Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([NH:14][C:15]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[NH2:18][CH2:17][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 ml of dichloromethane and 20 ml of trifluoroacetic acid were added to 687 mg (2.74 mmol) of t-butyl phenylcarbamoylmethylcarbamate, and they were stirred at room temperature for 3 hours. Dichloromethane and trifluoroacetic acid were evaporated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue. After the extraction with ethyl acetate and then with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1.O>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:18][C@H:15]1[CH2:16][CH2:17][O:13][CH2:14]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.05 mL) and methanesulfonyl chloride (1.05 mL) were added to a solution of (S)-tetrahydrofuran-3-ol (1.0 g) in toluene (10 mL), and the reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, then the reaction solution was extracted with toluene and washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum to obtain (S)-tetrahydrofuran-3-yl methanesulfonate as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][C:15]([OH:18])([CH3:17])[CH3:16]>>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)(O)CCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(C)(C)O
Yield: 51 %

Procedure:
The compound was also obtained, inter alia, by a two-stage synthesis from 3-methylxanthine, which was first reacted with 1-chloro-2-hydroxy-2-methylpropane to give 7-(2-hydroxy-2-methylpropyl)-3-methylxanthine (melting point: 268°-269° C.; yield 51% of theory), the product then being alkylated in the 1-position with 1-chloro-5-hydroxy-5-methylhexane from Example 1a analogously to Example 5b to give the end product (yield: 79.5% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10](I)[C:3]=12.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16][CH:15]1[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10]([C:20]3[CH:21]=[C:22]4[C:17]([CH2:16][CH:15]([CH3:32])[N:14]4[CH3:13])=[CH:18][CH:19]=3)[C:3]=12
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2N1C
Reactant: Cn1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: CC1Cc2ccc(-c3cn(C)c4nccc(Br)c34)cc2N1C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
4-Bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) (1.1 g, 3.26 mmol), 1,2-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (970 mg, 3.55 mmol), bis(triphenylphosphine) palladium(II) chloride (0.229 g, 0.326 mmol) and 2M sodium carbonate aqueous solution (16.32 mL, 32.6 mmol) were suspended in DMF (10 mL), ACN (10 mL) and DCM (5 mL). This was degassed under nitrogen for 10 mins before being heated to 70° C. and left stirring at this temperature for 30 mins. The reaction mixture was partitioned between ethyl acetate/water (ca. 40 mL each). The aqueous layer was separated and extracted with ethyl acetate (ca. 25 mL twice). The combined organic layer were dried over MgSO4 and concentrated. The residue was purified using chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford title compound (544 mg). LCMS (A): m/z (M+H)+ 356/358, C18H18BrN3 requires 355/357 (acidic).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[O:20])[N:15]=[C:16](I)[C:3]=12.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[O:20])[N:15]=[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[C:3]=12
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Yield: 30.6 %

Procedure:
Nitrogen was bubbled through a suspension of 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (70 mg, 0.144 mmol), 4-fluorophenylboronic acid (22 mg, 0.158 mmol) and K3PO4 (92 mg, 0.43 mmol) in DMF (1.1 mL) and water (0.4 mL) for 20 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.014 mmol) was added and the tube sealed and heated using microwave irradiation to 60° C. for 30 min. The crude reaction mixture was filtered and partially purified by preparative HPLC. The residue was purified by chromatography (silica gel, isohexane/ethyl acetate 1:0 to 7:3) to provide Compound 1 (20 mg).
Reaction SMILES: C([O:3][C:4](=[O:31])[C@:5]([F:30])([CH3:29])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])C.O.[OH-].[Li+]>O1CCCC1.O>[CH:18]1([CH2:17][N:14]2[C:15](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[C@@:5]([F:30])([CH3:29])[C:4]([OH:31])=[O:3])[C:10]3[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=3[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]2=3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Yield: 87.3 %

Procedure:
0.22g (0.52 mmol) (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid ethyl ester in 3 ml tetrahydrofurane was reacted with a solution of 0.02 g (0.52 mmol) lithium hydroxide monohydrate in 1 ml water at room temperature for 2 hours. Evaporation of the tetrahydrofurane, extraction with diethylether, acidification with 0.5 ml 1 N aqueous hydrochloric acid and extraction with ethylacetate gave 0.18 g (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid as white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].[C:11](#[N:13])[CH3:12]>O1CCCC1.O>[C:4]([C:5]([CH2:12][C:11]#[N:13])=[O:6])([CH3:10])([CH3:9])[CH3:3]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of 9.6 g of sodium hydride in 300 ml of tetrahydrofuran was stirred at 60° C. while a mixture of 23.2 g of methyl trimethylacetate and 8.2 g of acetonitrile was added in one portion. The reaction mixture was heated at reflux for five hours, and then cooled to room temperature and concentrated by evaporation of the solvent under reduced pressure. The product thus formed was dissolved in water and washed with dichloromethane. The aqueous layer was made acidic with 1N hydrochloric acid, and the acidic solution was extracted with fresh dichloromethane. The organic extracts were combined, washed with water, dried, and the solvent was removed by evaporation to give 14.0 g of cyanomethyl tert.-butyl ketone.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([N:38]2[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]2)[CH3:37])[CH2:31][CH2:30]1>>[ClH:25].[ClH:25].[OH:44][CH:41]1[CH2:40][CH2:39][N:38]([C@@H:36]([CH3:37])[CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:34][CH2:33]2)[CH2:43][CH2:42]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(F)ccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:12])OCC)=[CH:4][CH:3]=1.[NH2:13][NH:14][CH:15]=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:15][NH:14][N:13]=2)=[CH:6][CH:7]=1
Reactant: NNC=O
Reactant: CCOC(=N)c1ccc(Br)cc1
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2nc[nH]n2)cc1

Procedure:
Into a 1000 mL 3-necked flask, was placed a solution of ethyl 4-bromobenzenecarboximidoate (54.0 g, 237 mmol) in xylene (500 mL) To the mixture was added NH2NHCHO (14.22 g, 237 mmol). The resulting solution was heated to reflux overnight. The reaction mixture was cooled in an ice bath and filtered. The solid was washed with 700 mL of petroleum ether and dried in an oven under reduced pressure to afford 3-(4-bromophenyl)-1H-1,2,4-triazole (crude) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)=[O:26].O1CCOCC1.C([O-])(O)=O.[Na+]>[Pd].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:7](=[O:18])[CH:6]4[CH2:19][O:20][CH2:21][CH2:22][N:5]4[C:4]=3[N:3]=2)=[CH:30][CH:29]=1)=[O:26]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2C(=O)N3C2CCOCC2)cc1
Temperature: 120 °C
Yield: 8.2 %

Procedure:
To a 5 mL microwave vial were added 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x55, 190 mg, 0.585 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (404 mg, 1.463 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (24.07 mg, 0.029 mmol). After the vial was sealed, dioxane (2 mL) and aqueous saturated NaHCO3 (0.500 mL) were added, and the mixture was degassed by bubbling nitrogen through a syringe needle for 10 minutes. The mixture was heated in a microwave to 120° C. for 60 minutes. Since the reaction was not complete, another 0.025 equivalents of palladium catalyst were added, and the mixture was heated in the microwave to 130° C. for another 60 minutes. DMF (1 mL) was added and the mixture was filtered by syringe filter. The crude product was purified by preparatory HPLC using a gradient of 15-25% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave the title compound as a white powder (21 mg, 8.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.56-1.74 (m, 2H), 2.58-2.69 (m, 4H), 2.97 (td, J=12.8, 3.8 Hz, 1H), 3.41 (t, J=10.9 Hz, 1H), 3.47-3.63 (m, 3H), 3.88-4.05 (m, 3H), 4.14-4.24 (m, 2H), 4.39 (d, J=11.9 Hz, 2H), 6.05-6.15 (m, 1H), 7.45-7.55 (m, 2H), 8.15-8.23 (m, 2H), 8.46 (s, 1H), 8.75 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C22H26N6O4, 439.2. found 439.5.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH3:15])=[CH:11][CH:12]=1
Reactant: CCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-1-methyl-5-(4-n-propylphenyl)-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.166 mmol, 72.2 mg), methanol was added, and 1 M aqueous sodium hydroxide (5 eq., 0.831 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.831 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was recovered by filtration and dried to give the desired product as a yellow solid (47.1 mg, yield 670).
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][NH:9][C:10]([NH:12][NH2:13])=[S:11]>CO>[CH:1](=[N:8][NH:9][C:10]([NH:12][NH2:13])=[S:11])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: NNC(=S)NN
Solvent: CO
Product: NNC(=S)NN=Cc1ccco1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
24 g of furfural and 26.5 g of thiocarbohydrazide in 150 ml of methanol are vigorously stirred. Stirring is continued for 30 minutes after the exothermic reaction has died down. The precipitate is suction filtered and recrystallised from methanol. 30.1 g of furfurylidene thiocarbohydrazide, melting at 186° to 187° C. are obtained.
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.[NH2:22][C@@H:23]([CH2:27][CH2:28][S:29][CH3:30])[C:24]([NH2:26])=[O:25]>>[C:24]([C@@H:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:27][CH2:28][S:29][CH3:30])(=[O:25])[NH2:26]
Reactant: CSCC[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CSCC[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-4-(methylthio)-butanamide, monohydrochloride (CAN 14510-08-1) as starting materials. MS (EI): m/e=415.16 [M+H]+.
Reaction SMILES: B.[C:2]([N:12]1[CH2:19][CH:18]([OH:20])[CH2:17][C@H:13]1[C:14](O)=[O:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].O.Cl>C1COCC1>[OH:15][CH2:14][C@@H:13]1[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To 200 ml (0.2 mol) of borane. THF complex was added 27.8 g (0.1 mol) of 1-(carbobenzyloxy)-4-hydroxy-L-proline in 50 ml of THF at 0° C. After 16 hours of stirring at room temperature, 100 ml of water was added carefully followed by 12 ml of 6N aqueous HCl solution and the mixture was extracted with 3×100 ml of methylene chloride. The combined organic extracts were dried over MgSO4 and evaporated to yield 22.6 g of the product (oil, 90% yield). NMR(CDCl3): 7.40 (m,5H), 5.10 (m,2H), 4.90 (m,1H), 4.65 (m,1H), 4.35 (m,1H), 4.17 (m,1H), 3.60 (m,3H), 2.05 (m,1H), 1.70 (m,1H).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[C:4]1=[O:17].[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>>[ClH:1].[CH:18]1([NH:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=3[O:13][CH3:14])[C:4]2=[O:17])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Cl
Product: COc1ccc2c(c1OC)CCC(NC1CCC1)C2=O

Procedure:
In a manner similar to that of Reference Example 3, 10.5 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is reacted with 10 volume parts of cyclobutanone. The procedure yields 8.2 parts of 2-cyclobutylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride. Melting point: 146°-164° C (decomposition).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O)([O:41][CH3:42])=[O:40].O>O1CCCC1>[CH3:42][O:41][C:39](=[O:40])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:28][CH:27]=1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CCCCCCCC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCC=Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 18.2 g (43 mmol) of 4-chlorobenzyltriphenylphosphonium chloride in 200 mL of dry tetrahydrofuran at -78° C. is added dropwise, 30.7 mL (43 mmol) of a 1.4M solution of potassium hexamethyldisilazide in tetrahydrofuran. This is allowed to stir for 1 hour when 8.0 g (43 mmol) of 8-carbomethoxyoctanal is added dropwise. The solution is stirred at -78° C. for 2 hours, allowed to warm to room temperature, and stirred for 2 days. The reaction is worked up by adding water and extracting three times with diethyl ether. The ether extracts are combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. Pad filtration through flash silica gel eluting with 10% ethyl acetate/hexane, gives a yellow oil after concentration in vacuo. Flash chromatography on a 60 mm×150 mm silica column eluting with 5% ethyl acetate/hexane gives 1.62 g (13%) of 10-(4-chlorophenyl)-dec-9-enoic acid methyl ester as a mixture of E and Z isomers.
Reaction SMILES: Br[CH2:2][C:3]1C=C(C#N)C=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].C(C1C=CC(C(OC)=O)=C(C)C=1)#N.[CH2:28]1[C:33](=O)[N:32](Br)[C:30](=[O:31])[CH2:29]1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O.CCOC(C)=O>[O:31]=[C:30]1[C:29]2[C:28](=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][CH:2]=2)[CH2:33][NH:32]1
Reactant: COC(=O)c1ccc(C#N)cc1CBr
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COC(=O)c1ccc(C#N)cc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
methyl 2-(bromomethyl)-4-cyanobenzoate. To a stirred solution of methyl 4-cyano-2-methylbenzoate (1 g, 5.7 mmol) in CCl4 (30 mL), was added NBS (1.4 g, 6.2 mmol), and catalytic AIBN. The reaction mixture was stirred for 48 h at 80° C. The reaction progress was monitored by TLC (10% EtOAc in hexanes). The reaction was cooled to room temperature and diluted with water (25 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography silica (60-120 mesh silica with 80-100% EtOAc in petroleum ether) as eluent to give the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 7.6 (d, J=8.0 Hz, 1H), 4.9 (s, 2H), 4.0 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:27]>CN(C=O)C.O>[C:3]([O:7][C:8]([N:10]([CH3:27])[C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of 60% dispersion of sodium hydride in mineral oil (1.5 g, 37.5 mmol) in anhydrous DMF (20 mL) cooled on an ice-bath to 0° C. was added dropwise a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (10 g, 31.2 mmol) in anhydrous DMF (100 mL). The resulting mixture was stirred at 0° C. for 1 hour then at ambient temperature for 2 hours. The mixture was subsequently cooled to 0° C. and treated dropwise with iodomethane (2.1 mL, 34.3 mmol), and the mixture stirred at 0° C. for 1 hour then warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with water (300 mL) and the mixture extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Biotage, 65M; 10-20% ethyl acetate:hexanes) to afford (S)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate (7.2 g, 69%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([N:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20]([OH:27])=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=2)[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O>[C:11]([C:9]1[CH:8]=[C:7]([N:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20]([OH:27])=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1)([OH:13])=[O:12]
Reactant: COC(=O)c1cc(N=Nc2ccc(O)c(CC(=O)O)c2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cc(N=Nc2cc(C(=O)O)cc(C(=O)O)c2)ccc1O

Procedure:
12 g of 5-(3,5-bis-(methoxycarbonyl)-phenylazo)-2-hydroxyphenylacetic acid, 350 ml of water and 7 g of sodium hydroxide were boiled for 1 hour. 50 ml of ethanol was added, and the solution was diluted with water to 500 ml. The hot solution was acidified with hydrochloric acid to pH 2 and cooled. The crystals were filtered off, washed with water and dried.