Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C(N3CCN(C(C4C=NC(F)=CC=4C)=O)CC3)=NC=C(C3CC3)C=2)CC1.COC1C=CC(CN)=CC=1.Cl[CH2:40][CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].[NH2:47][C:48]1[N:53]=[CH:52][C:51]([C:54]([N:56]2[CH2:61][CH2:60][N:59]([C:62]3[C:67]([CH:68]4[CH2:70][CH2:69]4)=[CH:66][C:65]([CH:71]4[CH2:73][CH2:72]4)=[CH:64][N:63]=3)[CH2:58][CH2:57]2)=[O:55])=[C:50]([CH3:74])[CH:49]=1>>[CH:68]1([C:67]2[C:62]([N:59]3[CH2:58][CH2:57][N:56]([C:54]([C:51]4[CH:52]=[N:53][C:48]([N:47]5[CH2:40][CH2:41][CH2:42][S:43]5(=[O:45])=[O:44])=[CH:49][C:50]=4[CH3:74])=[O:55])[CH2:61][CH2:60]3)=[N:63][CH:64]=[C:65]([CH:71]3[CH2:73][CH2:72]3)[CH:66]=2)[CH2:69][CH2:70]1
Reactant: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (410 mg) described in Preparation Example 178, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.24 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (295 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone.
Reaction SMILES: [C:1]([CH:3]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:23])#[N:2].[CH:24](N(CC)C(C)C)(C)C.C(O)(=O)C>CO.C(#N)C.CCCCCC>[C:1]([C:3]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:21][CH:22]=2)[CH2:6][CH2:5][C:4]=1[O:23][CH3:24])#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CCC2CCC(=O)C2C#N)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Solvent: CC#N
Product: COC1=C(C#N)C(CCc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl 4-[2-(2-cyano-1-cyclopentanon-3-yl)-ethyl]benzoate (0.43 g, 1.37 mmol) prepared in the Preparative Example 105 and N,N-diisopropylethylamine (0.21 g, 1.64 mmol) were dissolved in a methanol/acetonitrile (1:5) mixture, followed by the addition of 3.2 g of a 10% by weight solution of trimethylsilyldlazomethane in hexane. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of a small amount of acetic acid. The mixture this obtained was stirred and distilled to remove the solvent. The residue was dissolved in diethyl ether, washed with diluted hydrochloric acid, dilute alkali ind an aqueous solution of common salt, dehydrated and concentrated to dryness. The residue was purified by silica gel column chromatography to give the objective compound. yield: 0.23 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[C:14]([CH3:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[C:14]([CH3:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2cc3n(c2nc1Cl)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(nc1Cl)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Yield: 80.3 %

Procedure:
To a solution of 0.26 g (0.77 mmol) (R)-6-chloro-4,7-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 mL acetic acid was added 0.24 g (3.87 mmol) sodium cyanoborohydride. After 2 h the volatile components were removed at a rotary evaporator and the residue was taken up in ethyl acetate and treated with 32% aqueous sodium hydroxide solution until a pH of 11 was obtained. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:7) as eluant to give the product as a colourless oil (80.3%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.[ClH:32].COC1CCCC1>>[ClH:32].[CH:28]1([CH2:27][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: COC1CCCC1
Product: Cc1ccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NCC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(cyclopropylmethyl)(trans-2-{4-[(4-methylbenzoyl)amino]phenyl}cyclopropyl)carbamate (104.3 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (4 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (65.0 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:27](O)=[O:28])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:27]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:28])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (275 μl) was condensed with Boc-3-(1-naphthyl)-L-alanine (970 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-[Boc-3-(1-naphthyl)-L-alanyl]morpholine (1.18 g) as a white powder (yield quantitative). After Boc group elimination with TFA, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (620 mg) as obtained in Reference Example 8 to yield the title compound (compound 79; 1.09 g) as a white powder (yield 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[C:24]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[C:24]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC(C)(C)[C@@H]1COC(=O)N1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)(C)C)cc3)CC2)c(C)c1
Yield: 1.1 %

Procedure:
To a mixture of [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (841 mg) described in Preparation Example 8, (R)-(+)-4-tert-butyloxazolidin-2-one (214 mg), potassium carbonate (553 mg) and copper (I) iodide (76 mg) were added toluene (2 mL) and N,N′-dimethylethylenediamine (100 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (7 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17]1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:25][C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and benzo[1,3]dioxole-5-carbaldehyde. 1H NMR (400 MHz, CDCl3): 7.36-7.24 (m, 4H), 7.05-6.99 (m, 1H), 6.86 (br s, 1H), 6.77-6.72 (m, 2H), 6.43 (br s, 1H), 5.95 (s, 2H), 3.50-3.46 (m, 4H), 3.43 (s, 2H), 2.46-2.42 (m, 4H).
Reaction SMILES: Br.C[O:3][C:4](=[O:15])[C:5]([CH2:11][CH2:12][CH2:13][Br:14])(C)[C:6](OC)=O.[OH-].[Na+]>>[Br:14][CH2:13][CH2:12][CH2:11][CH:5]([CH3:6])[C:4]([OH:15])=[O:3]
Reactant: COC(=O)C(C)(CCCBr)C(=O)OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CC(CCCBr)C(=O)O
Temperature: 120 °C
Yield: 62 %

Procedure:
HBr aq 48% (10 mL, 88.4 mmol) was added at room temperature to 2-(3-bromo-propyl)-2-methyl-malonic acid dimethyl ester (1.80 g, 6.74 mmol) and the mixture was stirred and heated at 120° C. for 24 hours. After cooling to room temperature, NaOH solution was added to reach pH 3 and the product was extracted using a mixture DCM:MeOH 95:5. The obtained crude (0.81 g, 62% yield) was clean enough to be used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)([CH2:19][OH:20])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][C:16]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)([CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C2CCCCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (1.8 mL, 23.0 mmol) is added to a stirred solution of 4-cyclohexyl-4-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester, 3, (3.42 g, 11.48 mmol) and triethylamine (4.8 mL, 2.8 mmol) in dichloromethane (30 mL) at 0° C. The reaction mixture is then allowed to warm to room temperature and stir for 1 hour. The reaction is quenched with a saturated solution of NaHCO3 and the resulting mixture is extracted twice with dichloromethane (50 mL). The organic layers are combined, dried, filtered and concentrated in vacuo to yield the desired product in quantitative yield. The material is used for the next step without need for purification.
Reaction SMILES: [CH3:1][Li].[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)([OH:6])=O.O>CCOCC>[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)(=[O:6])[CH3:1]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)O)c2C1
Reactant: [Li]C
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A 5% solution of methyl lithium in ether (0.6 ml, 0.96 mmol) was added to a chilled slurry of (±)-8-Carboxy-2-(dipropylamino)tetralin hydrochloride (100 mg, 0, 32 mmol) in ether. The mixture was stirred at room temperature and under nitrogen for three days. Water was added carefully and the mixture was extracted with ether. The organic layer was dried (potassium carbonate) and concentrated. The residue was purified by chromatography on an alumina column eluted with ether/light petroleum 1:4. The pure fractions were pooled, concentrated and converted into the hydrochloride. Recrystallization from acetonitrile/ether gave 55 mg (56%) of pure 8-acetyl-2-(dipropylamino)tetralin hydrochloride.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[NH:10][CH:9]1[CH2:18][NH2:19])=O)(C)(C)C>Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[NH:10][C:9]([CH2:18][NH2:19])=[N:8][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)ccc2NC1CN
Agent: Cl
Product: NCc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.62 g (16.4 mmol) N′-tert.-butoxycarbonyl-C-(5-chloro-1H-benzimidazol-2-yl)methylamine are dissolved in 100 ml saturated ethanolic hydrogen chloride solution and stirred for 2 hours at ambient temperature. Then all the volatile constituents are eliminated under reduced pressure and the crude product is further reacted.
Reaction SMILES: [CH2:1]([CH:11]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:12]([OH:14])=[O:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C(OCC)(=O)C>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:13][C:12](=[O:14])[CH:11]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)=CCC/C(C)=C/CC(C/C=C(\C)CCC=C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC(C/C=C(\C)CCC=C(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Digeranylacetic acid (300 mg, 0.9 m mol) and p-nitrophenol (139 mg, 1 m mol) were dissolved in acetonitrile-ethyl acetate (1:1) (10 ml), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (227 mg, 1.1 m mols) was added. The mixture was stirred at 0° C. for 3 hours and at room temperature for 15 hours. The crystalline precipitate was removed and the solvent was distilled off under reduced pressure, whereby digeranyl acetic acid p-nitrophenyl ester was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1([C:13]2[C:14]([OH:30])=[C:15]([C:25](OCC)=[O:26])[CH:16]=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([C:13]2[C:14]([OH:30])=[C:15]([C:25]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)=[O:26])[CH:16]=[N:17][C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)c1O
Product: O=C(Nc1nccs1)c1cnc(-c2ccccc2)c(-c2ccccc2)c1O
Yield: 64.1 %

Procedure:
Using the procedure of Example 5, 2.5 g of 2-aminothiazole and 1.6 g of the product of Step A were reacted to obtain 1.2 g of the expected product melting greater than 260° C. after crystallizing from acetonitrile.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN2C(=O)OC[C@H]2C)cc1
Yield: 74.4 %

Procedure:
Using methyl 4-bromomethylbenzoate (1.00 g) and (R)-4-methyloxazolidin-2-one (0.49 g) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (0.81 g) was obtained.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:23](=[O:24])[C:22]2[CH:26]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])/[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1cn(C[C@@H]2CCCO2)c(=N)s1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCO1

Procedure:
The products from Example 315A and 5-chloro-2-methoxy-benzoic acid were processed using the method described in Example 300 to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H), 1.62-1.95 (m, 3H), 2.00-2.12 (m, 1H), 3.72-3.87 (m, 2H), 3.90 (s, 3H), 4.18-4.34 (m, 2H), 4.42 (dd, J=12.0, 2.4 Hz, 1H), 6.86 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.32 (dd, J=8.8, 2.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H). MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [OH-].[Na+].CO.[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([O:15]CC)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C(\c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
20 ml of a 10% w/v aqueous solution of sodium hydroxide were added to 35 ml of a methanol solution containing 3.41 g of ethyl (E)-3-phenyl-3-(4-pyridyl)acrylate (prepared as described in Preparation 2), and the mixture was stirred for 1 hour at room temperature. At the end of this time, the reaction solution was poured into 50 ml of water and washed with methylene chloride. Sufficient hydrochloric acid was added to the aqueous phase to adjust the pH to a value of 2.8. The resulting precipitate was collected, giving 2.131 g of the title compound, as a white powder, melting at 239°-241° C.
Reaction SMILES: [P+3]=O.[F:3][C:4]1[CH:9]=[C:8]([CH:10](O)[CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]([F:16])[CH:5]=1>CCCCC>[F:3][C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]([F:16])[CH:5]=1
Reactant: CCCCC(O)c1cc(F)cc(F)c1
Agent: O=[P+3]
Solvent: CCCCC
Product: CCCC=Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus(v) oxide (64.5 g, 0.45 mol) is added to a stirred solution of compound 9A (35.0 g, 0.175 mol) in dry pentane (150 ml) at room temperature. The mixture is stirred at room temperature overnight (glc analysis revealed absence of starting material) and filtered.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:6]=1[CH2:7][CH2:8][CH:9]([CH3:11])[CH:10]=2>[Pd].C(OCCCC)(=O)/C=C\C(OCCCC)=O>[CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][C:3]1=[O:12]
Reactant: CC1=C2CCC(C)C=C2OC1=O
Agent: [Pd]
Agent: CCCCOC(=O)/C=C\C(=O)OCCCC
Product: Cc1ccc2c(c1)OC(=O)C2C
Temperature: 170 °C
Yield: 74.4 %

Procedure:
A mixture of 1000 g of 5,6-dihydro-3,6-dimethyl-2(4H)-benzofuranone, 2000 ml of dibutyl maleate and 50 g of palladium-on-charcoal, 5% by weight, was heated for approx. 3 hours at 170° C. in an autoclave under autogenous pressure. After filtration, the product was purified by fractionating on an 80 cm packed column. Approx. 735 g of pure 3,6-dimethyl-2(3H)-benzofuranone were obtained at a b.p. of approx. 90° C. at 1 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:14][CH:13]=[CH2:12])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cc(Br)ccc1O
Reaction time: 72 h
Yield: 90.7 %

Procedure:
A mixture of 5-bromosalicylic acid (10 g, 46 mmol), allyl bromide (6.12 g, 51 mmol) and sodium bicarbonate (4.65 g, 55 mmol) in 50 ml of DMF was stirred under a drying tube for 72 hr. The reaction mixture was poured into water, extracted with ethyl acetate. and the organic layer dried over MgSO4. Concentration under vacuum gave 10.73 g (91%) of product (1-Scheme 2) with the expected NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH:20]([F:31])[O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH:20]([F:31])[F:19])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS1174323-34-2, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=431.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl>[CH3:20][NH:21][C:22]([O:12][C@H:11]1[C@H:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:10]1)=[O:23]
Reactant: CN(C)C(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1CN(C(=O)N(C)C)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A solution of 1.0 g. (0.003 mole) of trans-3-(4-chlorophenoxy)-4-hydroxy-N,N-dimethyl-1-pyrrolidinecarboxamide and 1.0 g. (0.02 mole) of methylisocyanate in 20 ml. of methylene chloride was let stand at ambient temperature for 48 hr. The solution was concentrated to give an oil which crystallized upon standing. The solid was recrystallized from benzene-cyclohexane to yield 0.6 g. (50%) of white solid, m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.C(O)=O.C(=O)(O)[O-].[Na+]>CO.C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: Cc1cccc(N)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Solvent: CO
Product: Cc1cccc(NCc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.170 g, 0.56 mmol) and 2-amino-6-picoline (0.050 g, 0.46 mmol), in methanol (10 mL) was refluxed overnight. The reaction was concentrated and the residue was flash chromatographed on silica gel (25 g). Elution proceeded as follows: 10% ethyl acetate/hexane (500 mL), nil; 20% ethyl acetate t hexane (300 mL), nil; (100 mL), 0.082 g of intermediate imine; (300 mL), 0.192 g of a mixture of starting material and imine. The pure imine (0.082 g 0.21 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (0.082 g) and formic acid (0.357 mL, 9.45 mmol) were added. The reaction was stirred at ambient temperature for 24 hours. The reaction was carefully neutralized with sodium bicarbonate and then filtered through celite. The pad was well washed with ethyl acetate. The filtrate was concentrated to afford 0.068 g (82%) of 3-(2-chloro-phenyl)-6-fluoro-2-[(6-methyl-pyridin-2-ylamino)-methyl]-3H-quinazolin-4-one as a colorless oil which had: 1H NMR δ 7.92 (dd, J=3, 8 Hz, 1H), 7.80 (dd, J=5, 9 Hz, 1H), 7.65-7.64 (m, 1H), 7.53-7.48 (m, 4H), 7.43-7.40 (m, 1H), 7.37-7.31 (m, 1H), 6.47 (d, J=7 Hz, 1H), 6.25 (d, J=8 Hz, 1H), 4.18 (dd, J=5, 18 Hz, 1H), 4.00 (dd, J=5, 18 Hz, 1H), 2.37 (s, 3H); APCI MS m/z=395 (P+1).