Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34].CNC[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O[N:45]1[C:49]2C=CC=C[C:48]=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:48][CH2:49][N:45]([C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[C:28]([C:25]1[N:17]2[C:16]([CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:31]=[CH:32][C:8]([C:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([OH:1])[C:3]=4[CH3:34])=[C:9]([CH3:33])[CH:10]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18]2)=[CH:27][CH:26]=1)=[O:29]
Reactant: On1nnc2ccccc21
Reactant: CNCc1cccnc1
Reactant: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)O)n4Cc4ccccc43)cc2C)CCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(C(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=C(C)[C@H](O)CCC3)c(C)c1)C2)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
10-[4-((3R)-3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C (0.250 g, 0.548 mmol), 3-(methylaminomethyl)pyridine (0.080 mL, 0.658 mmol), 1-hydroxy benzotriazole (0.081 g, 0.603 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.116 g, 0.603 mmol) were combined in amine-free N,N-dimethylformamide (2.2 mL), followed by addition of N,N-diisopropylethyl amine (0.143 mL, 0.822 mmol). The reaction was stirred at room temperature for 18 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 8% of methanol in chloroform, to afford 0.270 g of the title compound as an oil which was dissolved in diethyl ether and precipitated with petroleum ether to afford a white solid, m.p.100-144° C., [α]589=+18.49 (c=1.0, chloroform).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[O:14]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH2:31][C:30]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 169.3 %

Procedure:
To a solution of 4-phenoxybenzoic acid (10.4 g, 48.7 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (8.68 g, 53.6 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (7.67 g, 26.8 mmol), and the mixture was stirred at room temperature for 2 hrs. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (12.9 g, 93%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C

Procedure:
After dissolving 2-amino-3-nitrobenzoic acid (1.00 g, 5.49 mmol) in methanol (40 ml), sulfuric acid (0.50 ml) was added and the mixture was heated to reflux for 2 days. The reaction mixture was cooled to room temperature, and then the pH was adjusted to approximately 9 with saturated aqueous sodium bicarbonate and the mixture was concentrated under reduced pressure to approximately 10 ml. Water (20 ml) was added, the mixture was extracted with ethyl acetate (10 ml×3 times), and the obtained organic layer was dried over anhydrous magnesium sulfate. It was then concentrated under reduced pressure, and the produced crystals were dried to obtain 2-amino-3-nitrobenzoic acid methyl ester. The compound was identified by NMR.
Reaction SMILES: [CH:1]1([N:6]([CH3:30])[C:7]2[N:8]=[C:9]3[C:15]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:14][N:13](COCC[Si](C)(C)C)[C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O.O.O.C([O-])(=O)C.[Na+]>ClCCl>[CH:1]1([N:6]([CH3:30])[C:7]2[N:8]=[C:9]3[C:15]([C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(c1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C)C1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1)C1CCCC1
Reaction time: 16 h

Procedure:
A solution of impure 1-[2-(cyclopentyl-methyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, prepared according to general procedures as described in these Examples, (0.030 g, 0.071 mmol) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 3 h, then concentrated, chasing with toluene, to a yellow oil. The oil was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.103 g, 0.760 mmol). The yellow mixture was stirred for 16 h, then concentrated to a yellow solid. Column chromatography (two columns: first run, 0→40% EtOAc/hexanes; second run, 66% ether/hexanes) afforded 0.0045 g (21% from impure, 12% two-step) of 1-[2-(cyclopentyl-methyl-amino)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:64][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[CH:64][CH:63]=3)[C:57]([O:59][CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The methyl (2S)-2-amino-3-biphenyl-4-ylpropanoate (36 mg, 0.14 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (5 mg, 10%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=525.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.[CH3:16][C:17]1([CH3:30])[CH2:22][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][C:19]([CH3:29])([CH3:28])[NH:18]1.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:24]([N:23]([C:2]1[N:7]=[C:6]([N:23]([CH:21]2[CH2:22][C:17]([CH3:30])([CH3:16])[NH:18][C:19]([CH3:28])([CH3:29])[CH2:20]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1)[CH:21]1[CH2:20][C:19]([CH3:29])([CH3:28])[NH:18][C:17]([CH3:30])([CH3:16])[CH2:22]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCOC(=O)CNc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCN(c1nc(NCC(=O)OCC)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Yield: 96.3 %

Procedure:
2.36 g of ethyl N-(2,4-dichloro-1,3,5-triazin-6-yl)-glycinate [obtained as described in Preparation 4(A)], 4.19 g of 2,2,6,6-tetramethyl-4-(butylamino)piperidine [obtained as described in Preparation I(A)] and 2.77 g of sodium bicarbonate were heated under reflux in 20 ml of xylene for 29 hours. At the end of this time, the xylene was removed by distillation under reduced pressure, and a mixture of methylene chloride and water was added to the resulting residue, after which the mixture was shaken. The methylene chloride layer was separated, dried and concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using a 20:10:1:1 by volume mixture of hexane, diethyl ether, ethanol and triethylamine as eluent), to yield 5.46 g of the title compound melting at40° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([Br:28])[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:17][C:18]1[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:25]=[C:26]([Br:28])[CH:27]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: COC(=O)c1cc(N)cc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-Boc-trans-4-fluoro-L-proline (500 mg, 2.14 mmol), methyl 3-amino-5-bromobenzoate (592 mg, 2.57 mmol) and HBTU (1.22 g, 3.22 mmol) in DMF (6 mL) was added DIPEA (734 μl, 4.29 mmol) and the resulting solution was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane 100% to c-hexane/EtOAc 70:30) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:2)=0.8; MS (LC/MS): 467.0/469.0 [M+Na]+, 345.1/347.0 [MH−Boc]+, 443.1/445.1 [M−H]−; tR (HPLC conditions a): 3.77 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)C(Cl)=O.[CH2:15]([NH:19][SH:20](=[O:22])=[O:21])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[C:6]([S:20]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])=[O:21])[CH:5]=[C:4]([CH:11]=[O:12])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1C=O
Reactant: CCCCN[SH](=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNS(=O)(=O)c1cc(Br)c(OC)c(C=O)c1
Temperature: 25 °C
Yield: 103.1 %

Procedure:
5-Bromo-3-formyl-4-methoxybenzoyl chloride (501 mg, 1.8 mmol) was dissolved in in dichloromethane (5 mL) and the solution was added dropwise to a vigorously stirring solution of N-butylsulfonamide (272 mg, 2.0 mmol), triethylamine (2.5 mmol) and a catalytic amount of N,N′-dimethylaminopyridine (10 mL in dichloromethane). The mixture was stirred at room temperature until the reaction was complete and concentrated under reduced pressure. The residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the filtrate was evaporated to give 3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide as a white solid (650 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:12]2[CH:16]=[C:15]([CH2:17]O)[N:14]=[CH:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl.CN(C=O)C.CCCCCC>[Cl:3][CH2:17][C:15]1[N:14]=[CH:13][N:12]([C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Thionyl chloride (0.82 g) was added over 1 min. to a stirred suspension of 1-(triphenylmethyl)-1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1.0 ml) at 23°. The solution so obtained was stirred for 15 min. and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139°-141°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1COCC1>[ClH:12].[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cn1
Solvent: C1CCOC1
Product: Cc1ccc(CCl)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (6-methylpyridin-3-yl)methanol (1.24 g) in THF (12.4 mL) was added thionyl chloride (1.10 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was suspended in ethyl acetate. The precipitate was collected by filtration, and washed with ethyl acetate-hexane to give the title compound (1.64 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28]>N1C=CC=CC=1>[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH:28][C:4]([C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[NH2:1])=[O:6]
Reactant: Nc1cnccc1C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: COC(=O)CNC(=O)c1ccncc1N
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of 100 mg of 3-amino-isonicotinic acid in pyridine (2.5 mL) is added 117 mg of 1,1′-carbonyldiimidazole and the mixture is stirred for 20 min at 55° C. Then the mixture is cooled to room temperature and 91 mg of glycine methylester hydrochloride is added and the resulting mixture is stirred for 30 min at 55° C. and 1 h at room temperature. Then the solvent is removed under vacuum and the residue is purified by flash chromatography on silica gel to give 100 mg (66%) of [(3-amino-pyridine-4-carbonyl)-amino]-acetic acid methyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]2[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[O:19][C:13]=2[CH:12]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[F:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]2[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([O:27][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:24]([CH3:26])[CH:25]=3)[O:19][C:13]=2[CH:12]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
110 mg of potassium carbonate were added to a solution of 70 mg of 4-[6-(2-fluorophenoxy)oxazolo[4,5-c]pyridin-2-yl]-2,6-dimethylphenol in 1 ml of dimethylformamide, and 51 mg of tert-butyl bromoacetate were then added. The mixture was stirred at room temperature for 16 h. The reaction mixture was then added to water and extracted twice with ethyl acetate. The collected organic phases were dried and concentrated. This gave 93 mg (100%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=N)=[CH:6][CH:5]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[N:20]1C=CC=CC=1>>[ClH:1].[NH2:20][N:10]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([NH:3][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: c1ccncc1
Reactant: O=C1CCC(=O)O1
Reactant: N=C(N)c1ccc(N)cc1
Agent: Cl
Product: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1

Procedure:
treating 4-aminobenzamidine dihydrochloride with succinic anhydride and pyridine in the presence of an aprotic solvent to give 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride;
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:59].S([O-])([O-])(=O)=[O:61].[Al+3].[K+].S([O-])([O-])(=O)=[O:68]>O1CCOCC1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:61].[OH2:68].[OH2:59]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: [Al+3]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 27.5 °C
Reaction time: 0.46 h
Yield: 70 %

Procedure:
Crude docetaxel (1.0 g,) was dissolved in 1,4-dioxane (5 ml) at 25-30° C. under constant stirring. Demineralised water (7 ml) containing 0.02 g of potassium aluminum sulfate was added slowly at 25-30° C. with constant stirring. The precipitated solid was stirred for 25-30 minutes at 25-30° C., then filtered, washed with a 1:1 solution of 1,4-dioxane and demineralised water (1 ml), dried under vacuum under humid atmosphere (until the moisture content was between 5-7% by Karl Fischer method) to afford Docetaxel trihydrate in 70-90% yield
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20]CC(C1C=C(O)C=CC=1O)=O.C(=O)C1C=CC=CC=1>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[CH:17]([CH3:20])[C:16]2=[O:18]
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: CCC(=O)c1cc(O)ccc1O
Solvent: O=Cc1ccccc1
Product: CC1C(=O)c2cc(O)ccc2OC1c1ccccc1

Procedure:
6-Hydroxy-3-methyl-2-phenylchroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2,5-dihydroxypropiophenone and 1.63 ml of benzaldehyde. The product was purified by column chromatography using heptane-ethyl acetate (3:1) as an eluant. 1H NMR (300 MHz, d6-DMSO) δ: 9.37 (s, 1H), 7.53 (m, 2H), 7.47-7.39 (m, 3H), 7.13 (d, 1H, J 3.1 Hz), 7.02 (dd, 1H, J 8.9, 3.1 Hz), 6.89(d, 1H, J 8.9 Hz), 5.17 (d, 1H, J 12.3), 3.18 (dq, 1H, J 12.3, 6.9 Hz), 0.84 (d, 3H, J 6.9 Hz).
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][CH:2]([C:3]1[O:4][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)C(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(O)C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 2-hydroxy-3-methylbutanoic acid (70 mg, 0.6 mmol) in DMF (6 mL) were added DIPEA (0.125 mL, 0.7 mmol) and HATU (0.23 g, 0.6 mmol). After stirring at rt for 15 min 17 (0.2 g, 0.6 mmol) was added as a solution in DMF (2 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 1 h. The reaction was cooled to rt, purified by preparative LCMS to afford crude material, which was further purified by flash column chromatography on silica with DCM/2% MeOH as eluant to give 3-(5-(5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A64) as an off white solid. 1H NMR (400 MHz, CD4OD) δ 8.76 (s, 1H), 7.93 (s, 1H), 7.47 (s, 1H), 7.39 (dd, J=8, 2 Hz, 1H), 7.36 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 4.51 (d, J=6 Hz, 1H), 3.76 (s, 3H), 2.69 (s, 3H), 2.16 (m, 1H), 2.14 (s, 3H), 1.02 (d, J=6 Hz, 3H), 0.94 (d, J=6 Hz, 3H). MS m/z 420.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OC(C)(C)C)(=O)[NH:15][NH2:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:15][NH2:16])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid (9.83 g, 50 mmol), tert-butyl carbazate (7.93 g, 60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.54 g, 55 mmol), 1-hydroxybenzotriazole monohydrate (7.43 g, 55 mmol), and triethylamine (12.65 mL, 125 mmol) in N,N-dimethylformamide (100 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. A 4 M solution (62.5 mL) of hydrochloric acid in 1,4-dioxane and methanol (200 mL) were added to the partially purified product, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, hexane was added to the obtained partially purified product, and the solid was collected by filtration to obtain the title compound (9.06 g, 86%) as a light brown solid.