Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.Cl[C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=[C:21]([C:29]([F:31])([F:32])[F:30])[N:20]=2)=[CH:8][CH:7]=1)([O-:17])=[O:16]
Reactant: NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1ccc(CNc2nc(C(F)(F)F)nc3c2CCCC3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 2.56 g (11.2 mmol) of 2-(4'-aminomethylphenyl)nitrobenzene, 2.88 g (12.2 mmol) of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, and 8.0 g (58 mmol) of potassium carbonate in DMF was stirred at 100° C. overnight. The reaction mixture was quenched with water and extracted intomethylene chloride/tetrahydrofuran. The organic phase was washed with brine, dried over potassium carbonate, and purified by flash chromatography (elutions of ether/petroleum ether (1:2, then 1:1), then 10% ether/methylene chloride) to give 3.86 g (81%) of 5,6,7,8-tetrahydro-N-[(2'-nitro[1,1'-biphenyl]-4-yl)methyl]-2-(trifluoromethyl)-4-quinazolinamine, mp 150°-151° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[C:23]([Cl:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c3ccccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cc(NC2CCNCC2)nc2ccccc12

Procedure:
A solution of 4-(4-chloro-quinolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.61 mmol) in 4 M HCl in dioxane (30 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 262.3 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24](Cl)[C:23]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=2[F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][Mg]Cl.Cl>CC(C1C=CC=C(C(C)C)C=1N1[C-]=[N+](C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1COCC1.C(OCC)C>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([CH2:36][C:37]([CH3:42])([CH3:41])[CH3:38])[C:23]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=2[F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2Cl)c1
Reactant: CC(C)(C)C[Mg]Cl
Agent: CC(C)c1cccc(C(C)C)c1N1[C-]=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, to a solution of 6-((tert-butyldiphenylsilyloxy)methyl)-2-chloro-3-(2-fluoro-5-methoxyphenyl)pyridine (10.0 g) and a PEPPSI™-SIPr catalyst (trade name) (1.33 g) in THF (100 mL) was added a 1.5 M solution of 2,2-dimethylpropylmagnesium chloride in diethyl ether (50 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10.0 g) as a brown crude oil. This compound was used for the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:28](=[O:30])[NH2:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[NH2:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1)[C:28]([NH2:29])=[O:30]
Reactant: CC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)COc1ccc(C[C@H](N)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of {(S)-1-carbamoyl-2-[4-(2-oxopropoxy)phenyl]ethyl}carbamic acid tert-butyl ester (2.65 g, 7.88 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. The latter procedure was repeated once. The crude product was purified by C-18 reversed phase chromatography on a HPLC, using a gradient of 13-33% acetonitrile in water in a buffer of trifluoroacetic acid (0.1%) to give 460 mg of (S)-2-amino-3-[4-(2-oxopropoxy)phenyl]propionamide.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH2:26])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=O)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>ClCCl.C(N(CC)C(C)C)(C)C>[CH:44]1([C:48]([NH:26][C:14]2[CH:15]=[C:16]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:17]=[CH:18][C:13]=2[C:12]([NH:11][C:10]2[C:9]3[CH2:28][N:29]([S:33]([C:36]4[CH:37]=[C:38]([F:43])[CH:39]=[C:40]([F:42])[CH:41]=4)(=[O:34])=[O:35])[C:30]([CH3:32])([CH3:31])[C:8]=3[NH:7][N:6]=2)=[O:27])=[O:49])[CH2:47][CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)c(NC(=O)C3CCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a solution of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (105 mg, 0.17 mmol) in dichloromethane (5 mL) and N,N-diisopropylethylamine (1 mL), cyclobutanecarbonyl chloride (28.5 microL, 0.25 mmol) was added and the reaction mixture stirred at room temperature for 2 hours. The mixture was then diluted with dichloromethane (30 mL), washed with water (30 mL), dried over sodium sulphate and evaporated to dryness. The crude oil was then treated with MeOH (5 mL) and triethylamine (3 mL) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH-30% NH4OH 100:10:1 as the eluant, affording the title compound as white solid (21 mg).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[F:36])[O:23][N:22]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])[O:23][N:22]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: Fc1ccc(C(F)(F)F)cc1-c1nc(CCl)no1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(C(F)(F)F)ccc3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 3-(chloromethyl)-5-[2-fluoro-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (Example 366A): 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 7.85 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.49 (s, 1H), 5.68 (s, 2H), 2.14 (m, 1H), 1.15 (m, 2H), 0.92 (m, 2H); MS (ES) m/z 495 (M+1).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:25])[CH2:5][O:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C:10]([C:22](=[O:24])[CH3:23])=[CH:9][CH:8]=1.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH:29]=O>C(O)C.O>[CH3:25][C:4](=[CH2:3])[CH2:5][O:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C:10]([C:22](=[O:24])[CH:23]=[CH:29][C:28]2[C:27]([Cl:26])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[CH:9][CH:8]=1
Reactant: C=C(C)COc1ccc(C(C)=O)c2oc3ccccc3c(=O)c12
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)COc1ccc(C(=O)C=Cc2c(Cl)cccc2Cl)c2oc3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(2-methylallyloxy -4acetyl-xanthen-9-one (2.31 g, 0.0075 mol) and 2,6dichloro-benzaldehyde (1.31 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.1 g of product m.p. 135-137° C., 1H-NMR (CDCl3)δ:4.74 (m, 2H), 5.4 (m, 2H), 5.95 (m, 1H), 7.06-8.5 (m, 11 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].N1(CCCCCOC2C=CC(O)=CC=2)C=CN=C1.BrCCCCC(C)(C)C(OCC)=O>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCn2ccnc2)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: CCOC(=O)C(C)(C)CCCCBr
Agent: Oc1ccc(OCCCCCn2ccnc2)cc1
Product: CCOC(=O)C(C)(C)CCCCCOc1ccc(OCCCn2ccnc2)cc1

Procedure:
p-[3-(1-Imidazolyl)propoxy]phenol and ethyl 7-bromo-2,2-dimethylheptanoate were used as starting compounds in place of p-[5-(1-imidazolyl)pentyloxy]phenol and ethyl 6-bromo-2,2-dimethylhexanoate, respectively, in EXAMPLE 30. The starting compounds were heated and treated in a manner similar to EXAMPLE 30 to give the desired product, ethyl 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoate, as an oily substance. ##STR88##
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(S)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: SCCc1ccccc1
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCc2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of trans-N-cyanomethyl-2-(4-methylsulfanylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.1 g, 0.298 mmol), phenethyl mercaptan (0.103 mL, 0.764 mmol) and cesium carbonate (0.25 g, 0.764 mmol) was dissolved in dimethylformamide (1.5 mL) and heated at 100° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, evaporated to dryness, and purified on a short plug of silica gel (2040% ethyl acetate/CHCl3), yielding the desired product. NMR (DMSO-d6): 1.1 (3H, m); 1.3 (1H, m) 1.6-1.7 (3H, m); 2.03 (2H, m); 2.16 (1H, d): 2.92 (3H, m); 3.15 (1H, dd); 3.36 (2H, m); 4.03 (2H, d); 7.1 (1H, d); 7.25 (4H, m); 7.47 (2H, d); 7.68 (2H, d); 8.56 (1H, t). MS [ESI, (M+Na)+] m/z=479 amu.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26]>>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[C:7]3[NH:8][C:25](=[O:26])[C:24](=[O:30])[NH:1][C:2]=3[N:3]=[CH:4][CH:5]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1
Yield: 25 %

Procedure:
A solution of tert-butyl 4-(2,3-diamino pyridin-4-yloxy)phenylcarbamate (0.320 g, 1.0 mmol) in diethyl oxalate (2 ml) is reacted twice for 10 minutes in a microwave reactor (180 C, 150 W). The solution is cooled and the solid filtered and washed with cold ethanol. Obtained 8-(4-aminophenoxy)pyrido[2,3-b]pyrazine-2,3(1H,4H)-dione (70 mg, 25% yield) as a grey solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])=[O:25]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19]([C:31]4[CH:30]=[CH:29][C:28]([CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:33][CH:32]=4)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid isopropyl ester and [4-[(methylsulfonyl)methyl]phenyl]boronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:44][CH2:45][CH3:46])=[C:24]([NH:27][C:28](=[O:43])/[CH:29]=[CH:30]/[C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OC(C)(C)C)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:47]#[N:48])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:44][CH2:45][CH3:46])=[C:24]([NH:27][C:28](=[O:43])/[CH:29]=[CH:30]/[C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:47]#[N:48])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1CCCN1
Reaction time: 12 h
Yield: 14.6 %

Procedure:
tert-Butyl (2S)-2-[(E)-3-[[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]amino]-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate 2d (161 mg, 0.24 mmol) was dissolved in a solution of hydrogen chloride (2M) in 25 mL of 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S)-pyrrolidin-2-yl]prop-2-enamide 2 (20 mg, yield 14.6%) as a yellow solid.
Reaction SMILES: C(O[CH:4]=[C:5]([CH2:8][CH3:9])[C:6]#[N:7])C.[NH2:10][C:11]([NH2:13])=[O:12].CC[O-].[Na+].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH2:8]([C:5]1[C:6]([NH2:7])=[N:10][C:11](=[O:12])[NH:13][CH:4]=1)[CH3:9]
Reactant: NC(N)=O
Reactant: CCOC=C(C#N)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCc1c[nH]c(=O)nc1N
Yield: 66.1 %

Procedure:
25 g (0.2 mol) of 3-ethoxy-2-ethyl-acrylonitrile were added over a period of 1 hour to a refluxing mixture of 15.6 g (0.26 mol) of urea and 15.7 g (0.23 mol) of sodium ethylate in 50 g of xylene, and the resulting mixture was heated for 3 additional hours at its boiling point. Thereafter, the ethanol in the reaction mixture was distilled off, and the residue was taken up in 120 g of water. The aqueous phase was separated and admixed with 13.8 g (0.23 mol) of acetic acid. The precipitated product was collected by suction filtration and recrystallized from water in the presence of activated charcoal. 18.4 g (66.3% of theory) of pure 5-ethyl-cytosine were obtained.
Reaction SMILES: [N+:1]([CH:4]1[CH2:7][O:6][CH2:5]1)([O-:3])=[O:2].[OH-].[Na+].[N:10]([O-:12])=[O:11].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C(Cl)Cl>[N+:1]([C:4]1([N+:10]([O-:12])=[O:11])[CH2:7][O:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: O=[N+]([O-])C1COC1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])C1([N+](=O)[O-])COC1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of 1.5 g (14.5 mmoles) of 3-nitrooxetane and 0.87 g (22 mmoles) of sodium hydroxide in 10 mL of water was stirred for 10 minute and 10 mL of methylene chloride was added. Then, a solution of 4.0 g (58 mmoles) of sodium nitrite in 10 mL of water was added, followed by 3.5 g of solid sodium persulfate and a solution of 0.96 g (2.9 mmoles) of potassium ferricyanide in 5 mL of water. A cold water bath was used to moderate the slightly exothermic reaction. After 30 minutes, the phases were separated and the aqueous layer extracted with two 30 mL portions of ether. The combined etheral extracts were washed with brine, dried and concentrated. Care was taken not to lose the very volatile product in this concentration step. The crude material was purified by sublimation at 120°-140° C. at atmospheric pressure to give 1.6 g (75% yield) of 3.3-dinitrooxetane, m.p. 70°-71° C. Its IR was identical with that of an authentic sample. 'H NMR (CDCl3): & 5.20 (s, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[CH:4]=[C:3]([C:18]([F:21])([F:20])[F:19])[C:2]([C:22]#[N:23])=[N:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CNc2cnc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CNc2cnc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
An oil bath was preheated to 180° C. A mixture of 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine (19.45 g, 61.55 mmol), Zn(CN)2 (8.7 g, 73.86 mmol), and dppf (6.8 g, 12.31 mmol) in DMF (250 mL) was stirred at room temperature while bubbling nitrogen for 5 min. Pd2(dba)3 (2.8 g, 3.07 mmol, 0.05 eq.) was then added and the reaction mixture was placed inside the pre-heated bath. The bath temperature dropped to 160° C. The mixture started refluxing when the bath temperature reached 170° C. (takes 20 min). Refluxed for 10 min. The reaction mixture was cooled to room temperature and it was filtered through a pad of celite. The pad of celite was washed with EtOAc. The solvent was removed using a rotovap hooked up to a high vac. pump. The black residue was partitioned between EtOAc and water. An orange solid (some dppf by-product) precipitated and was filtered and washed with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, and concentrated to dryness. The black residue was dissolved in DCM and loaded onto a silica gel plug. The plug was washed with DCM (to get rid of some of the fast eluting impurities) followed by 1:1 EtOAc/hexanes (to move the desired). The fractions containing the desired were combined, evaporated to dryness and the residue obtained was purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/hexanes to afford 15 g of 5((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile as reddish thick oily residue. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (t, 1H), 7.31 (m, 3H), 6.92 (d, 2H), 4.41 (d, 2H), 3.73 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7][CH:6]=[C:5]2[C:17]([CH3:20])([CH3:19])[CH3:18].C([Li])CCC.CN(C)[CH:28]=[O:29]>CCOCC>[C:17]([C:5]1[C:4]2[CH:3]=[C:2]([CH:28]=[O:29])[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:9]=2[C:8]([CH3:16])([CH3:15])[CH2:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: CCOc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOc1cc2c(cc1C=O)C(C(C)(C)C)=CCC2(C)C
Temperature: -40 °C

Procedure:
To a solution of 6-bromo-4-tert-butyl-7-ethoxy-1,1-dimethyl-1,2-dihydronaphthalene (Compound A-6, 600 mg, 1.78 mmol) in ether (10 mL) at −78° C. was added n-butyllithium (2.3 mL 1.6 M in hexane, 3.9 mmol). After stirring at −78° C. for 25 nm, N,N-dimethylformamide (2 mL) was added and the reaction mixture was allowed to warm to −40° C. over 10 min. The reaction mixture was quenched with water and extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 3% to 10% ethyl acetate in hexane) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.OS(O)(=O)=O>C(O)CCC>[CH2:7]([O:18][C:17](=[O:19])[CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)[CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid are heated under reflux with 1 ml. of concentrated H2SO4 and 30 ml. of n-butanol for 7 hours. The mixture is evaporated and taken up in chloroform and the chloroform solution is washed with NaHCO3 solution, dried and evaporated to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid n-butyl ester.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].FC(F)(F)C(O)=O.[NH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A solution of 3,5-bis-trifluoromethyl-benzoyl chloride (17.4 g, 63 mmol) in dichloromethane (30 mL) was added with cooling to a solution of 4-piperidone trifluoroacetate (13.4 g, 63 mmol) and triethylamine (22 mL, 158 mmol) so that the temperature did not rise above 20° C. Stirring continued for 2 h at room temperature. Water was added, the phases were separated and the water phase was extracted with dichloromethane. The organic phases were pooled, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (ethyl acetate/n-hexane 1:1) yielded the desired product (20.2 g, 94%), m.p. 155-157° C. and MS: m/e=339.1 (M+).