Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2cccnc12
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methylfuro[3,2-b]pyridin-2-yl)methyl]amino}benzoate (789 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (718 mg, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9]=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[NH2:11][C:12](N)=[O:13]>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[C:3]([N:4]=1)=[CH:9][NH:11][C:12](=[O:13])[N:1]=2
Reactant: NC(N)=O
Reactant: Nc1ccc(Cl)nc1C=O
Solvent: O
Product: O=c1nc2ccc(Cl)nc2c[nH]1
Temperature: 180 °C

Procedure:
3-amino-6-chloro-pyridine-2-carbaldehyde (3.2 g, 13.0 mmol) is mixed thoroughly with urea (7.8 g, 130 mmol) and heated to 180° C. in the preheated oil bath for 3 h. Then the reaction mixture is suspended in H2O, the precipitate is filtered off and 6-chloro-3H-pyrido[3,2-d]pyrimidin-2-one is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([O:23][CH3:24])(=[O:22])[C:20]#[CH:21].CN1CCOCC1>CC#N>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18]/[CH:21]=[CH:20]/[C:19]([O:23][CH3:24])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccc(O)c1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)/C=C/Oc1cccc(CCCO[Si](C)(C)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
To a solution of 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenol (1.78 g) in MeCN (10 mL) were added methyl propiolate (0.667 mL) and NMM (0.0441 mL) at ambient temperature and the mixture was stirred at the same temperature for 3 hours. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=97:3) to afford methyl (2E)-3-[3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenoxy]-acrylate (1.80 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C@@H:23]2[OH:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([O:26][C@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:27])[C:25]3[C@:2]4([O:1][C:24]1=3)[O:29][C@H:3]4[C@@H:4]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:28])[C@H:5]1[CH2:6][CH2:7][C@@H:8]2[CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])(=[O:38])[CH3:37]
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
To a mixture of 0.202 g (0.50 mmole) of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3β-ol, 0.5 ml (6.18 mmoles) of dry pyridine and 10 ml of methylene chloride was gradually added 0.1 ml (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the resulting solution was stirred at room temperature for 14 hours. The reaction mixture was then worked up in the same manner as Example 10 to recover 0.185 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-ene-3β-yl acetate (yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].CN1CCOCC1>CO>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CN(C)CCCN
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCCN(C)C)cc2s1
Yield: 1.7 %

Procedure:
the title compound (2 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N1,N1-dimethylpropane-1,3-diamine (77 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 395.3 (M+1, 100%). Yield=2%.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[CH:7][C:8]([OH:15])=[C:9](C(=NO)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C[N:23](C)[C:24](=O)[CH3:25]>C(#N)C>[C:1]([C:5]1[C:6]([OH:16])=[CH:7][C:8]2[O:15][C:24]([CH3:25])=[N:23][C:9]=2[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N(C)C
Reactant: CC(=NO)c1cc(C(C)(C)C)c(O)cc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cc(C(C)(C)C)c(O)cc2o1
Temperature: 0 °C
Yield: 85 %

Procedure:
In a mixture of 30 ml of N,N-dimethylacetamide and 30 ml of acetonitrile was dissolved 11 g of 5'-t-butyl-2',4'-dihydroxyacetophenone oxime. To the resulting solution, which was cooled on an ice bath with stirring, was dropwise added 20 ml of phosphorus oxychloride over a period of 30 minutes. The reaction mixture continued to be stirred for an additional 30 minutes as it was and, then, 200 mol of ice water was gradually added thereto over a period of an hour. The crystals thus precipitated were recovered by filtration, and 50 g of 5-t-butyl-2-methyl-6-benzoxazolol (Compound 1) was obtained. Yield 85%, Melting Point 264° to 266° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=2)[C:8]([CH3:21])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:29])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=2)[C:8]([CH3:21])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1coc(-c2cc(NC(C)=O)ncc2C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cc(NC(C)=O)ncc2C)oc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-3-furoate (20.0 g, 69.9 mmol) in DMF (90 mL) was added NBS (29.6 g, 168.1 mmol). The reaction mixture was allowed to stir at 80° C. overnight and then concentrated. The residue was washed with EtOH and filtered to give ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoate (20 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15].N[C:17](N)=[O:18].O.Cl>CN(C=O)C>[O:18]=[C:17]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=2[O:15]1
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C

Procedure:
A solution of Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate (205 mg, 0.978 mmol) in DMF (5 mL) was added urea (305 mg, 5.19 mmol) and refluxed for 5 hrs. The reaction mixture was cooled to room temperature and added water (30 mL). The mixture was acidified with conc. HCl (1 ml) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]1[CH2:17][CH2:16][N:15]([C:18]([CH2:20][C:21]#[N:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:19]=[C:18]([N:15]1[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1)[CH:20]=[C:21]1[NH:22][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#CCC(=O)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NC(=CC(=O)N2CCCCC2)Sc2ccccc21
Yield: 25 %

Procedure:
Methyl thiosalicylate (1.7 g, 10.1 mM) and 1-cyanoacetylpiperidine (2.0 g, 13.1 mM) were dissolved in toluene (5 ml), and triethylamine (2 ml, 14.4 mM) was added to the solution. After heating for 30 hours under reflux, the reaction solution was concentrated to give crude crystals. The crude crystals were recrystallized from ethanol to give the title compound as needles (730 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:16]([CH:18](/[CH:27]=[CH:28]/[C:29]1[C:34]([O:35][CH3:36])=[CH:33][C:32]([O:37][CH3:38])=[CH:31][C:30]=1[O:39][CH3:40])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH:49]O>C(O)(=O)C>[CH3:36][O:35][C:34]1[CH:33]=[C:32]([O:37][CH3:38])[CH:31]=[C:30]([O:39][CH3:40])[C:29]=1/[CH:28]=[CH:27]/[CH:18]([S:16]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:41]([O:47][CH3:48])=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:3]=1[O:2][CH3:1])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:49])=[O:17])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(/C=C/c2c(OC)cc(OC)cc2OC)S(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)cc2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccc(C(/C=C/c2c(OC)cc(OC)cc2OC)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-2,4,6-trimethoxystyryl-4-methoxybenzyl sulfoxide (3 g) is dissolved in glacial acetic acid (30 mL) and cooled to 0° C. To the cooled solution is added hydrogen peroxide (7.5 mL of a 30% solution) to form a reaction mixture. The reaction mixture is heated to reflux temperature and maintained at reflux for 1 hour. After 1 hour, the heated reaction mixture is poured onto crushed water ice (200 g). A solid precipitate is formed. The precipitate is separated by filtration, dried, and recrystallized from 2-propanol to yield the desired (E)-2,4,6-trimethoxystyryl-4-methoxybenzyl sulfone.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:13])=[C:2]=[S:3].[CH2:14]([NH2:17])[CH2:15][NH2:16]>C1(C)C=CC=CC=1>[NH2:16][CH2:15][CH2:14][NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:13]
Reactant: Cc1c(N=C=S)ccc2c1OCO2
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)ccc2c1OCO2
Reaction time: 0.08 h

Procedure:
To a stirred solution of 0.78 g of 5-isothiocyanato-4-methyl-1,3-benzodioxole in 50 mL of toluene at 25° C. is added 0.80 mL of ethylenediamine. After five minutes, the mixture is concentrated under reduced pressure to yield 1.0 g of 5-[N'-(2-aminoethyl)thioureido]-4-methyl-1,3-benzodioxole as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:14]=[CH:13][C:12](=O)[N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23]1COCC1>C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]1[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:13]2[C@@H:14]1[CH2:23]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 4-3 (0.25 g, 0.76 mmol) in diethyl ether (3.8 mL) at 0° C. was added a solution of CH2N2 (7.6 mmol, made from treatment of 1-methyl-3-nitro-1-nitrosoguanidine with 40% KOH) in diethyl ether (5 mL) under nitrogen and the reaction mixture was stirred 2 h. The reaction was dried over magnesium sulfate and concentrated directly to yield an oil of >90% purity. The product was used without further purification. The oil was resuspended in THF (1.7 mL) at ambient temperature and to the mixture was added borane-tetrahydrofuran complex in THF (2.4 mL, 2.4 mmol, 1.0M solution). The reaction was stirred 15 h and quenched with methanol (2 mL). The combined organic phase was dried over magnesium sulfate and concentrated. The residue was purified by normal phase silica gel chromatography (0 to 65% EtOAc in hexanes) to afford the product (4-4) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22].[OH-].[K+].Cl>CO.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])/[CH:20]=[CH:1]/[C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2ccc(C(=O)O)cc2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
Commercially available 4-formylbenzoic acid (15.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 M HCl, filtered, washed with water (200 mL), and dried in the air. 25 g (87%) of a yellowish solid was obtained.
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[CH2:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:15]1>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[CH2:13][C:14]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[O:15]2)[O:2][N:3]=1
Reactant: C=C1OC(=O)c2ccccc21
Reactant: ClON=Cc1ccc(Cl)cc1Cl
Product: O=C1OC2(CC(c3ccc(Cl)cc3Cl)=NO2)c2ccccc21

Procedure:
By a method similar to the procedure of Example 2, a reaction of 2,4-dichlorobenzaldehyde chlorooxime and 3-methylenephthalide was carried out. The solid collected from the reaction mixture afforded 12.2 g of the desired product after workup, and the ether solution gave 4 g of the desired product (yield 70.2%). Recrystallization from chloroform led to pure white crystals of the desired product, m.p. 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19])=[O:15].Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3-methyloxycarbonyl-4-methoxyaniline (0.88 g, 4.86 mmol), MeOH (3 mL), H2O (7 mL) and 2,4-dichloro-5-fluoropyrimidine (0.81 g, 4.86 mmol). The reaction mixture was stirred at 60° C. for 30 min., diluted with H2O (50 mL), acidified with 2N HCl (6 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to produce 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine R940302. 1H NMR (DMSO-d6): δ 10.10 (1H, s), 8.39 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=2.7 Hz), 7.98-7.93 (1H, m), 7.30 (1H, d, J=9 Hz), 3.92 (3H, s), 3.89 (3H, m); purity 96%; MS (m/e): 312 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Product: Cn1cc(C=O)c2ccc(F)cc21
Yield: 94 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 6-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) for the ethyl indole-2-carboxylate, the title compound (0.3 g, 94%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11]([C@@H:13]3[C@@H:15]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14]3)=[O:12])=[CH:4][C:3]=2[O:2]1.[N-:20]=[N+:21]=[N-:22].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:12])[C@@H:13]([OH:14])[C@@H:15]([N:20]=[N+:21]=[N-:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=2[O:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC[C@H]1O[C@@H]1C(=O)Nc1ccc2c(c1)OCO2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Yield: 70.1 %

Procedure:
30 ml of a methanol suspension containing 484 mg (1.84 mmol) of (2S-trans)-N-[(3,4-methylenedioxy)phenyl]-3-butyl-oxiranecarboxamide, 239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with water, and then, with a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 395 mg (Yield: 70%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)c2cc(OCCCCBr)ccc2O1
Reaction time: 5 h

Procedure:
A suspension of 96.5 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one and 76 g of potassium carbonate in 300 ml of 1,4-dibromobutane is stirred for 5 hours in a bath at 120°-130°. The reaction mixture is filtered, and the excess 1,4-dibromobutane is distilled off at about 1 Torr. The crystalline residue is triturated with ether, and filtered off under suction. There is thus obtained crude 2,3-dihydro-2,2-dimethyl-6-(4-bromobutoxy)-4H-1,3-benzoxazin-4-one, m.p. 139°-142°, which is sufficiently pure for the further reaction.
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1>CN(C1C=CN=CC=1)C.ClCCl>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:25][C@@H:21]([C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][C:17]=1[N+:26]([O-:28])=[O:27])[CH:22]([CH3:24])[CH3:23])=[O:11]
Reactant: CC(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.1 %

Procedure:
Under a nitrogen atmosphere (1S)-camphanic acid chloride (0.89 g, 4.09 mmol) was added to a solution of (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (1.10 g, 3.41 mmol) and DMAP (0.50 g, 4.09 mmol) in anhydrous dichloromethane (30 mL). The mixture was stirred for 1.5 hours at room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography to (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanates (1.44 g, 84%, 1:1 mixture of diastereomers) as a solid, which was dissolved in boiling methanol (70 mL) and left at room temperature overnight. Crystals formed were filtered to yield pure (R)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.465 g, 65%). The mother liquor was evaporated, and the residue was dissolved in boiling isopropanol (40 mL) and left at room temperature overnight. Crystals formed were filtered and recrystallized from boiling isopropanol (20 mL) to yield pure (S)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.288 g, 40%). 1H NMR (400 MHz, CDCl3) for (R,S)-camphanate: δ 8.30 (d, 1H, J=1.8 Hz, Ph-H), 7.92 (dd, 1H, J=1.8 and 8.3 Hz, Ph-H), 7.56 (d, 1H, J=8.3 Hz, Ph-H), 6.27 (d, 1H, J=6.8 Hz, Ph-CH), 2.40 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.92 (m, 1 H), 1.72 (m, 1H), 1.11 (s, 3H, CH3), 1.03 (d, J=6.8 Hz, 3H, CH3), 1.02 (s, 1H, CH3), 0.98 (d, J=6.8 Hz, 3H, CH3), 0.82 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) for (R,S)-camphanate: δ 178.21 (C), 166.92 (C), 148.67 (C), 142.07 (CH), 134.80 (C), 133.34 (CH), 129.73 (CH), 92.59 (C), 90.75 (C), 76.07 (CH), 54.79 (C), 54.34 (C), 33.27 (CH), 31.03 (CH2), 28.88 (CH2), 19.07 (CH3), 17.40 (CH3), 16.70 (CH3), 16.66 (CH3), 9.61 (CH3).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)[CH:12]=2)[NH:7][C:6]1=[O:19])C.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[O:18]1[C:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:19])[C:5]3=[CH:4][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[CH:15][N:16]=[CH:17]1
Reactant: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield from ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and 4-aminobenzenesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-6): δ 10.79 (d,1H), 10.73 (s, 1H), 8.76 (d, 1H), 8.38 (s, 1H), 8.0 ( s, 1H), 7.77 (d, 2H), 7.56 ( d, 2H), 7.43 (s, 1H), 7.40 (d, 1H), 7.26 (s, 2H), 6.91 (d, 1H); APCI−MS: m/z 381 (MH)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.N1C=CC=C[CH:34]=1.C1COCC1>ClCCCl>[CH3:34][C:19]1[N:18]=[C:17]([NH:20][C:21]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])[CH:16]=[CH:15][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:12]=1
Reactant: c1ccncc1
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)CC4CCOCC4)nc3)ccn2)cn1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)NC(=O)CC2CCOCC2)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A solution of crude 2-(tetrahydro-2H-pyran-4-yl)acetyl isocyanate (0.110 g, 0.650 mmol, see Example 4) in DCE (7 mL) was treated with Example A6 (0.183 g, 0.650 mmol) and stirred at RT overnight. Pyridine (0.11 mL, 1.3 mmol) was added, the mixture stirred at RT for 4 h, treated with THF, then washed with satd. NaHCO3 and brine, dried over MgSO4 and concentrated to dryness. The resulting material was treated with MeCN, and the solid collected via filtration and dried to afford N-((6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide (56 mg, 19%) as a pale tan solid. MS (ESI) m/z: 451.2 (M+H+).