Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([CH3:12])[NH:4][C:3]=1C(OCC)=O>S(=O)(=O)(O)O>[C:7]([CH2:6][CH2:5][N:4]1[C:5]([CH3:12])=[C:6]([C:7]([OH:9])=[O:8])[C:2]([CH3:1])=[CH:3]1)([OH:9])=[O:8]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Agent: O=S(=O)(O)O
Product: Cc1cn(CCC(=O)O)c(C)c1C(=O)O
Reaction time: 8 h
Yield: 157.7 %

Procedure:
3,5-Dimethyl-2,4-pyrrole dicarboxylic acid, diethyl ester (200 g, 836 mmol) was placed in a 1 L beaker and treated with 400 mL concentrated sulfuric acid (H2SO4). The mixture was stirred, heated to 45 C with the aid of a heat gun and then maintained at 36-42 C for 25 minutes. The reaction mixture was poured into 3 L crushed ice and stirred for 30 minutes. The yellow solid was recovered by filtration and washed with 200 mL water. The solid was transferred to a 4 L Erlenmeyer flask and treated with 2 L 1 N sodium hydroxide solution (NaOH) followed by 100 mL 10 N NaOH. The basic mixture was filtered and the yellow solid residue was discarded. The filtrate was acidified with H2SO4. The resulting solid was recovered by suction filtration and washed with 2×500 mL water. After suction drying, the material was transferred to a 6 L Erlenmeyer flask and digested briefly in 4 L acetone. After standing overnight at room temperature (RT), the solid was collected by filtration and dried in a vacuum dessicator to afford 139 g, 659 mmol, 79% of the title compound. 1H NMR (DMSO-d6) δ4.22 (q, 2H), 2.44 (s, 3H), 2.38 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH:29]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]=1[C:36]1[CH:37]=[CH:38][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=1)[CH3:28]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 88.8 %

Procedure:
4′-[(5-Bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.50 g), 4-isopropoxyphenylboronic acid (0.31 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.050 g) were dissolved in 2 M aqueous cesium carbonate solution (2 mL) and 1,4-dioxane (10 mL), and the mixture was stirred at 90° C. overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.50 g, 89%) as a colorless solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[N+:17]=1[CH3:18].[Cl:23][C:24]([Cl:35])([Cl:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:17]1[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14][C:13]1=[CH:12][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([C:24]([Cl:23])([Cl:34])[Cl:35])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Cc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1C(=CC(=O)c2ccc(C(Cl)(Cl)Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dimethylbenzothiazolinium-p-toluene sulphonate (10 g) was slurried in dry toluene (50 ml) and cooled to 5 degC. A solution of 4-trichloromethylbenzoyl chloride (8.9 g) in dry toluene (10 ml) was added dropwise to the stirred slurry over a period of 30 minutes, maintaining the temperature at 10-15 degC. A solution of triethylamine (7 ml) in dry toluene (10 ml) was then added dropwise over a period of 30 minutes, the temperature again being maintained at 10-15 degC. The reaction mixture was stirred for two hours at room temperature. The solid product was filtered off, reslurried in methanol and recrystallised from a 3/1 chloroform/methanol solution.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:20]=1[F:34].C(Cl)Cl>CO.Cl[Pd]Cl.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:21][C:20]=1[F:34]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(Cl)c(F)c2)c1
Temperature: 100 °C
Yield: 79.3 %

Procedure:
Methyl 2-chloroisonicotinate (1.2 g, 6.99 mmol), potassium carbonate (0.580 g, 4.20 mmol) and PdCl2 (dppf) (0.122 g, 0.17 mmol) were combined in a microwave vial. 2-(4-Chloro-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.19 mmol) dissolved in MeOH (15 mL) was added. The reaction mixture was heated in a single node microwave reactor at 100° C. for 15 min. DCM (125 mL) and water (125 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (125 mL). The combined organic phases were washed with brine (250 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 10% EtOAc in heptane over 3 CV and then 10 to 50% EtOAc in heptane over 12 CV was used as mobile phase. The product was collected using the wavelength 253 nm. Methyl 2-(4-chloro-3-fluorophenyl)isonicotinate (1.473 g, 79%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 7.48-7.54 (m, 1H), 7.76-7.83 (m, 2H), 7.88-7.94 (m, 1H), 8.24-8.27 (m, 1H), 8.83 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].[CH2:25](I)[CH3:26].Cl>O1CCCC1.C(OCC)C.O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:25][CH3:26])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 48 h

Procedure:
To a solution of 9.58 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone in 150 ml of tetrahydrofuran were added 1.20 g of a 60% dispersion of sodium hydride in mineral oil. After gas evolution ceased, 2.4 ml of ethyl iodide were added and the reaction mixture was stirred for two days under an argon atmosphere. The mixture was heated at reflux for six hours, cooled, diluted with diethyl ether and water, and adjusted to pH 3 with 1N hydrochloric acid. The layers were separated, and the organic layer was washed with a saturated sodium bicarbonate solution followed by a saturated sodium chloride solution. Concentration of the dried organic solution and chromatography of the resulting residue over silica gel eluting with a 10-30% ethyl acetate in hexane gradient provided 3.65 g of the desired title product, m.p. 169°-172.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:37])[CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O-:36])=[O:35])[CH2:30][CH2:29]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:45]1([CH3:68])[CH:50]=[CH:49][C:48]([S:51]([O:54][CH2:55][CH2:56]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:53])=[O:52])=[CH:47][CH:46]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:37])[CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:32][CH2:33]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:56][CH2:55][O:54][S:51]([C:48]2[CH:49]=[CH:50][C:45]([CH3:68])=[CH:46][CH:47]=2)(=[O:53])=[O:52])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)[O-])CC2)C1)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2cncc([C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]3CCCN(C(=O)CCC4CCN(C(=O)OC(C)(C)C)CC4)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154.7 %

Procedure:
4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-hydroxypyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (200 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (39 mL). Cesium carbonate (277 mg, 0.85 mmol) and ethylene glycol bis-p-toluenesulfonate (188 mg, 0.51 mmol) were added. The mixture was stirred at room temperature for 4 hours, the addition of cesium carbonate (277 mg, 0.85 mmol) and ethylene glycol bis-p-toluenesulfonate (188 mg, 0.51 mmol) was repeated and stirring at 5° C. was continued for 17 hours. The mixture was quenched by addition of saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane 20% to 100% followed by dioxane in ethyl acetate 0 to 60%) to yield 207 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[C:1]1([C:7]2[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=2[OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1C=CC(=O)C(c2ccccc2)=C1
Product: Oc1ccc(O)c(-c2ccccc2)c1

Procedure:
The oxidation of biphenyl using a solution containing ceric ammonium nitrate to produce 2-phenylbenzoquinone, i.e. ##STR3## is disclosed in U.S. Pat. No. 3,873,580 to Rennie. 2-phenylbenzoquinone can be reduced with hydrogen to produce phenylhydroquinone, i.e. ##STR4##
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Temperature: 85 °C
Yield: 99.4 %

Procedure:
Seal tube containing 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperidin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (product of step-iii of example 82) (125 mg, 0.194 mmol), (S)-2-methyloxirane (23 mg, 0.389 mmol), DIPEA (100 mg, 0.778 mmol) and ethanol were heated at 85° C. for 3 hours and distilled the solvent on rotavapor to get 128 mg (99% yield) of the titled compound. MS: m/z=664.4 (M+1).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:5].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>ClCCl>[N:13]1([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=2)=[O:5])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CBr)c1ccc(Cl)cn1
Reactant: c1c[nH]cn1
Agent: Br
Solvent: ClCCl
Product: O=C(Cn1ccnc1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 g of 2-bromoacetyl-5-chloropyridine hydrobromide are dissolved in 50 ml of dry dichloromethane, 9.7 g of imidazole are added and the mixture is stirred for 24 hours at room temperature. Evaporation of the solvent in vacuo and subsequent chromatography of the residue over silicagel (dichloromethane/methanol/heptane=7/1/4) yield the compound as a cream coloured solid; m.p.: 122°-129°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH3:26])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=3)[N:15]=[C:14]([CH3:25])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC1C2C(=CC=C([N+]([O-])=O)C=2)N=C(C)N=1.COC1C=C(NC)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH3:26])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[N:15]=[C:14]([CH3:25])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC
Agent: CNc1ccc(OC)c(OC)c1
Agent: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Product: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)cc1OC

Procedure:
(3,4-Dimethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine: The title compound was prepared from 4-chloro-2-methyl-6-nitro-quinazoline (110 mg, 0.492 mmol) and (3,4-dimethoxy-phenyl)-methyl-amine (97 mg, 0.58 mmol) by a procedure similar to Example 177, with a final purification by MPLC (SiO2/0-100% EtOAc in CHCl3). LC-MS (ESI+; 355 ([M+H]+)).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)CCl>[Cl:12][CH2:13][C:14]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2][CH:3]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: O=C(O)CCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-phenylpropionic acid (50g.) in ethylenedichloride (200ml.) was added over 1 hour to a stirred mixture of chloroacetyl chloride (37.7g.) and aluminum chloride (48.9g.) in ethylene dichloride (550ml.) at room temperature. The resulting mixture was stirred for 1 hour and was then poured cautiously onto a mixture of ice (2kg.) and concentrated hydrochloric acid (50ml.). After stirring for a further 16 hours, the crude product was separated by filtration and recrystallised from water to give 3-[4-(chloroacetyl)phenyl]propionic acid, m.p. 151°-153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])=[CH:31][CH:30]=1)[CH3:28].Cl>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:38])([CH3:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(CC(C)(C)N)cc1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: Cl
Product: CCc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1

Procedure:
The target compound is prepared analogously to the method for Example 8(d) from 2.14 g (6.0 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1.0 g (5.6 mmol) of 2-(4-ethylphenyl)-1,1-dimethylethylamine. White solid. Yield: 1.7 g (54%, hydrochloride); melting point 210C.–214° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.O.C[C:23]([N:25](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:18]([Si:11]([CH:15]([CH3:16])[CH3:17])([CH:12]([CH3:13])[CH3:14])[N:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:23]#[N:25])[C:3]=2[CH:10]=[CH:9]1)([CH3:19])[CH3:20]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C#N)ccnc21
Yield: 25 %

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2.84 g, 9.2 mmol), zinc cyanide (650 mg, 5.5 mmol), and zinc dust (120 mg, 1.8 mmol) were suspended in dimethylacetamide (40 mL). The mixture was degassed thoroughly, bis(tri-t-butylphosphine)palladium (511 mg, 0.46 mmol) was added, and the mixture was stirred at 80° C. for 3d. The mixture was poured into water (80 mL) and filtered. The solids were washed with ethyl acetate and the filtrates were combined. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and concentrated. The oily residue was triturated with hexanes, the solution was decanted and the solvent was evaporated to give 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (676 mg, 2.25 mmol, 25% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)=[O:31])[CH:27]=2)[CH:22]=[CH:21]1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[C:36]([C:35]4[CH:34]=[CH:33][C:32]([C:30]([NH:29][C:26]5[CH:27]=[C:28]6[C:23]([CH:22]=[CH:21][NH:20]6)=[CH:24][CH:25]=5)=[O:31])=[CH:39][CH:38]=4)[NH:16][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Product: Cc1noc(C)c1-c1ccc2nc(-c3ccc(C(=O)Nc4ccc5cc[nH]c5c4)cc3)[nH]c2c1

Procedure:
Compound 651 was prepared according to the procedure similar to that described in Scheme III from 1-(3,5-dimethylisoxazol-4-yl)-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C27H21N5O2: 448.17; found: 447.97.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH:26](O)[CH2:27][CH3:28])[CH2:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][CH2:27][CH2:28][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CCC(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.213 g (1.5 mmol) of (3-cyclohexyl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.33 g).
Reaction SMILES: C[O-].[Na+].CS(C)=O.[C:8]([O:16]C)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>CO.O1CCOCC1>[C:21]1([C:18](=[O:20])[CH2:19][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
An apparatus as described in Example 1 is charged with 18.0 g of sodium methylate (97%), 100 g of DMSO, 100 g of dioxane and 6 g of methanol and the mixture is cooled to 0° C. Then a mixture of 45 g of methyl benzoate and 36 g of acetophenone are added dropwise over 35 minutes. The reaction mixture is then stirred for ca. 45-60 minutes at 30° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13](O)=[O:14])=[CH:4][CH:3]=1.CN.C1COCC1.C1C=CC2N(O)N=[N:34][C:32]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13]([NH:34][CH3:32])=[O:14])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid (1 g, 3.7 mmol, 1 eq), methylamine in THF (2 M solution) (0.689 g, 21.5 mmol, 1 eq), HOBT (0.83 g, 6.2 mmol, 1.7 eq), EDC.HCl (1.24 g, 6.6 mmol, 1.8 eq) in DMF at ambient temperature under nitrogen was added Diisopropyl ethylamine (2.32 g, 18.5 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The LCMS indicated the desired product. The mixture was concentrated cooled in an ice-water bath, further diluted with water. The white solid was filtered and washed with water and dried in vacuum. Yield: 0.85 g (90%). 1H NMR (400 MHz, DMSO-d6): δ 2.81-2.82 (d, 3H, J=4.5 Hz), 6.80-6.83 (m, 1H), 6.94-6.95 (d, 1H, J=2.3 Hz), 7.34-7.38 (t, 2H, J=8.7 Hz), 7.44-7.47 (d, 1H, J=8.8 Hz), 7.90-7.93 (m, 2H), 8.39-8.40 (d, 1H, J=4.4 Hz), 9.3 (s, 1H). LCMS: (ES+) m/z=286.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:38][CH:39]=1)=[O:11]
Reactant: COC(=O)CCNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)NCCC(=O)O)c4)c3)cc2)c1
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate (85 mg, 0.16 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was heated at 50° C. for one hour and poured into 100 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoic acid as white solid. Yield: 80 mg, 96%.