Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:34]4[C:30](=[O:40])[C:31]5[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:33]4=[O:35])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 4/500 mg, 1.21 mmol), phthalimide (534 mg, 3.63 mmol) and triphenylphosphine were dissolved in a 1:1 mixture of THF and DMF (10 ml). Ditertbutyl azodicarboxylate (698 mg, 3.03 mmol) was added at 0° C. and mixture was stirred at room temperature for 4 hours. After evaporation, the crude mixture was purified by silica gel chromatography (6% methanol/CH2Cl2) to give the title compound (33% yield); NMR Spectrum: 4.09 (t, 2H), 4.50 (t, 2H), 5.31 (s, 2H), 7.31 (d, 1H), 7.38 (t, 1H), 7.60 (d, 1H), 7.77 (dd, 1H), 7.83-7.90 (m, 4H), 7.99 (s, 1H), 8.05 (d, 1H), 8.31 (s, 1H), 8.61 (d, 1H); Mass Spectrum: 542 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]([CH3:40])[CH3:41])=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (160 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.O.[C:11](O)(=O)[CH:12]=[O:13]>O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]=[CH:11][C:12](=[O:13])[NH:9][C:4]=2[CH:3]=1
Reactant: O=CC(=O)O
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Product: O=c1cnc2ncc(Br)cc2[nH]1
Yield: 65.8 %

Procedure:
A solution of 5-bromo-2,3-pyridinediamine (465 mg, 2.473 mmol) and glyoxylic acid monohydrate (284 mg, 3.09 mmol) in water (5 ml) was stirred at rt for 3 h and the resultant precipitate was filtered and washed with water (50 ml), MeOH (20 ml) and finally diethyl ether (20 ml) before drying in vacuo gave the desired product as a light brown solid (368 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11]>C1(C)C(C)=CC=CC=1>[OH:11][CH:10]([C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: OC(c1ccccc1)c1nc2ccccc2s1

Procedure:
A mixture of o-aminothiophenol (23.5 g) and dl-mandelic acid (25 g) was refluxed in xylene with a Dean-Stark tube for two days.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 95.2 %

Procedure:
26.5 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are introduced into a solution of 26.7 parts by weight of piperazine in 200 parts by volume of water, which is heated to reflux. The mixture is kept under reflux for 90 minutes and then cooled. The precipitate is separated off, washed with water and dried. 31.5 parts by weight (95.2% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are obtained.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[OH:9][C@H:10]([CH3:43])[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[N:22]3[N:28]=[CH:29][C:30]([C:31]4[CH:32]=[N:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][CH:36]=4)=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>CN(C=O)C>[Cl:8][C:25]1[C:24]2[C:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:11](=[O:12])[C@H:10]([OH:9])[CH3:43])[CH2:18][CH2:17]3)=[N:20][C:21]3[N:22]([N:28]=[CH:29][C:30]=3[C:31]3[CH:32]=[N:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[C:23]=2[NH:27][CH:26]=1
Reactant: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]cc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
NCS (3.7 mg, 0.027 mmoL) was added to a solution of (R)-2-hydroxy-1-(4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yl)piperidin-1-yl)propan-1-one (25, prepared in Example 15) (12.8 mg, 0.027 mmoL) in DMF (1 mL). The mixture was stirred at room temperature for 3 days. Purification by prep-LC afforded (R)-1-(4-(6-chloro-3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yl)piperidin-1-yl)-2-hydroxypropan-1-one (34): LCMS tR=3.70 Min (10 min run, UV254nm). Mass calculated for, M+500.1, observed 501.5 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:17]#[C:18][Si](C)(C)C)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>CCCCCC>[C:13]([C:9]1[CH:8]=[C:7]([C:17]#[CH:18])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1c(C(C)(C)C)cc(C#C[Si](C)(C)C)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Product: C#Cc1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1

Procedure:
Following General Procedure E and (3,5-di-tert-butyl-4-methoxy-phenylethynyl)-trimethyl-silane (Intermediate 168, 0.28 g, 0.9 mmol), potassium carbonate (0.98 g, 7.1 mmol) and methanol (10 mL) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained (0.23 g, 100%).
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])(=[O:7])[C@@H:4]([CH3:6])[OH:5].Cl[CH2:14][O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:14][O:15][CH2:16][O:5][C@H:4]([CH3:6])[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCO[C@H](C)C(=O)OCC(C)C
Yield: 94.7 %

Procedure:
2.0 g of 60% sodium hydride was suspended in 50 ml of toluene. The suspension was cooled on an ice bath. Thereto was dropwise added 7.3 g of isobutyl (R)-(+)-lactate with stirring, followed by stirring for 1 hour. Thereto was dropwise added 5.0 g of chloromethoxymethane, followed by stirring for 3 hours. The reaction mixture was washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 30 ml of water in this order. The washed material was subjected to vacuum distillation to remove the solvent, whereby was obtained 9.0 g (yield: 86.6%) of an oily title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:18]Br>CCOCC>[Br:18][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: BrBr
Reactant: CCCCCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(Br)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Anhydrous aluminium chloride (0.120 g.) is added to an ice-cooled solution of n-hexanophenone (21.1 g.) in anhydrous ether (20 ml.). The mixture is stirred and ice-cooled to a temperature below 10° C. during the dropwise addition of bromine (6.0 ml.) during 1 hour. The mixture is evaporated and the residual oil dissolved in ether (100 ml.). The solution obtained is washed first with a saturated aqueous solution of sodium thiosulphate (3 × 30 ml.) and then with water. After drying (sodium sulphate) the ethereal solution is evaporated to give α-bromo-n-hexanophenone as an oil (28.0 g.) which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:38])[CH2:25][CH:26]([CH3:37])[O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:38][N:24]([CH3:23])[CH2:25][CH:26]([CH3:37])[O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1OC(C)CN(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OC(C)CN(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-dimethylamino-1-methylethoxy)-4-methoxyaniline (D6) using a similar procedure to Example 1 (61 %) mp 60°-65° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][N:7]([CH3:25])[CH:8]=[C:9]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16](C=O)[CH:15]=1)[CH:10]=[N+](C)C.[OH-:26].[Na+]>>[CH3:6][N:7]([CH3:25])[CH:8]=[C:9]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH:10]=[O:26]
Reactant: [OH-]
Reactant: CN(C)C=C(C=[N+](C)C)c1cn(C=O)c2ccccc12
Agent: F[B-](F)(F)F
Agent: [Na+]
Product: CN(C)C=C(C=O)c1c[nH]c2ccccc12

Procedure:
The trimethinium salt obtained in Step A (990 mg., 3 mmole) is stirred with 1N sodium hydroxide solution at 70° C. for one hour. The solid is filtered off and washed with water yielding 564 mg. (88%) of compound, m.p. 188°-190° C. (dec.). Recrystallization of the crude product from alcohol (11.5 ml.) affords the pure compound crystallizing in cream-colored prisms, m.p. 191°-192° C. with slight darkening.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]CC.[Na+].[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=[CH2:23].Cl>C(O)C.O>[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH:6]([C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CC(=O)CCCCCCC
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCC(=O)CCC(C(=O)OCC)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a stirred solution of 0.91 g of ethyl 2-chlorobenzoylacetate in 10 cc of ethanol was added 0.27 g of sodium ethoxide at room temperature, and the mixture was stirred at room temperature for 10 minutes. Then, 0.62 g of 3-oxo-1-decene in 10 cc of ethanol was added and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the aqueous layer was acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane =1/9) to obtain 0.90 g of compound I. Yield: 59.1%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].IC.[C:16]([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:16])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(C(=O)C(C)C)c(O)c1
Temperature: 25 °C

Procedure:
The above prepared 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (1.13 g, 5.55 mmol, corrected for purity) was dissolved in 22 mL of acetonitrile and treated successively at 0° C. with iodomethane (0.36 mL, 1.05 eq.) and Cs2CO3 (1.998 g, 1.1 eq.), and the mixture then stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=95/5), delivered 0.740 g of the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2>>[Cl:34][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2)=[C:24]([O:23][CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:11]3[C:6]4[O:5][CH2:4][C:3](=[O:19])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:14][CH2:15]2)[CH:33]=1
Reactant: Cc1ccc2c(OCCBr)cc(Cl)cc2n1
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-chloro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[S:15][C:14]=1Br)=[O:12].C[O-].[Na+].O.Cl>CN(C)C=O>[CH3:18][C:16]1[S:15][C:14]2[O:1][C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=3[NH:10][C:11](=[O:12])[C:13]=2[CH:17]=1
Reactant: COc1cccc(NC(=O)c2cc(C)sc2Br)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1Oc1sc(C)cc1C(=O)N2
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of N-(2-hydroxy-3-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.30 g) and sodium methoxide (549 mg) in N,N-dimethylformamide (12 ml) was stirred under reflux with heating for 19 hours. The reaction system was cooled to room temperature, and the reaction mixture was poured into water (50 ml). The mixture was neutralized with hydrochloric acid, extracted twice with chloroform and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent hexane:ethyl acetate=1:1) to give 2-methyl-9-methoxythieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([OH:35])(=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([OH:35])=[O:34])=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: C#CCCCCC(=O)O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Product: Cc1noc(-c2ccc(C#CCCCCC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and 6-heptynoic acid. Mass spec. data (M+H)=481.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>O1CCCC1>[NH2:4][C:5]1[N:10]=[C:9]([N:2]([CH3:3])[CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc(N)nc(OC(F)(F)F)n1
Reaction time: 8 h

Procedure:
5.0 g (0.111 mol) of gaseous dimethylamine were passed into a solution of 11 g (0.055 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran in the course of 20 minutes at 0° C. while stirring. Stirring was continued for one hour at 0° C. and overnight at 22° C. Evaporating down, washing with water and drying gave 9.9 g (80.7% of theory) of the title compound of melting point 114°-118° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:35])=O>>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)=[C:14]([C:16]([NH2:35])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1cncn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cn1cncc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 66 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 127 mg (66% yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:24][C:25]([NH2:27])=[S:26])[CH3:23]>C(O)C>[CH2:22]([NH:24][C:25]1[S:26][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:27]=1)[CH3:23]
Reactant: CCNC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.405 g, 1.09 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-ethylthiourea (0.114 g, 1.09 mmol) and the solution was heated to reflux for 14 hours. The reaction was cooled to room temperature and the resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), sodium carbonate solution (10%, 3×20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from methylene chloride and isooctane yielding 2-ethylamino-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (0.218 g, 53%) as a white powdery crystals: mp 218°-219° C., 1HNMR (DMSO d6) 400 mHz 7.94 (t, 5.38 Hz, 1 H), 7.78 (d, J=8.56 Hz, 2 H), 7.45-7.40 (m, 2 H), 7.37 (d, J=8.56 Hz, 2 H), 7.15 (t, J=9.05 Hz, 2 H), 3.31 (q, J=7.10 Hz, 2 H), 3.18 (s, 3 H), 1.18 (t, J=7.10 Hz, 3 H); MS m/z 377 (M+H). HRMS Δ=0.5 mmu.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]4[N:21]=[CH:22][NH:23][C:19]=4[CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:31])=[CH:2]1.[OH-].[K+].Cl>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:31])[CH:13]=[C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]4[N:21]=[CH:22][NH:23][C:19]=4[CH:18]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(Nc2ccc3nc[nH]c3c2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 20.2 %

Procedure:
To a solution of the compound (0.055 g, 0.13 mmol) of Example 119 in ethanol (6.0 mL), 50% potassium hydroxide solution (3.0 mL, 0.053 mol) was added at ambient temperature. The mixture was refluxed for 1.5 h. Cooled to ambient temperature, 1M hydrochloric acid was added to adjust pH to acidic, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound (0.0090 g, y. 20%) as solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[C:12]=1[CH3:18]
Reactant: Cc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
208 mmole concentrated nitric acid and 270 mmole concentrated sulfuric acid were mixed and cooled to ambient temperature. 200 mmole 2,3-dichlorotoluene was added to a reaction flask and was cooled in an ice-water bath. The acid mixture was added slowly with stirring to the dichlorotoluene keeping the dichlorotoluene in the ice-water bath. After all the acid had been added, the mixture in the ice-water bath was stirred for about 10 minutes. A drying tube was attached to the reaction flask and the reaction mixture warmed to ambient temperature. The reaction mixture was heated at 50° C. with stirring for three hours.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2OC(=O)C=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Yield: 86 %

Procedure:
To the same flask as used in Example 6 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 151.18 g (1.0 mole) of cinnamic acid, 500 g of toluene and 118.65 g (1.5 moles) of pyridine. After replacing the air in the container with nitrogen, 286.43 g (1.5 moles) of p-toluenesulfonyl chloride was added little by little with stirring. After completion of the addition, temperature maintenance and after-treatment were carried out in the same manner as in Example 6, and the residue was recrytallized from toluene to obtain 404.8 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monocinnamoate having a melting point of 164° to 169° C. Yield, 86%.