Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH3:55][O:56][CH2:57][CH2:58][NH2:59].[BH4-].[Na+]>ClCCl.CO.C(OCC)(=O)C>[CH3:55][O:56][CH2:57][CH2:58][NH:59][C:18]([C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: COCCN
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (100 mg, 0.30 mmol.) in dichloromethane (6.7 mL) was added N-hydroxybenzotriazole (59.7 mg, 0.44 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (169.7 mg, 0.44 mmol.), followed by 4-methylmorpholine (89.5 mg, 0.89 mmol) and the resultant mixture was stirred at room temperature for 1 h. Then 2-methoxyethanamine (26.6 mg, 0.44 mmol) was added to the flask and the reaction mixture was stirred under nitrogen overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was complete. The reaction was quenched with water and extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and water (3 times), dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 130 mg of crude product as a yellow oil, which was dissolved in methanol (3 mL) and treated with sodium borohydride (20 mg, 0.53 mmol) for an additional 3 h. LC-MS showed the reaction was complete. The reaction was quenched with water and extracted with ethyl acetate, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford crude product, which was further purified by column chromatography (petroleum ether:ethyl acetate=1:1) from methanol to give 100 mg of methyl 2-(3-(2-methoxy ethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white crystal. Yield: 85.6%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[N:4][CH:3]=1.[CH2:17]([C:24]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:17]([C:24]1([OH:30])[CH2:29][CH2:28][N:27]([C:10]([C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:6]=[CH:7][N:2]=[CH:3][N:4]=2)=[O:12])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccccc1-c1ccncn1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1-c1ccncn1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)benzoic acid hydrochloride (0.20 g), 4-benzyl-4-hydroxypiperidine (0.24 g), HATU (0.48 g) and triethylamine (0.59 mL) in DMF (3.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:25]([C:24]3[C:19]([CH3:18])=[N:20][CH:21]=[N:22][CH:23]=3)=[O:26])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: Cc1ncncc1C(=O)O
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cncnc1C
Yield: 80 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-methoxy-9H-beta-carbolin-8-ylamine and 4-methyl-5-pyrimidine carboxylic acid in 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl-].[C:20](#[N:22])[CH3:21]>CN(C)C=O>[C:20]([CH2:21][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:22]
Reactant: CC#N
Reactant: CCOC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(OC)cc2n1CC#N

Procedure:
Under nitrogen, dissolve 2.15 g of ethyl 6-methoxy-1H-indole-2-carboxylate in 10 ml of dimethylformamide. Add 0.59 g of sodium hydride in small portions at 0° C. and stir the reaction at 0° C. for 30 minutes. Add 0.93 ml of acetonitrile chloride at 0° C. and stir the reaction at ambient temperature for 24 hours. Add water and extract with ethyl acetate. Wash the organic phase with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution. Dry the organic phase over sodium sulfate, filter and evaporate. Purify the compound by column chromatography on silica gel using dichloromethane as eluant. The title compound is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=1.C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23](=[O:28])[C:24](=[CH:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C(=O)CC(C)=O)c1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)c1

Procedure:
250 mg (1.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 280.9 mg (1.46 mmol) of 1-(3-methoxyphenyl)butane-1,3-dione, 99.7 mg (1.66 mmol) of acetic acid and 11.3 mg (0.13 mmol) of piperidine in 5 ml of dichloromethane and, after addition of molecular sieves, heated under reflux under argon for 4 h. The solvent is removed after filtration in vacuo. 479 mg (98% of theory) of the title compound are obtained and are employed without further purification in the next stage.
Reaction SMILES: C(=O)([O-])N.[CH2:5]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=1)=[O:21])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH:6]=[CH2:7].C(N(CC)CC)C.[C:39]([SiH2:43][O:44][C:45]([CH3:67])([CH3:66])[CH:46]1[CH2:50][CH2:49][CH2:48][N:47]1[C:51]([C:53]1[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[CH:55][C:54]=1[N:63]=[C:64]=[O:65])=[O:52])([CH3:42])([CH3:41])[CH3:40].NC1C=C(OC)C(OC)=CC=1C(N1CCCC1C(C)(C)O[SiH2]C(C)(C)C)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:5]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:30][C:64](=[O:65])[NH:63][C:54]2[CH:55]=[C:56]([O:61][CH3:62])[C:57]([O:59][CH3:60])=[CH:58][C:53]=2[C:51]([N:47]2[CH2:48][CH2:49][CH2:50][CH:46]2[C:45]([CH3:67])([CH3:66])[O:44][SiH2:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:52])=[CH:27][CH:28]=1)=[O:21])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH:6]=[CH2:7]
Reactant: COc1cc(N=C=O)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reactant: C=CCOC(=O)CCC(NC(=O)Oc1ccc(CO)cc1)C(=O)OCC=C
Agent: COc1cc(N)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Agent: NC(=O)[O-]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)OCC=C
Reaction time: 4 h

Procedure:
A solution of the carbamate progroup 42 (1.48 g, 3.92 mmol) and triethylamine (0.45 g, 0.6 mL, 4.3 mmol) in anhydrous CH2Cl2 (30 mL) was added to a solution of the isocyanate 7 prepared from the amine 5 (1.54 g, 3.92 mmol), triphosgene (0.42 g, 1.4 mmol) and triethylamine (0.535 g, 0.74 mL, 5.3 mmol) in anhydrous toluene (50 mL). The reaction was complete in 4 h. The product was obtained (flash column chromatography 40% EtOAc/60% n-hexane) as a colourless oil (1.76 g, 56). 1H NMR (CDCl3) δ 9.22 (bs, 1H), 7.87 (s, 1H), 7.40 (d, J=10 Hz, 2H), 7.13 (d, J=7.5 Hz, 2H), 6.83 (s, 1H), 5.93 (m, 2H), 5.74 (d, J=8.3 Hz, 1H), 5.30 (m, 4H), 5.17 (d, J=12.5 Hz, 1H), 5.15 (d, J=12.5 Hz, 1H) 4.68 (d, J=5 Hz, 2H) 4.61 (d, J=5 Hz, 1H), 4.48 (m, 1H), 4.35 (m, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 3.65 (m, 1H), 3.50 (m, 2H), 2.55 (m, 2H), 2.30 (m, 1H), 2.1 (m, 3H), 1.95 (m, 1H), 1.8 (m, 1H), 0.9 (s, 9H), 0.04 (s, 6H). IR (neat) 3338, 2953, 2857, 1735, 1615, 1597, 1522 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH:13]1([C:19]([C:7]2[C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:9][C:8]=2[CH3:10])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc2cc(C)oc2c1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1ccc2c(C(=O)C3CCCCC3)c(C)oc2c1
Reaction time: 1 h
Yield: 47 %

Procedure:
To a mixture of 6-methoxy-2-methyl-1-benzofuran (1.50 g), cyclohexanecarbonyl chloride (1.36 mL) and nitromethane (15 mL) was added aluminum chloride (1.85 g) at 0° C., and the mixture was stirred for 1 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (1.18 g, 47%) as a yellow oil.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=NOC)C1=CSCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)C1=CSCCO1
Yield: 24.9 %

Procedure:
A mixture of ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (16 g.), methanol (160 ml.) and a 1 N aqueous solution (85 ml.) of sodium hydroxide was stirred at room temperature for 25 minutes. The resultant solution was adjusted to pH 4.5 with 10% hydrochloric acid and concentrated at 40° C. in vacuo. To the residue was added ethyl acetate, and the solution was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, and then shaken sufficiently. The organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. The extract and the aqueous layer were combined together and adjusted to pH 1.0 with 10% hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with water and then dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was washed with diisopropyl ether to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (anti isomer, 3.5 g.), yellow crystals, mp. 108° to 110° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]3[O:17][C@@:18]45[CH2:28][CH:27]=[CH:26][C:25]([CH3:30])([CH3:29])[C@@H:24]4[CH2:23][CH2:22][C@H:21]([CH3:31])[C@@:19]5([CH3:32])[CH2:20][C:13]=3[C:12]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:11][C:10]=2[C:9]1=[O:41])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Si:34]([O:33][C:12]1[C:13]2[CH2:20][C@:19]3([CH3:32])[C@@H:21]([CH3:31])[CH2:22][CH2:23][C@H:24]4[C:25]([CH3:30])([CH3:29])[CH:26]=[CH:27][CH2:28][C@@:18]34[O:17][C:14]=2[C:15]2[CH2:16][NH:8][C:9](=[O:41])[C:10]=2[CH:11]=1)([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a solution of Compound (40b) (115 mg, 0.20 mmol) in 10 ml of dry dichloromethane were added 50 μl (0.46 mmol) of anisole and 32 μl (0.42 mmol) of trifluoroacetic acid under ice-cooling, and the mixture stirred for 4 hours at room temperature and allowed to stand over night. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; n-hexane:ethyl acetate=3:2) to give 94 mg (98%) of Compound (41b).
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([CH3:32])([CH3:31])[CH3:30])[C:17](OCC)=[O:18])(=O)[CH3:14]>>[CH3:32][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][C:16]1[C:13]([CH3:14])=[N:2][N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[C:17]=1[OH:18])([CH3:30])[CH3:31]
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Reactant: CCOC(=O)C(Cc1ccccc1C(C)(C)C)C(C)=O
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccccc4C(C)(C)C)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-[(1,1-dimethylethyl)phenyl]propanoate (41), and by a method similar to that in Example 1, step 4, 4-[[(1,1-dimethylethyl)phenyl]methyl]-3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-5-ol (42) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[Cl:13][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1cccc(CO)c1
Solvent: c1ccccc1
Product: CSc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (3-methylsulfanyl-phenyl)-methanol (23.8 g, 0.156 mol) in benzene (250 mL) was added thionyl chloride (26.9 g, 0.234 mol) under cooling with an ice-bath. The ice-bath was removed and the reaction mixture stirred for 48 hours at room temperature. The solution was concentrated and used without further work-up (26.9 g).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[CH:3]=1.[Li]>N>[O:8]=[C:4]1[CH2:3][CH:2]([C:1]([OH:11])=[O:10])[CH:7]=[CH:6][CH2:5]1
Reactant: COc1cccc(C(=O)O)c1
Agent: N
Agent: [Li]
Product: O=C1CC=CC(C(=O)O)C1

Procedure:
To synthesize methyl cis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylate, m-anisic acid is subjected to the Birch reduction with lithium in ammonia to produce 5-oxocyclohex-2-ene-1-carboxylic acid, followed by methylation of thus-produced cyclohex-2-ene-1-carboxylic acid to methyl 5-oxocyclohex-2-ene-1-carboxylate with diazomethane, trimethylsilyl-ethynylation of thus-produced cyclohex-2-ene-1-carboxylate with cerium dichloride trimethylsilylacetylene to produce methyl cis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-1-carboxylate, conversion to an epoxide and opening of the resulting epoxide ring to produce the cis-3,5-dihydroxy compound.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C@@:25]3([N:30]=[C:29]([NH2:31])[CH2:28][O:27][CH2:26]3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=3)[O:18][C:15]2=[N:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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].C(Cl)Cl.O>[Br:11][C:12]1[CH:13]=[C:14]2[C@@:25]3([N:30]=[C:29]([NH2:31])[CH2:28][O:27][CH2:26]3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:23]=3)[O:18][C:15]2=[N:16][CH:17]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(COC1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C
Yield: 72.1 %

Procedure:
A vial was charged with 2-fluoropyridin-3-ylboronic acid (0.094 g, 0.667 mmol), PdCl2(dppf)-CH2Cl2-adduct (0.026 g, 0.032 mmol), (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.300 g, 0.635 mmol), and potassium carbonate (0.351 g, 2.54 mmol). Dioxane (3.5 mL) and water (1.5 mL) were added. The vial was flushed with argon, sealed and heated to 80° C. for 1 hour. The reaction mixture was then diluted with EtOAc, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-80% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.202 g, 0.458 mmol)
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[NH2:14][C:12]1[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CO
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1

Procedure:
A solution of 15.2 g of 2-tert-butyl-5-[4-methylpiperidin-1-yl]-6-nitrobenzothiazole in 600 ml of methanol is hydrogenated in presence of 6.5 g of raney nickel at room temperature. After removing the catalyst the solution is concentrated and the solid filtered to give 6-amino-2-tert-butyl-5-[4-methylpiperidin-1-yl]benzothiazole melting at 146°-148°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][CH3:23].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl.CO>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][C:33]([N:22]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1)[CH3:23])=[O:34]
Reactant: CNc1ncnc2cc(OCC3CCN(C)CC3)c(OC)cc12
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2c(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 85 °C
Yield: 5.1 %

Procedure:
6-Methoxy-4-methylamino-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.195 g) was added to 2,6-dichlorophenyl isocyanate (0.3 g) under argon and the solids were mixed together using a spatula. The mixture was heated to 85° C. with gentle mixing for 40 minutes. The mixture was cooled to ambient temperature, dissolved in a mixture of chloroform (15 ml) and methanol (5 ml) and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.016 g); NMR Spectrum: (CDCl3) 1.5 (m, 2H), 1.98 (m, 5H), 2.3 (s, 3H), 2.91 (d, 2H), 3.6 (s, 3H), 4.02 (s, 3H), 4.03 (d, 2H), 7.1 (t, 1H), 7.28 (s, 2H), 7.37 (d, 2H), 8.61 (s, 1H), 8.96 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:36][C:35]4[CH:34]=[N:33][N:32]([CH3:37])[C:31]=4[NH:30][C:29]4[CH:38]=[CH:39][CH:40]=[CH:41][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:42])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.CO>[ClH:1].[CH3:37][N:32]1[C:31]2[NH:30][C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]=3[N:27]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)=[C:20]([CH3:42])[CH:21]=3)=[O:26])[CH2:36][C:35]=2[CH:34]=[N:33]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
4M HCl solution in dioxan (1 ml) was added to a solution of 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperidine-1-carboxylic acid tert-butyl ester from Example E68.4 (71 mg, 0.13 mmol) in methanol (3 ml). The mixture was stirred for 20 h at room temperature then solvents were concentrated in vacuo. The residue was triturated with diethyl ether to yield the title compound (61 mg, 97%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]([CH3:12])[CH:10]=O.S(OC)(OC)(=O)=O.C[O-].[Na+].[C:23]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:32]2[C:45]([F:46])=[CH:44][C:35]([C:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:37])=[C:34]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])[N:33]=2)[CH2:28]1)(=[O:25])[CH3:24]>O.C(Cl)(Cl)Cl>[C:23]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:32]2[C:45]([F:46])=[CH:44][C:35]([C:36]([C:38](=[CH:8][N:9]([CH3:12])[CH3:10])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:37])=[C:34]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])[N:33]=2)[CH2:28]1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 84.9 %

Procedure:
To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C.