=O)N(c2ncc(O)cn2)C(=O)C1
Temperature: 190 °C
Yield: 64.2 %

Procedure:
A mixture of 1-(5-methoxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione (0.99 g, 3.97 mmol) and pyridine hydrochloride (1.50 g, 7.99 mmol) was heated at 190° C. for 2.5 hours. After cooling to room temperature the reaction mixture was dissolved in a small amount of dichloromethane and filtered over a short pad of silicagel and washed with ethyl acetate. Evaporation of the solvent in vacuo yielded the title compound (0.60 g, 64% yield) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.[CH2:11]([O:18][C:19]([NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](O)=[O:30])[CH2:25][CH2:24]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N=C=NCCCN(C)C)C.Cl.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:20])[NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](=[O:30])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:25][CH2:24]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-chloropyrazin-2-yl)methanamine hydrochloride (5 g, 21.38 mmol), (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (6.23 g, 21.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (4.51 g, 23.52 mmol), 1-hydroxy-7-azabenzotriazole (1.455 g, 10.69 mmol), and triethyl amine (4.76 ml, 34.2 mmol) in dichloromethane (60 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane with gradient 0.5 to 5% of methanol) to yield benzyl((trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl)methylcarbamate (8.79 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH3:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21]>>[F:11][C:10]1[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][N:25]=[C:17]([CH3:16])[CH:18]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH3:15])[CH3:14]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)c(F)c21
Reactant: Cc1cc(C(=O)O)ccn1
Product: Cc1cc(C(=O)Nc2ccc3c(c2F)N(C)C(=O)C3(C)C)ccn1

Procedure:
Prepared in analogy to example 26 from 6-amino-7-fluoro-1,3,3-trimethylindolin-2-one (example 13d) and 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.