Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCOCC1>[CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: C[C@H](Oc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12)C(=O)N1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](Oc1cccc2c(CC(C)(C)N)c[nH]c12)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of tert-butyl (1,1-dimethyl-2-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}ethyl)carbamate (166 mg, 0.373 mmol) in methylene chloride (2 mL) is added a 4N hydrogen chloride solution in dioxane (0.5 mL), and the mixture is stirred at room temperature for 3 hours. The reaction solution is poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated. The obtained crude product is purified by silica gel column chromatography (a saturated ammonia solution in chloroform ) a saturated ammonia solution in chloroform-methanol=50:1) to give the title compound (68.4 mg, yield: 53%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[C:8]2[CH:13]=[N:12][C:11](OC)=[N:10][C:9]=2[N:16]([CH2:18][CH3:19])[CH:17]=1)=[O:5])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[C:8]2[CH:13]=[N:12][C:11]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]=2[N:16]([CH2:18][CH3:19])[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)ncc2c1=O
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCCC3)ncc2c1=O

Procedure:
5.9 g of 6-ethoxycarbonyl-8-ethyl-2-methoxy-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine, 4.6 g. of pyrrolidine and 12 g of toluene are heated for 2 hours at 90° C. After cooling, 100 cm3 of water are added to the mixture. The precipitate is filtered off and washed with water. After drying, 5.5 g of 6-ethoxycarbonyl-8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydro-pyrido[2,3-d]pyrimidine are obtained. After recrystallisation from ethanol, it melts at 202° C and is identical to the product described in the literature.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:23]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:27]=[CH:26][N:25]=[CH:24]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCCCCCn1ccnc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCCCn1ccnc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 1.58 g of 6-chloronicotinic acid and 1.62 g of 1,1'-carbonyldiimidazole in 30 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then 1.52 g of 1H-imidazole-1-pentanamine was added. The procedure of Example 36 was followed to conclusion and gave 2.3 g of the compound of the Example as white crystals, mp 110°-112° C.
Reaction SMILES: [O:1]([CH:3]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]([O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:22]([F:40])[CH:21]=1)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[NH2:2].O=[C:42]([C:46]1[N:47]=[C:48]([NH:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[S:49][CH:50]=1)[C:43]([OH:45])=[O:44]>CO>[F:40][C:22]1[CH:21]=[C:20]([CH:3]([O:1][N:2]=[C:42]([C:46]2[N:47]=[C:48]([NH:51][C:52]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[S:49][CH:50]=2)[C:43]([OH:45])=[O:44])[C:4](=[O:5])[O:6][CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=1[O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39]
Reactant: COCCOCOc1cc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc(F)c1OCOCCOC
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Product: COCCOCOc1cc(C(ON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc(F)c1OCOCCOC
Yield: 56 %

Procedure:
0.640 g of the product of Step D and and 0.474 g of oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetic acid (Belgian Patent Application No. 864,828) were stirred for 4 and a half hours under nitrogen and at ambient temperature in the presence of 20 ml of methanol. Then, the solvent was eliminated, and the residue was chromatographed on silica, eluting with a dichloromethane-methanol (95-5) mixture to obtain 0.612 g of the expected product with a Rf=0.35 [eluant: dichloromethane-methanol (9-1)].
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([CH2:14][NH:15][C:16](=O)[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].O>O1CCCC1>[OH2:21].[ClH:2].[ClH:1].[O:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][NH:15][CH2:14][C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:23][CH2:22]1
Reactant: O=C(CN1CCOCC1)NCC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(C2(CNCCN3CCOCC3)CCC2)cc1Cl

Procedure:
Borane-methyl sulphide complex (2 ml) was added to a refluxing solution of the morpholinoacetamide prepared in a similar manner to that described above in the form of its free base (3.6 g) in dry tetrahydrofuran (20 ml) and the mixture heated under reflux for four hours. The mixture was cooled and water (10 ml) added. Dimethylsulphide and tetrahydrofuran were removed by evaporation and excess 5N hydrochloric acid added. The solution was basified and extracted with ether. Hydrogen chloride gas was passed into the washed and dried ether extract. Evaporation to dryness gave a residue which was triturated with dry ether and recrystallised from an 8:2 mixture of propan-2-ol and ethanol to give N-(2-morpholinoethyl)-[1-(3,4-dichlorophenyl)cyclobutyl]methylamine dihydrochloride monohydrate (m.p. 230°-244° C.).
Reaction SMILES: [OH-].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N+:8]3[C:15]([OH:16])=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)C(=O)N(C)[C:9]=32)=[CH:5][CH:4]=1.[C:25]([O:29][CH3:30])(=[O:28])[C:26]#[CH:27]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:27][C:26]([C:25]([O:29][CH3:30])=[O:28])=[C:9]32)=[CH:5][CH:4]=1
Reactant: Cn1c2[n+](c(O)c(-c3ccccc3)c1=O)Cc1ccc(Cl)cc1-2
Reactant: C#CC(=O)OC
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1C2
Yield: 48.3 %

Procedure:
A mixture of 333 mg of 9-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-phenyl-6H-pyrimido [2,1-a]isoindole-5-ium hydroxide (internal salt) and 41 ml of toluene was treated with 0.86 g of methyl propiolate and heated to boiling under reflux for about 6.5 days, and 0.86 ml of methyl propiolate was added thereto every 24 hours. The reaction mixture was then cooled in an ice bath and the separated crystals were filtered off under suction. After recrystallization from N,N-dimethylformamide there was obtained 165 mg of methyl 9-chloro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 269°-273°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[C:15]1(O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.O1CCCC1>[C:23]1([O:1][CH2:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: Oc1cccc2ccccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)C1
Reaction time: 24 h
Yield: 49.9 %

Procedure:
A solution of 1.0 g (4.9 mmol) of 1,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (described in WO 0066557), 0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g (6.9 mmol) of tri-n-butylphosphine in 40 ml of toluene and 20 ml of tetrahydrofuran, cooled under nitrogen by means of an ice bath, is admixed dropwise with a solution of 1.74 g (6.9 mmol) of ADDP. The reaction mixture is allowed to return to ambient temperature and stirring is continued for 24 hours. The mixture is filtered and the precipitate is rinsed with toluene. It is evaporated to dryness. The residue is taken up in dichloromethane and washed with a 1M aqueous sodium hydroxide solution. It is dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 98/2 mixture of dichloromethane and methanol, to give 0.80 g of product in colorless oil form.
Reaction SMILES: COC1C=CC(C[N:8]([C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[O:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:19][CH2:18][O:17][C:16]=3[CH:32]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:34]1[CH:35]=[CH:36][N:37]=[C:33]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[O:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:19][CH2:18][O:17][C:16]=2[CH:32]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)COc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.2 %

Procedure:
To a solution of 2-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (300 mg, 0.53 mmol) in DCM (30 mL) was added TFA (0.5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 5 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by prep HPLC purification to obtain 2-(2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (55 mg, 13.7%) as an off white solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](O)([CH3:42])[CH3:41])[CH:35]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:7])([CH3:42])[CH3:41])[CH:35]=1
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cccc(C(C)(C)O)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cccc(C(C)(C)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of 34 μl (0.258 mmol) of diethylaminosulphur trifluoride (DAST) in 0.5 ml of anhydrous dichloromethane was added dropwise to a solution of 100 mg (0.215 mmol) of the compound of Example 141 in 4.5 ml of anhydrous dichloromethane. The reaction mixture was stirred at −78° C. for 1 h, about 5 ml of saturated aqueous sodium bicarbonate solution were then added and the mixture was warmed to RT. The mixture was diluted with about 10 ml of water and extracted three times with in each case about 10 ml of dichloromethane. The combined organic extracts were washed once with saturated aqueous sodium chloride solution and dried over magnesium sulphate. After filtration and evaporation, the residue obtained was separated into its components by preparative HPLC (Method 9). Evaporation of the product fractions and drying of the residue under high vacuum gave 40 mg (39% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:12]2=[O:13])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:12]2=[O:13])=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(N2C(=O)CCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(N2C(=O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 1-(4-methoxycarbonylphenyl)-3,4-dihydrocarbostyril (1.84 g) in methanol (40 ml) is added a 5 aqueous sodium hydroxide solution (20 ml) and the mixture is stirred at room temperature overnight. Methanol is distilled off under reduced pressure and to the residue is added water. After the solution is washed with dichloromethane, the aqueous layer is made acidic with concentrated hydrochloric acid and extracted with diethyl ether and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography, followed by recrystallization from ethanol to give 1-(4-carboxyphenyl)-3,4-dihydrocarbostyril (0.87 g) as pale yellow powders, m.p. 265°-270° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-])=O)=[CH:9][CH:10]=2)[C:5]=1[OH:23])[CH:2]=[CH2:3].C(O)C.[H][H]>CC(C)=O.[Pd]>[CH2:1]([C:4]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([NH2:20])=[CH:9][CH:10]=2)[C:5]=1[OH:23])[CH2:2][CH3:3]
Reactant: C=CCc1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCc1c(-c2ccccc2)cc2ccc(N)cc2c1O

Procedure:
14 g of 2-Allyl-3-phenyl-7-nitro-1-naphthol prepared in step (4) were dissolved in 200 ml of acetone. 300 ml of ethanol and one pinchful of a 10% palladium on charcoal catalyst were added. The resulting mixture was hydrogenated at room pressure and temperature until the theoretical amount of hydrogen was absorbed. The catalyst was then removed by filtration and the residual solution was evaporated to dryness under reduced pressure. The resulting crystals were washed with petroleum ether, filtered off and dried under sulfuric vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([F:43])([F:42])[C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>CN(C=O)C>[OH:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:17][CH3:18])[N:9]=[CH:8][N:7]=[C:6]2[O:5][C:4]1[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:23]([F:43])([F:42])[F:22])[O:31][N:30]=2)=[O:34])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)c2cc1O
Temperature: 60 °C

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (70 mg, 0.247 mmol) described in Example 107A in anhydrous DMF (3 mL), was added phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (90 mg, 0.287 mmol) and the mixture was heated to 60° C. for 15 h. Concentration in vacuo followed by trituration of the resulting solid with methanol afforded, after filtration and drying, 1-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (73 mg, 59%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.75 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 7.55 (dd, J=2.1, 2.1 Hz, 1H), 7.50 (s, 1H), 7.37-7.43 (m, 2H), 7.27 (dd, J=9, 1.2 Hz, 1H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.88 (s, 1H), 4.00 (s, 3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]1[CH:23]2[CH2:24][CH:25]([NH2:26])[CH:21]([CH2:22]2)[CH2:20]1>ClCCl>[CH:21]12[CH2:22][CH:23]([CH2:19][CH2:20]1)[CH2:24][CH:25]2[NH:26][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: NC1CC2CCC1C2
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(C#N)c(NC2CC3CCC2C3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a 0° C. solution of 10.0 g (53.9 mmol) of 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile in 100 mL of dichloromethane is added 9.0 mL (64.6 mmol) of triethylamine followed by dropwise addition of 7.0 mL (59.3 mmol) of exo-2-aminonorbornane. The reaction mixture is stirred at 0° C. for 2 hours. The resulting precipitate of triethylamine hydrochloride is filtered. The filtrate is washed three times with saturated aqueous solution of sodium bicarbonate. The aqueous phase is back extracted twice with dichloromethane. The combined organic phase is concentrated, and the residue is purified by filtering through a short column of silica gel eluted with dichloromethane to give 8.9 g (64%) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[F:13]>O.C(O)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[F:13]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Powered sodium cyanide (12.0 g, 0.24 mol) was dissolved in a 20 mL of water, and was added a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (60 g, 0.22 mol) in 30 mL of ethanol. After heating at reflux for 4 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was diluted with CH2Cl2, filtered, and concentrated to afford (4-bromo-3-fluorophenyl)acetonitrile, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[CH3:19])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>>[CH3:19][N:14]1[C:15]2[C:11](=[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][CH2:26][CH:28]3[CH2:29][O:30]3)=[O:9])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Cn1ccc2c(C(=O)c3ccccc3O)cccc21
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc2c(C(=O)c3ccccc3OCC3CO3)cccc21

Procedure:
Using the procedure of Step A of Example 3, 3 g of the product of Step D, 6.6 of potassium carbonate and 4.7 ml of epichlorhydrin were added in 5 stages. After a total of 48 hours at reflux, filtration was carried out. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed as indicated in Example 2 to obtain 3.7 g of the expected product.
Reaction SMILES: [F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:36])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C3CCOCC3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C3CCOCC3)ccc2F)C1(F)F
Yield: 80.5 %

Procedure:
The reaction of (R)-6,6-difluoro-5-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (244 mg, 657 μmol) with Lawesson's reagent (266 mg, 657 μmol) in 1,4-dioxane (20 ml) yielded the (R)-6,6-difluoro-5-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-thione (205 mg, 81% yield) as a white foam. MS (ISP): m/z=388.2 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.[CH3:12][Mg]Cl.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][CH:3]1[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: C[Mg]Cl
Reactant: O=C1COc2ccccc2N1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1COc2ccccc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of 2H-1,4-benzoxazin-3(4H)-one (2.00 g, 13.4 mmol) in tetrahydrofuran (20 ml) was added dropwise at 5° C. a THF solution of methylmagnesium chloride (17.9 ml, 3 M, 53.7 mmol) and the reaction mixture was then stirred at 50° C. for 90 min. The reaction mixture was then cooled to 5° C. and quenched by dropwise addition of 20 ml acetic acid. Sodium borohydride (1.27 g, 33.5 mmol) was then added portionwise and the mixture was stirred at room temperature overnight. The resulting suspension was then cooled to 0° C. and 3 N aq. sodium hydroxide solution was added dropwise until the mixture was pH 10. Ethyl acetate was then added, the phases separated, and the organic phase dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colorless oil (0.92 g, 46%); MS (ISP): 150.3 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH3:18])([CH3:17])[C:4]([C:19]#[C:20][C:21]([CH3:25])=[CH:22][CH:23]=[O:24])=[C:3]1[CH3:26].[BH4-].[Na+].O>C(O)C>[O:1]=[C:2]1[CH:6]([C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([CH3:17])([CH3:18])[C:4]([C:19]#[C:20][C:21]([CH3:25])=[CH:22][CH2:23][OH:24])=[C:3]1[CH3:26]
Reactant: CC(C#CC1=C(C)C(=O)C(C(=O)COc2ccccc2)C1(C)C)=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C#CC1=C(C)C(=O)C(C(=O)COc2ccccc2)C1(C)C)=CCO
Reaction time: 0.17 h

Procedure:
42 g of 5-[3-oxo-4-phenoxyacetyl-2,5,5-trimethyl-cyclopent-1-en-1-yl]-3-methyl-pent-2-en-4-yn-1-al are dissolved in 420 ml of ethanol. The solution is treated at -40° C. with 1.16 g of sodium borohydride and stirred for 10 minutes. The mixture is then introduced into water and extracted with ether. The 5-[3-oxo-4-phenoxyacetyl-2,5,5-trimethyl-cyclopent-1-en-1-yl]-3-methyl-pent-2-en-4-yn-1-ol is obtained as a viscous oil.