Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[Br:31])[C:24]([O:26][CH3:27])=[O:25].O1CCOCC1.C[Si](Cl)(C)C>CO>[CH2:1]([N:8]1[CH2:9][C:10]2[NH:20][C:21]3[C:30]([Br:31])=[CH:29][CH:28]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:22]=3[C:14](=[O:16])[C:11]=2[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: COC(=O)c1ccc(Br)c(N)c1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Temperature: 110 °C
Yield: 25.4 %

Procedure:
A mixture of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (16.1 g, 70 mmol), methyl 3-amino-4-bromobenzoate (21.9 g, 84 mmol), polyphosphoric acid (120 g) and dioxane (120 mL) was heated at 110° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice water, filtered and the filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried, and concentrated to give crude residue, which was chromatographed on silica gel using gradient eluant of 20% to 50% ethyl acetate in petroleum ether to give the crude product. Then the crude product was dissolved in MeOH (1 L), TMSCl (150 mL) was added, and the mixture was stirred at reflux for 12 h. After cooling to room temperature, the solvent was evaporated and the residue was recrystallized from MeOH to afford methyl 2-benzyl-9-bromo-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (7.6 g). 1H NMR (CDC3-d1) δ 10.9 (s, 1H), 8.06 (d, 1H, J=7.8 Hz), 7.51-7.74 (m, 5H), 7.20 (d, 1H, J=7.8 Hz), 4.36-4.62 (m, 4H), 3.82 (s, 3H), 3.67-3.72 (m, 2H), and 2.82-2.83 (m, 2H). MS (ESI) m/e [M+1]+427.0.
Reaction SMILES: [Cl:1][C:2]([CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:28])[N:20]2[CH3:27])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].C(O)(=O)C.Cl.O>C(O)C>[Cl:1][CH:2]([CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:28])[N:20]2[CH3:27])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)(CCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
Diethyl 2-chloro-2-[2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]malonate (2.38 g) was added to a mixture of acetic acid (10 ml) and 6N hydrochloric acid (15 ml), and the resulting mixture was heated under reflux overnight. After cooling to room temperature, water and a small quantity of ethanol was added to the reaction mixture, followed by ice cooling. The precipitated solid was collected by filtration, washed with water and dried to thereby obtain 0.99 g (yield: 55%) of 2-chloro-4-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)butyric acid as a gray powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH:24](/[C:17](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)/[CH2:18][CH3:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccccc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and aniline
Reaction SMILES: [C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Reaction time: 6 h
Yield: 99.2 %

Procedure:
To a solution of 3.00 g of 4-fluorenyloxycarbonylmorpholine-2-carboxylic acid in 150 mL of acetone was added 1.77 g of potassium carbonate and 1.33 g of dimethyl sulfate. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 3.10 g of the title compound, which was used without further purification. 1H NMR (500 MHz, CDCl3): δ7.76 (d, J=7.6 Hz, 2H), 7.57 (br d, J=6.6 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 4.51 (br s, 2H), 4.25 (br t, J=6.2 Hz, 1H), 3.90-4.10 (m, 4H), 3.80 (s, 3H), 3.40-3.70 (m, 1H), 3.04-3.23 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1.[S:14]([O-:17])([O-:16])=[O:15].[Na+].[Na+].Cl>O>[OH:17][S:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1)(=[O:16])=[O:15]
Reactant: Cc1cc(C)c2ccc(Cl)nc2n1
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2ccc(S(=O)(=O)O)nc2n1
Reaction time: 12 h
Yield: 64.6 %

Procedure:
9.6 g (50 mmol) of 2-chloro-5,7-dimethyl-1,8-naphthyridine prepared in accordance with Lit.8),9) is introduced into a solution of 8.2 g (65 mmol) of sodium sulfite in 40 ml of water which has been adjusted to a pH of 7-8 with dilute aqueous hydrochloric acid. The suspension which is obtained is heated for 12 hours under reflux. After cooling, solid residues are removed from the solution and the solution itself is acidified with aqueous hydrochloric acid (pH about 1). The acidified solution is left for 12 hours at 0° to 5° C., the product crystallizing out. There is obtained 7.7 g (65%) of the title compound; m.p.: >280° C.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:14][N:15]([CH3:32])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:32])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:21]=1
Reactant: COc1ccc(NCc2ccc(N(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2ccccc21
Product: COc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cn1
Yield: 68.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and [(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.49 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35](N[C@H](C(O)=O)C)=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35]([NH:3][C@H:4]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH2:5][C:6]([OH:8])=[O:7])=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)C(=O)O
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)c1cccnc1

Procedure:
Following the procedure described for 1-7, but substituting β-alanine ethyl ester hydrochloride (Aldrich) for ethyl 3-amino-3(S)-(3-pyridyl)propionate dihydrochloride, the title compound was prepared. Rf (silica, EtOAc)=0.3. ##STR37## N-{[7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetyl}--alanine (1-14)
Reaction SMILES: [CH:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:9]([O:8][C:7]2[CH:30]=[CH:31][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(C(C)C)cc1
Yield: 91.4 %

Procedure:
In a similar manner to that described in Reference example 3 (h), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-3-[4-(2-methanesulfonyloxyethoxy)phenyl]propionate (19.6 g), which is the product of Reference example 5(g), and sodium azide (7.06 g), and the reaction mixture was treated to afford the desired compound (15.8 g) as a syrup.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:43])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=4[Cl:42])[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[Cl:42][C:36]1[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:35]=1[C:28]1[O:29][C:30]([C:31]([F:33])([F:34])[F:32])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:44])=[O:4])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)=[O:43])=[O:25])[N:27]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(Cl)cc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(Cl)cc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaOH (23.94 mg, 0.56 mmol) was added to trans-{4-[4-(3-{[2-(2,4-dichlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (75 mg, 0.12 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 15 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2, stirred for 30 minutes, and filtered. Then, the filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified. Accordingly, the desired compound (71 mg, 97%) was obtained as a white solid.
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH3:4][OH:5]>[Cr]([O-])([O-])=O.[Cu+2].O>[C:1](=[O:3])=[O:2].[CH:4]([O:2][CH3:1])=[O:5].[CH3:4][O:3][CH3:1]
Reactant: CO
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: O=C=O
Solvent: O
Product: COC
Product: COC=O
Yield: 0.05 %
Yield: 0.7 %

Procedure:
Synthesis gas having an inlet composition of 66.6% H2, 33.3% CO and 0.1% CO2 was fed to a 300 cc. stainless steel autoclave charged with 3 gms. of activated copper chromite (containing 31.1% copper and 29% chromium) impregnated with 1% Ca-nitrate-tetrahydrate and 150 cc. methanol and then reduced in situ using a stream of pure H2 flowing at 25 cc/min. for 16 hrs. at 170° C. The catalyst was added as a powder. The reactor was pressurized to 910 psig. and the temperature was adjusted to 150° C. Synthesis gas at a flow rate of 105 cc/min. (measured under standard conditions) was made to react under isothermal conditions. After an initial transient period, the process reached a steady state with respect to the amount of synthesis gas converted. A methanol production rate based on the H2 consumption of 3.2 gmole/h/kg. cat was obtained with 11% synthesis gas conversion and 95% selectivity towards methanol. An exit gas composition of 68.0% H2, 30.0% CO, 0.4% CO2, 0.8% methanol, 0.7% methyl formate, 0.1% H2O and 0.05% dimethyl ether was obtained. A liquid composition of 95.6% methanol, 4% methyl formate, 0.3% water and traces of dimethyl ether and dissolved gases was obtained. No higher alcohols were detected.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[O:13])[CH2:6][CH2:5]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:22]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[CH2:11][CH:12]=[O:13])[CH2:8][CH2:9]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(CC=O)[C@H]1CC[C@H](CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC[C@H]1CC[C@H](C(CC=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 1-(trans-4-(2-hydroxyethyl)cyclohexyl)-3-oxopropylcarbamate (1.88 g, 6.28 mmol) in DCM (60 mL) was added DMAP (cat. amount), followed by addition of TEA (2.63 mL, 18.84 mmol) and acetic anhydride (0.89 mL, 9.42 mmol) at 0° C. under N2. The mixture was stirred at rt for 3 h, and diluted with DCM, quenched by addition of aqueous NaHCO3 solution. The organic phase was separated and dried over Na2SO4. Purification by flash column chromatography (eluent: 40% EtOAc in hexanes) gave the product as colorless gel (1.90 g, 88.6%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CSc1ccc(S)cc1
Reactant: O=Cc1cnccc1Cl
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2ccncc2C=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 114.8 %

Procedure:
4-Chloronicotinaldehyde [prepared according to D. Albanese, M. Penso, M. Zenoni, Synthesis 1999, 1294-1296] (500 mg, 3.5 mmol), 4-methylsulfanyl-benzenethiol (606 mg, 3.88 mmol) potassium carbonate (586 mg, 4.24 mmol) and DMF (7 mL) were combined, the mixture was heated together at 50° C. for 1.5 h and then stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and 10% aqueous K2CO3 (100 mL). The organic layer was dried (MgSO4) and evaporated to give the title compound (1.05 g) as a yellow oil. The 1H NMR spectrum showed the material to be of sufficient purity (90-95%) to be used without further purification; δH (CDCl3, 400 MHz) 2.54 (3H, s), 6.69 (1H, d), 7.35 (2H, d), 7.4 (2H, d), 8.35 (1H, d), 8.87 (1H, s), 10.24 (1H, s); MS m/z (TS+) 262 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.[C:31]([OH:40])(=[O:39])[C@H:32]([C@@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33]>C(O)C.N1CCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19].[C:31]([O-:40])(=[O:39])[C@H:32]([C@@H:34]([C:36]([O-:38])=[O:37])[OH:35])[OH:33]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
To a solution of 6.63 g (25 mmol) N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (I) and 3.78 g (25 mmol) 5-fluoroindolin-2-one (II) in ethanol (400 ml), 0.25 ml of pyrrolidine was added and mixture was refluxed for 5 h. To a boiling reaction mixture, a solution of D-tartaric acid (1.88 g, 12.5 mmol) in ethanol (20 ml) was added and a solution was left to cool to room temperature, with slow (as slow as possible) stirring. The stirring was continued for another 16 hours, then the product was filtered to get 4.53 g of sunitinib D-tartarate. Melting point: 220-226° C. (Form III), ratio sunitinib/tartaric acid (according to NMR) 2:1.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[N:25]1[C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[NH:27][C:26]=1[CH2:34][NH2:35].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:35][CH2:34][C:26]4[NH:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][C:33]=5[N:25]=4)[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: NCc1nc2ccncc2[nH]1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(NCc3nc4ccncc4[nH]3)c21
Temperature: 120 °C
Yield: 19.4 %

Procedure:
200 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 346.22 mg C-(3H-imidazo[4,5-c]pyridin-2-yl)-methylamine and 359.24 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.3 hours and heated for another 0.3 hours at 120° C. Then the reaction mixture is mixed with water. The precipitated substance is suction filtered and washed with water. The product is purified by semipreparative HPLC (method A). 50 mg of the product are obtained as a powder. Analytical HPLC-MS (method B): RT=1.55 min.
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:21])([F:20])[S:13]([O:16][CH2:17][C:18]#[CH:19])(=[O:15])=[O:14].[Te]1C2C=CC=CC=2N=C1>ClCCl.C(Cl)(Cl)(Cl)Cl>[F:11][C:12]([F:21])([F:20])[S:13]([O-:16])(=[O:15])=[O:14].[CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:19][C:18]#[CH:17]
Reactant: C#CCOS(=O)(=O)C(F)(F)F
Reactant: Cc1nc2ccccc2[te]1
Agent: c1ccc2[te]cnc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C#CC[n+]1c(C)[te]c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 20 h

Procedure:
2-Methylbenzotellurazole (Example 18) (0.81 g, 0.0033 mole) was dissolved in dichloromethane (30 ml). A solution in carbon tetrachloride (25 ml) of 2-propyn-1-yl trifluoromethanesulfonate, prepared as described above, (0.004 mole) was placed in a dropping funnel and added at room temperature under a nitrogen atmosphere to the benzotellurazole solution. The mixture was stirred for about 20 hours after the addition was complete, forming a white solid, which was isolated by filtration, washed with dichloromethane, and dried at room temperature under vacuum. Yield 0.60 g (42% of theory), m.p. 150°-152° C. The infrared, nuclear magnetic resonance and mass spectra were consistent with the structural formula.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].N1C=CC=CC=1.BrN1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Reaction time: 2 h
Yield: 87.8 %

Procedure:
1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (45 g, 191 mmol), pyridine (15.09 g, 191 mmol), and toluene (450 ml) were added to a 1000 ml flask, and N-bromosuccinimide (37.31 g, 210 mmol) was slowly added thereto at 20° C., followed by allowing the reaction to proceed for two hours. After the reaction, the solution was washed with water (180 mL,×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The resulting solid was recrystallized with toluene (67.5 ml) and hexane (337.5 ml), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (39.26 g, yield: 88.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:42])[CH2:38][CH2:39][CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:42][CH:37]([CH2:36][CH3:35])[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC(O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 62.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-heptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (46 mg, yield 57%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[NH3:17]>CO>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:17])[CH:3]=1
Reactant: CN(C)CCc1ccc([N+](=O)[O-])c(F)c1
Reactant: N
Agent: [OH-]
Solvent: CO
Product: CN(C)CCc1ccc([N+](=O)[O-])c(N)c1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of [2-(3-fluoro-4-nitro-phenyl)-ethyl]-dimethyl-amine (800 g, 3.76 mmol) in MeOH (20 mL) was added ammonia hydroxide (5 mL). The reaction mixture was heated at 100° C. under microwave heating for 1.5 hours. The resulting yellow solid was collected and washed with water, dried under vacuum and combined with a previous batch to give the pure title compound (560 mg, yield: 55%). MS (ESI): 210 [M+H]+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:4])=[O:16])=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 4.0 g of trans-2,4-dibenzyl glutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.