Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C.[C].[Pd]>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:5]1[NH:4][CH:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)[nH]c1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccccn2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
Ethyl 2-chloro-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate hydrochloride (2.73 g) was dissolved in ethanol (200 mL), and 10% palladium carbon (50% containing water, 2.73 g) was added under a nitrogen atmosphere. Under a hydrogen atmosphere, the mixture was stirred at 50° C. for 15 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as colorless crystals (yield 1.73 g, 84%).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=3)[C:10](=O)[C:9]=2[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=3)[C:10](=[CH2:1])[C:9]=2[CH:8]=1
Reactant: Cc1ccc2c(=O)c3cc(Br)ccc3oc2c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2ccc(C)cc2Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2664 mg, 7457 μmol) in THF (19 ml) at 0° C. was added butyllithium (1.6 M in Hexanes, 3995 μl, 6392 μmol) dropwise. After stirring at 0° C. for 30 minutes, a solution of 2-bromo-6-methyl-9H-xanthen-9-one (1540 mg, 5326 μmol) in THF (5 ml) was added dropwise. The solution was allowed to warm to RT and stirred for 1 hour. The reaction mixture was quenched with water and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude product was flashed with the MPLC (100% hexanes to 10% EtOAc in hexanes to 30% EtOAc in hexanes) MS m/z=289.1 [M+H]+. Calc'd for C15H11BrO2: 287.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:10](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21
Yield: 90.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-phenylamino-4,5,6,7-tetrahydroindazol-4-one (0.4 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.31 ml), water (0.31 ml) and ethanol (20 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethylacetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (5 ml) and concentrated. Precipitated crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-phenylamino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 146) (0.23 g) as colorless crystals.
Reaction SMILES: C(=O)(O)[O-].[Na+].[S:6]=[C:7]1[NH:11][CH2:10][N:9]=[N:8]1.C(O[CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:35])[CH:21]2[NH:25][C:26](=[O:34])[CH2:27][C:28]2[S:29][C:30](=[O:33])[S:31][CH:32]=2)[C:18]=1[C:36]([OH:38])=[O:37])(=O)C>>[C:36]([C:18]1[N:19]2[CH:22]([S:23][CH2:24][C:17]=1[CH2:16][S:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)[CH:21]([NH:25][C:26](=[O:34])[CH2:27][C:28]1[S:29][C:30](=[O:33])[S:31][CH:32]=1)[C:20]2=[O:35])([OH:38])=[O:37]
Reactant: S=C1N=NCN1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1csc(=O)s1)NC1C(=O)N2C(C(=O)O)=C(CSc3nc[nH]n3)CSC12
Temperature: 60 °C
Yield: 20.5 %

Procedure:
Sodium bicarbonate (5.55 g.) and 3-thioxo-1,2,4-triazoline (3.63 g.) are added to 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (12.9 g.) in a buffer (250 cc.) of pH 6.4. The mixture is heated to 60° C. for 7 hours. It is allowed to cool, sodium bicarbonate (1 g.) is added and the mixture is washed with ethyl acetate (250 cc.), which is discarded. The aqueous solution is treated with decolourising charcoal and is acidified to pH 2 by adding 4 N hydrochloric acid in the presence of ethyl acetate (200 cc.). The organic phase is separated off and the aqueous phase is then extracted with ethyl acetate (750 cc.). The combined organic extracts are dried over sodium sulphate, treated with decolourising charcoal and concentrated to dryness under reduced pressure (20 mm Hg). A residue (5.5 g.) is obtained, which is triturated with acetonitrile (25 cc.). The solid is filtered off and washed with acetonitrile (25 cc.) and isopropyl ether (20 cc.) to give 2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-3-[(1,2,4-triazol-3-yl)-thiomethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2.9 g.), m.p. 227° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1[CH:32]=[C:31]([CH3:33])[N-:30][N:29]=1
Reactant: Cc1cc(C)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)[C@@H]1CC(OCc2ccccc2)CN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)[n-]n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyloxycarbonyl-4-benzyloxy-L-proline (4.55 g.) [obtained from 4-benzyloxyproline [Biochem. Biophys. Acta 303, 198 (1973)] and benzyloxycarbonyl chloride] and 3,5-dimethylpyrazole (1.15 g.) are dissolved in chloroform (200 ml.). Dicyclohexylcarbodiimide (2.06 g.) is added and the mixture is stirred in an ice-salt bath for one hour and at room temperature for 16 hours. The precipitate is filtered and the filtrate is concentrated to dryness. The residue is dissolved in ethyl acetate, washed with N-hydrochloric acid and water. The organic layer is dried and concentrated to dryness in vacuo to yield 1-benzyloxycarbonyl-4-benzyloxy-L-proline-3,5-dimethylpyrazolide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:41]([C:40]3[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[O:42])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccc(OC)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 4-methoxybenzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H39N2O3Cl2 [(M+H)+] 629.2332, observed 629.2337.
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])#[N:4].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br>CN(C)C=O>[CH2:12]([O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[C:3]#[N:4])[CH:14]1[O:16][CH2:15]1
Reactant: BrCC1CO1
Reactant: N#C[C@@H]1CCCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1CCCCC1OCC1CO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 60 mg, 1.59 mmol) was added to a solution of trans-2-cyanocyclohexanol in N,N-dimethylformamide (2.0 mL) and stirred for 10 minutes at room temperature. Epibromohydrin (0.22 g, 1.59 mmol) was then added and the reaction stirred for an additional 3 hours. The solution was partitioned between diethyl ether/water, and the layers separated. The ether layer was washed with water (3×100 mL) and dried over magnesium sulfate and evaporated to give 0.17 g of 2-cyanocyclohexyl glycidyl ether.
Reaction SMILES: [C:1]1(/[C:7](/[CH2:37][CH3:38])=[C:8](\[C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=2)/[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.Cl>[NH:14]1[C:15]2[C:11](=[CH:10][C:9](/[C:8](/[C:24]3[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=3)=[C:7](/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)\[CH2:37][CH3:38])=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]ncc3c2)cc1
Temperature: 70 °C

Procedure:
To a solution of (E)-ethyl 3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (3.5 g, 69 mmol) in ethyl alcohol (69 mL), HCl (6 mL, 2M in diethyl ether) was added at room temperature. The resulting mixture was then heated at 70° C. for 2 h. Upon completion, the mixture was cooled down to room temperature and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-100% ethyl acetate in hexanes affording an off-white solid (2.5 g). 1H NMR (300 MHz, DMSO-d6): δ 13.10 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.48 (d, 1H), 7.39 (d, 2H), 7.27-7.11 (m, 6H), 6.89 (d, 2H), 6.45 (d, 1H), 4.20 (q, 2H), 2.43 (q, 2H), 1.22 (t, 3H), 0.87 (t, 3H); LCMS: 423 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:30][CH3:31])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNCc2ccc([C@H]3COc4ccccc4O3)cc2)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(Cc1ccc(C(=O)OC)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzylamino]-methyl}-benzoic acid methyl ester (prepared according to General Method E) (130 mg, 0.33 mmol), acetaldehyde (0.03 mL, 0.50 mmol), and sodium cyanoborohydride (42 mg, 0.67 mmol) in MeOH (15 mL) is treated with 2 drops of acetic acid. The mixture is stirred at room temperature for 16 h, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give 4-({[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-ethyl-amino}-methyl)-benzoic acid methyl ester.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:22]2[CH2:23][CH2:24][CH:19]([C@@H:17]([NH:16][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:18])[CH2:20][CH2:21]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)n1
Yield: 1.3 %

Procedure:
A solution of (S)-4-isopropyl-3-(2-((S)-1-(piperidin-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (225 mg, 0.675 mmol), 4-fluorobenzene-1-sulfonyl chloride (146 mg, 0.750 mmol) and DIPEA (1 ml) in CH2Cl2 was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water. Aqueous layer was extracted with CH2Cl2. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (S)-3-(2-((S)-1-(1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (4.5 mg, 0.009 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:36]#N)[C:11]([O:22][CH:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:24]([O:26][CH3:27])=[O:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].C1C[O:53]CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:36](=[O:53])[C:23]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=4)([C:24]([O:26][CH3:27])=[O:25])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Oc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N)c1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Product: COC(=O)C1(c2ccc(F)c(F)c2)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 1.20 g (2.14 mmol) the product of Step A dissolved in 12 mL of THF was slowly added 3.2 mL of a 1.0 N solution (3.2 mmol) of lithium bis(trimethylsilylamide) in THF at 0° C. The reaction mixture was stirred for 30 min and allowed to warm to room temperature. The reaction mixture was then quenched by addition of excesss 10% aqueous NaHSO4 and extracted into EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with chloroform. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])#[N:2].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1>N1C=CC=CC=1>[OH:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=1
Reactant: N#CCC(=O)NCCCCCC(=O)O
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#CC(=Cc1ccc(O)cc1)C(=O)NCCCCCC(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
7.5 g (38 mmol 6-(cyanacetamido) hexanoic acid was dissolved in 50 ml pyridine. 4.6 g (38 mmol) 4-hydroxybenzaldehyde and 0.7 ml (7 mmol) piperidine were added to the solution and the reaction mixture was stirred for 2 hours at 50° C. A further aliquot of 0.4 ml piperidine was then added to the reaction and the solution was stirred at RT for 60 hours. The residue after evaporation of the pyridine was acidified with HCl (2N) and was extracted with ethyl acetate. The organic layer was poured into 300 ml of a saturated solution of sodium hydrogen carbonate. The aqueous layer was then carefully acidified with HCl (2N). The precipitated residue was filtered and washed with water. The dried product was crystallized from dioxane.
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([O-:10])=[O:9])=[CH:5][CH:4]=1.[Na+].[PH2]([O-])=O.[K+].[PH2](O)=O.Cl>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Solvent: O
Product: O=C(O)Cc1ccc(O)cc1
Temperature: 143 °C
Yield: 67 %

Procedure:
A stirred mixture of sodium p-hydroxymandelate monohydrate (21.2 g.), potassium hypophosphite (52 g.), 50% w/v aqueous hypophosphorous acid (2.2. ml.) and water (10 ml.) is heated under reflux for 22 hours (internal temperature 143° C.) and then cooled. The mixture is diluted with water, acidified with hydrochloric acid and extracted with methyl isobutyl ketone. p-Hydroxyphenylacetic acid, which is formed in 67% yield, is isolated from the extract by conventional means.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1C2C(=CC=C(N)C=2)C=C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (6-amino-indol-1-yl)-acetic acid ethyl ester (prepared in two steps from 6-nitroindole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.33 (1H, s), 7.92 (1H, s), 7.45 (3H, m), 7.28 (1H, m), 7.02 (2H, m), 6.58 (1H, dd), 6.47 (1H, t), 4.84 (2H, s), 4.68 (2H, m), 4.40 (1H, d), 4.18 (1H, d), 2.78 (1H, m), 2.02-1.15 (19H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.25; H, 7.41; N, 10.61%; C32H37N5O5.C7H17NO5.2.0H2O requires: C, 58.38; H, 7.28; N, 10.47%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1)#[N:2].C[Si]([N:22]=[N+:23]=[N-:24])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:22]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[O:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=3[CH:17]=2)=[N:2][N:24]=[N:23]1
Reactant: COC(=O)C1=Cc2cc(C#N)ccc2OCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3nnn[nH]3)ccc2OCC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
In toluene (15 ml) was suspended methyl 7-cyano-2,3-dihydro-1-benzoxepine-4-carboxylate (642 mg, 2.80 mmol), and to the mixture were added trimethylsilylazide (0.929 ml, 7.00 mmol) and dibutyl tin oxide (70 mg, 0.28 mmol). The mixture was stirred at 100° C. for 24 hours and concentrated under reduced pressure. To the residue was added methanol, and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was extracted with saturated sodium bicarbonate solution (30 ml, 10 ml×2). To the aqueous layer was added 6N hydrochloric acid to make the solution about pH 1, and the mixture was extracted with ethyl acetate and THF ((30 ml50 ml) and (10 ml/10 ml)×2). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure, to the residue was added ethyl acetate. Insoluble materials were filtered, which were washed with ethyl acetate and dried under reduced pressure to give methyl 7-(1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (662 mg, 2.43 mmol, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].[BH4-].[Na+]>C(O)(=O)C>[CH2:33]([N:35]([CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH:9]2[NH:10][C:11]3[C:12]4[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:29][CH:28]=1)[CH2:36][CH3:37])[CH3:34]
Reactant: CCNCC
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a stirred solution of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (260 mg, 0.68 mmol) in dryness DCM (15 mL) was added acetic acid (0.2 mL) followed by diethylamine (148 mg, 2.03 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium borohydride (212 mg, 1.01 mmol) was added to the mixture at 0° C. The mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by flash chromatography to give the title compound as white solid (27.3 mg, yield 9%). LC-MS (ESI) m/z: 442 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.12-3.17 (m, 4H), 4.27 (s, 2H), 4.34 (d, 1H), 4.78 (d, 1H), 6.91 (t, 2H), 7.09-7.12 (m, 1H), 7.38-7.45 (m, 4H), 7.56-7.58 (m, 1H), 7.64 (t, 1H).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][C:27]([CH3:32])=[CH:28][CH2:29][CH2:30][OH:31]>CN(C=O)C>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([O:31][CH2:30][CH2:29][CH:28]=[C:27]([CH3:32])[CH3:26])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CC(C)=CCCO
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCCOc1cncc(Nc2ccc(I)cc2F)c1C(N)=O
Temperature: 70 °C
Reaction time: 24 h

Procedure:
500 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.253 mmol, 1. eq.) were dissolved in 5 ml of DMF, then 1225 mg of cesium carbonate (3.759 mmol, 3 eq.) and 125 mg of 4-methyl-3-pentene-1-ol (0.253 mmol, 1 eq.) were added. The resulting mixture was stirred at 70° C. bath temperature for 24 hours. Since the reaction was not complete, the mixture was stirred for another 2 days at 70° C. bath temperature. Since the reaction was not complete, another 125 mg of 4-methyl-3-pentene-1-ol (0.253 mmol, 1 eq.) and 408 mg of cesium carbonate (0.253 mmol, 1 eq.) were added, and the mixture was stirred for another 2 days at 70° C. bath temperature. The resulting mixture was partitioned between aq. NH4Cl solution (50 ml) and dichloromethane (50 ml). The phases were separated and the aqueouse layer was reextracted twice with dichloromethane (50 ml each). The combined organic layers were washed with brine (50 ml), dried over a silicone filter and concentrated in vacuo. The residue was suspended in ethyl acetate and stirred for 1 h, after which the precipitate was filtered off and dried in vacuo to yield 252 mg (0.52 mmol, 42%) of the analytically pure target compound.