Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:9])[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc(Cl)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc(Cl)c1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 3-chloro-2-fluoro-phenol (1.31 g, 8.93 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 61%) as a white solid: HR-ES-MS m/z calculated for C12H12O3FCl [M+H]+ 259.0532, observed 259.0531; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.03 (q, J=7.1 Hz, 2H), 4.76 (s, 1H), 7.27-7.39 (m, 2H), 7.50-7.61 (m, 1H).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].N12CCCN=C1CCCCC2>C(O)C>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CNC(N)=S
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(S)nc(-c2ccncn2)cc1=O
Yield: 82.8 %

Procedure:
A solution of ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (36.10 g, 0.186 mol), N-methylthiourea (25.40 g, 0.282 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (29.11 g, 0.191 mol) in ethanol (150 ml) was refluxed for 21 hrs. A half amount of ethanol was evaporated under reduced pressure and hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with water and dried. The precipitate was stirred in hot ethyl acetate (1 L), and the precipitate was collected by filtration and dried to give 2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (33.91 g, 83%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: NCCCN1CCCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(NCCCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 24 h

Procedure:
1 g (5.884 mmol) 4-fluoro-2-methoxy-1-nitro-benzene, 975 mg (7.369 mmol) 1-(3-aminopropyl)pyrrolidine and 1.5 ml (8.765 mmol) diisopropyethylamine are dissolved in 5 ml dioxane and stirred for 24 h at 95° C. The solvents are eliminated in vacuo and the crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.CN1CCNCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 188.8 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Methylpiperazine (9.0 g) and triethylamine (8 ml) are added to the bottle. The above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum for 5 h at to obtain solid purin (12.0 g). The yield is about 67.4%.
Reaction SMILES: [CH3:1][C:2]1([C:5](O)=O)[CH2:4][CH2:3]1.[NH2:8][NH:9][C:10]([NH2:12])=[S:11].O(Cl)Cl.[P+3]>O1CCOCC1>[CH3:1][C:2]1([C:5]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:4][CH2:3]1
Reactant: NNC(N)=S
Reactant: CC1(C(=O)O)CC1
Agent: ClOCl
Agent: [P+3]
Solvent: C1COCCO1
Product: CC1(c2nnc(N)s2)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 16.4 %

Procedure:
Combine 1-methylcyclopropane-1-carboxylic acid (10.00 g, 99.88 mmol), and thiosemicarbazide (9.10 g, 99.88 mmol) in dioxane (110 mL). Heat the mixture to 90° C. under N2, then add phosphorus(III) oxychloride (9.14 mL, 99.88 mmol) dropwise over 25 minutes. The reaction mixture is stirred for 6 hours at 90° C., then 8 hours at room temperature. Decant onto 200 g ice and add ammonium hydroxide to make basic. Filter to remove solids; the filtrate is extracted with ethyl acetate. The organic layer is washed with water. Dry the resulting organics over magnesium sulfate, filter, and concentrate to give product (2.54 g, 16%). MS (ES), m/z 156 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:17][CH2:28][CH2:27][CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCl
Reactant: CCOC(=O)c1cc2cc(Br)ccc2cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2cc1OCCCNC(=O)OC(C)(C)C
Yield: 99.6 %

Procedure:
A mixture of 3.8 g (12.88 mmol) ethyl 7-bromo-3-hydroxynaphthalen-2-carboxylate, 3.0 g (15.5 mmol) 1-(tert.-butoxycarbonylamino)-3-chloropropane (prepared according to Helv. Chim. Acta 76 (1993), 1644), 2.0 g (14.5 mmol) potassium carbonate, and a catalytic amount of potassium iodide in 20 ml dry DMF was stirred at 90° C. for 6 h. It was poured into water, extracted three times with ethyl acetate, and the combined organic layers were washed three times with water, dried over sodium sulfate, and concentrated in vacuo. The intermediate was purified by chromatography on silica gel with toluene/acetone 9:1 to give 5.8 g (100%) of a yellow oil, which solidified rapidly upon standing.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:35])[N:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:14]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.[NH2:48][C:49]1[NH:53][N:52]=[N:51][N:50]=1.O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:35])[N:13]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:48][C:49]3[N:50]=[N:51][NH:52][N:53]=3)=[O:31])=[CH:33][CH:34]=2)[CH:14]2[CH2:15][CH2:16][C:17]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:19]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Nc1nnn[nH]1
Reactant: CS(=O)(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)O)cc2)C2CCC3(CCCCC3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C2CCC3(CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid (32.2 mg, 64.6 μmol) was dissolved in DMF (1 mL) and added N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) (16.5 mg, 86 μmol) and 5-aminotetrazole.H2O (16,5 mg, 160 μmol). The mixture was stirred at 25° C. for 1 day and concentrated in vacuo. Brine (5 mL) was added to the residue followed by a mixture of ethanol and chloroform (1:2, 10 mL). The phases were separated and the aqueous layer was extracted with a mixture of ethanol and chloroform (1:2, 2×10 mL). The combined organic extracts were dried over MgSO4 and evaporated. The residue was purified by preparative HPLC affording the title compound.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH3:10][C:9]1([CH3:11])[CH:3]2[CH:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)=CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CC(=O)CC(C)=O
Product: CC1(C)C2COC(=O)C21
Yield: 73.9 %

Procedure:
A solution of 3-methyl-2-butenyl diazoacetate (41.3 mmole, 6.36 g) in dioxane (20 ml) was added dropwise to a refluxing solution of cupric acetylacetonate (1.03 mmole, 0.27 g) in dioxane (400 ml) over a period of 7 hours under an argon atomosphere. After completion of the addition, the reaction mixture was heated under reflux for 1 hour. The crude reaction mixture was distilled to afford (±)-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (3.85 g, 75% yield); bp 110°, 16 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14])[C:6]([CH3:12])=[N:7]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH3:12][C:6]1[C:5]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])=[CH:4][C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc2nccc(Cl)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1nc2nccc(N3CCOCC3)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 30.4 %

Procedure:
5-Chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide (100 mg, 0.26 mmol) was dissolved in THF (10 ml) together with morpholine (45 μl, 0.52 mmol) and refluxed for 18 hours. The reaction was cooled and evaporated, the residue was purified by flash chromatography using CH2Cl2/CH3OH (20:1→10:1) as eluent to give 34 mg (30%) of 2-methyl-5-morpholino-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide as a pale mass.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:34]=2[Cl:33])[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 1.8 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2,3-dichloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.4 mg, 1.8%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].OCC1N=CN(C)N=1.N1C=CC=CC=1CO[C:27]1[C:36]2[C:31](=[C:32](OCC3C=CC=CN=3)[CH:33]=[CH:34][CH:35]=2)[C:30]2=NN=C(C3C=C(C)ON=3)[N:29]2[N:28]=1.O>CN(C)C=O>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29][N:28]=1
Reactant: Cc1cc(-c2nnc3c4c(OCc5ccccn5)cccc4c(OCc4ccccn4)nn23)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cn1cnc(CO)n1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2cnncc2c1
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
Lithium hexamethyldisilazide (1.0 M solution in hexane) (0.22 ml, 1.10 mmol) was added to stirred solution of 3-hydroxymethyl-1-methyl-1,2,4-triazole (90 mg, 0.79 mmol) (prepared using the conditions of Itoh and Okongi, EP-A-421210) in N,N-dimethylformamide (10 ml) at −10° C. under nitrogen, and the mixture stirred for 0.25 h. After this time, Intermediate 6 (100 mg, 0.53 mmol) was added and the mixture stirred at −10° C. for 0.5 h and then room temperature overnight. Water was added to the reaction mixture and the resulting precipitate filtered off and recrystallised from dichloromethane/ethyl acetate to give the title-phthalazine (55 mg, 27%), mp 221-223° C.; 1H NMR (360 MHz, CDCl3) δ 1.54 (3H, t, J=10.2 Hz, CH3), 3.96 (3H, s, CH3), 4.47 (2H, q, J=10.2 Hz, CH2), 5.71 (2H, s, CH2), 6.26 (1H, s, Ar—H), 7.79 (1H, m, Ar—H), 7.94 (1H, m, Ar—H), 8.08 (1H, s, Ar—H), 8.25 (1H, d, J=11.0 Hz, Ar—H), 8.70 (1H, d, J=8.1 Hz, Ar—H); MS (ES30) m/e 393 [MH]+; Anal. Found. C, 54.87; H, 3.91; N, 28.27; C18H16N8O3 requires C, 55.09; H, 4.11; N, 28.55%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:13])[CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]([S:24](Cl)(=[O:26])=[O:25])([CH3:23])[CH3:22]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:13])[CH2:11][NH:12][S:24]([CH:21]([CH3:23])[CH3:22])(=[O:26])=[O:25])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@@H](CN)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and an addition funnel is charged with (2R)-2-(4-nitrophenyl)propylamine (11.75 g, 65.21 mmol), methylene chloride (150.0 mL) and triethylamine (18.2 mL, 130.4 mmol). To this solution at 0° C. was added isopropylsulfonyl chloride (8.92 mL, 63.9 mmol) over a period of 20 minutes. Reaction was then stirred to room temperature overnight, then quenched with 1N HCl (150.0 mL). The lower organic layer is separated and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (14.11 g, 97%) as an oil; 1H nmr (CDCl3, 300 MHz) δ 1.26 (d, 3H, J=6.7Hz), 1.31 (d, 6H), 3.06 (m, 1H), 3.30 (m, 1H), 4.25 (broad triplet, 1H), 7.38 (d, 2H), 8.10 (2H); 13C nmr (CDCl3, 300 MHz) δ 16.75, 18.95, 41.29, 50.15, 53.85, 124.22, 128.52, 151.26.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:12][C:13]([F:23])([F:22])[C:14]([C:18]([F:21])([F:20])[F:19])([OH:17])[CH2:15]O.Cl.C1(C)C=CC=CC=1>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]([C:18]([F:19])([F:21])[F:20])([OH:17])[CH2:15][O:9][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:11])=[O:10]
Reactant: OCC(O)(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
Under ice cooling, a solution of 54 g of p-toluene sulfonate in 140 g of pyridine was added dropwise to a mixture of 93 g of the 61 wt % IPE solution of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol prepared in Reference Synthesis Example and 140 g of pyridine. Stirring was continued for 48 hours at room temperature. The reaction solution was ice cooled and poured into a mixture of 678 g of 20 wt % hydrochloric acid aqueous solution and 100 g of ice to quench the reaction. Toluene, 500 g, was added to the reaction solution, which was separated into layers. The organic layer was washed with water, concentrated, and recrystallized from heptane, obtaining 74 g of 3,3,3-trifluoro-1-(p-toluene-sulfonyloxy)-2-trifluoromethylpropan-2-ol (yield 74%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: C=CCOc1ccc(C(=O)Cl)cc1

Procedure:
A mixture containing 29.9 g. of 4-allyloxybenzoic acid and 250 ml. of thionyl chloride was stirred and refluxed for 90 minutes and the excess thionyl distilled off, first at atmospheric pressure and then at reduced pressure. Ethylene dichloride was added and the solution evaporated in vacuo to remove the ethylene dichloride and remaining traces of thionyl chloride to give a quantitative yield of 4-allyloxybenzoyl chloride.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=O)C.NC1C=C(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=[O:27])C=2C=1>O>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:9])=[O:27]
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Solvent: O
Product: Cc1c(O)cccc1C(=O)O

Procedure:
The present invention relates to a process for the preparation of 3-acetoxy-2-methylbenzoyl chloride by reacting an alkali metal salt of 3-aminonaph-thalene-1,5-disulfonic acid with alkali metal hydroxide and water in the weight ratio 1:(1 to 1.6):(1 to 1.6) at 220 to 320° C. to give the dialkali metal salt of the 3-hydroxy-2-methylbenzoic acid, separating off insoluble constituents from the reaction mixture, then adjusting the reaction mixture to a pH of 11.5 to 13.5 by addition of acid and reacting with acetic anhydride at -5 to +25° C., precipitating the 3-acetoxy-2-methylbenzoic acid by addition of acid, separating off the 3-acetoxy-2-methylbenzoic acid and reacting it with an inorganic acid chloride to give 3-acetoxy-2-methylbenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=O.[C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:15]>C(#N)C>[NH2:15][C:14]1[CH:16]=[CH:12][C:3]2[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=2[N:1]=1
Reactant: Cn1c(N)c(C=O)c(=O)n(C)c1=O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Cn1c(=O)c2ccc(N)nc2n(C)c1=O
Yield: 39.5 %

Procedure:
0.18 g of 6-amino-5-formyl-1,3-dimethyluracil and 0.45 g of cyanomethylenetriphenylphosphorane were added to 20 ml of dried acetonitrile. The solution was heated under reflux for 12 hr in a stream of argon. After cooling, the precipitated crystal was separated by filtration to give 0.08 g of 7-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 15).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]1([CH3:55])[CH2:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:53]([NH2:54])[C:47]=2[O:46]1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:54][C:53]3[C:47]4[O:46][C:45]([CH3:55])([CH3:44])[CH2:49][C:48]=4[CH:50]=[CH:51][CH:52]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cccc4c3OC(C)(C)C4)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 2,2-dimethyl-2,3-dihydro-benzofuran-7-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=425.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:4].[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O.[F:30]OC(F)(F)F>FC(Cl)(Cl)Cl>[F:30][C:10]12[CH2:11][CH:12]3[CH2:14][CH:8]([CH2:7][C:6]([O:5][C:3](=[O:4])[C:2]([F:16])([F:17])[F:1])([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: FOC(F)(F)F
Reactant: O=C(OC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Solvent: FC(Cl)(Cl)Cl
Product: O=C(OC12CC3CC(CC(F)(C3)C1)C2)C(F)(F)F
Yield: 45.9 %

Procedure:
A solution of 1-trifluoroacetoxyadamantane (1.0 g, 4.0 mmole, prepared by reacting adamantan-1-ol with trifluoroacetic anhydride in dry pyridine) in fluorotrichloromethane (10 ml), containing m-dinitrobenzene (80 mg, 0.48 mmole), was treated with trifluoromethyl hypofluorite (4.5 mmole) at -25° for 24 hours, air being recrystallization admitted to the reaction vessel during this time. The product was recovered in a similar manner to that described in Example 3 and was chromatographed on silica (100 g). Elution with chloroform:hexane (1:5) afforded unreacted starting material (152 mg), while elution with chloroform:hexane (1:4) gave liquid 3-fluoro-1-trifluoroacetoxyadamantane (489 mg) which appeared homogeneous by g.l.c. This product sublimed at 70° (bath)/1 mm Hg to give a crystalline solid m.p. 28°-32°; νmax (film) 1780 cm-1 ; PMR 1.5-2.6 (m, adamantyl protons); FMR φ* + 76.2 (s, CF3COO--) and + 133.5 (broad s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:37]([C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([O-:39])=[O:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:43]2[CH:44]=[CH:45][C:40]([N+:37]([O-:39])=[O:38])=[CH:41][CH:42]=2)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
To a solution of N-Boc-trans-4-hydroxyproline methyl ester (10.0 g, 41 mmol) 150 mL of anhydrous THF at 0° C. under N2 was added triphenylphosphine (12.7 g, 48 mmol) and 4-nitrophenol (6.7 g, 48 mmol). To this mixture was added diethylazodicarboxylate (7.7 mL, 48 mmol) dropwise over a 30 minute period. The mixture was warmed to room temperature. After stirring for 2 days, the solvent was removed in vacuo, and the crude oil treated successively with 200 mL portions of toluene and ether to remove triphenylphosphine oxide and diethylazodihydrazide by crystallization. The resulting oil was then chromatographed (SiO2, 15-50% ethyl acetate/hexanes) to provide 5.2 g (34%) of N-Boc-4-(cis)-(4-nitrophenoxy)-L-proline methyl ester as a light yellow oil.