Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]([CH3:21])[C:15](=[O:22])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[CH3:24][C:25]1[O:29][N:28]=[CH:27][C:26]=1[C:30](O)=[O:31]>>[F:20][C:19]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:22])[N:16]2[CH3:21])=[CH:11][C:10]=1[C:6]1[C:5]([CH3:23])=[C:4]([CH2:3][NH:2][C:30]([C:26]2[CH:27]=[N:28][O:29][C:25]=2[CH3:24])=[O:31])[CH:9]=[N:8][CH:7]=1
Reactant: Cc1oncc1C(=O)O
Reactant: Cc1c(CN)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2
Agent: Cl
Product: Cc1oncc1C(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1C

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 226) has been coupled with 5-methyl-isoxazole-4-carboxylic acid to give the title compound as an off-white solid. MS: 409.6 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][N:22]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(C=O)ccn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)ccn1
Yield: 61 %

Procedure:
Obtained in 61% yield by General Synthetic Method 5, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 2-methylpyridine-4-carboxaldehyde
Reaction SMILES: [C:1]([CH:24](O)[CH2:25][CH2:26][C:27](=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:51]([OH:70])(=O)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[C:27]([CH2:26][CH:25]([C:51](=[O:70])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:24][C:1](=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CCC(O)C(=O)CCCCCCCCCCC/C=C\CCCCCCCC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CC(CC(=O)CCCCCCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
A triacylglycerol containing oil having an EOE content of at least 50% based on total triacylglycerol composition can be chemically synthesized using 1,3 dihydroxyacetone and free erucic and oleic fatty acids as starting materials. Oils chemically synthesized as described herein have EOE contents of 80% or greater, and preferably greater than 90%. In the first step, 1,3 dihydroxyacetone dimer and erucic acid can be reacted in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoylpropanone. The ketone group of 1,3 dierucoylpropanone can be reduced using, for example, sodium borohydride and water to form 1,3 dierucoylpropanol. EOE can be produced by reacting 1,3 dierucoylpropanol and oleic acid in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoyl 2-oleoyl propane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:41])[CH:5]=[C:6]([Cl:40])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([O:35]CC2CC2)[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:41])[CH:5]=[C:6]([Cl:40])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([OH:35])[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(O)c1
Yield: 66.3 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (500 mg, 0.823 mmol) (prepared in analogous manner as described in Example 4, Scheme 4) in 2,2,2-trifluoroacetic acid (7.5 ml, 0.823 mmol) was stirred at RT for 8 hours. Then the solvent was evaporated under vacuum, and the residue was taken up several times with AcOEt/Et20 and evaporated under reduced pressure to afford 302 mg of the title compound (66% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.[Cu]I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:18])[N:14]([C:26]4[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=4)[CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: Nc1ncc2c(n1)CCN(c1ccc[nH]c1=O)C2
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(-n2cccc(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 80 °C
Yield: 61.3 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyridin-2(1H)-one (52 mg, 0.20 mmol), 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 80° C. for 6 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then 5% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then triturated with an EtOAc/hexane mixture to give a pale greenish-beige solid (46 mg, 61%). 1H NMR (DMSO) δ: 8.03 (s, 1H), 7.48-7.54 (m, 2H), 7.28-7.33 (m, 2H), 7.27 (dd, J=6.7, 1.8 Hz, 1H), 6.87 (dd, J=7.3, 1.8 Hz, 1H), 6.37 (s, 2H), 6.27 (t, J=7.0 Hz, 1H), 4.07 (s, 2H), 3.46 (t, J=6.0 Hz, 2H), 2.69 (t, J=5.9 Hz, 2H), 1.33 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:8]3[NH:7][CH2:6][CH2:5]2)[CH:11]=1.[CH3:22]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:22])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To 1.69 g (5.5 mmol) of the compound (132) obtained in Example 24, 10 ml (109 mmol) of dimethylsulfate was added, and the solution was heated at 120° C. for 4.5 hours. After air-cooling, the solution was added to 90 ml of ice/water to which 15 g (109 mmol) of anhydrous potassium carbonate was added, and the solution was stirred for 1 hour. The solution was extracted with 200 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 60 g, eluent solvent; chloroform methanol=100:1) to obtain 600 mg of the subject compound (133) in a 36% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN4CCOCC4)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 22 h
Yield: 87.1 %

Procedure:
607 mg (1.16 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.00 mL (11.6 mmol) of morpholine was added and the mixture was stirred at 50° C. for 22 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 523 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-morpholinopropylamino)-4H-1-benzopyran-4-one (yield: 88%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[C:21]([O:36][CH2:37][C:38]2[N:39]([CH2:43][CH3:44])[N:40]=[CH:41][N:42]=2)=[N:22][N:23]2[C:28]=1[CH:27]=[N:26][N:25]=[C:24]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]>>[CH2:43]([N:39]1[C:38]([CH2:37][O:36][C:21]2[C:20]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)=[C:28]3[N:23]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[N:25][N:26]=[CH:27]3)[N:22]=2)=[N:42][CH:41]=[N:40]1)[CH3:44]
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1cccs1
Yield: 59 %

Procedure:
This was prepared in 59% yield using a similar procedure to that described in Example 53 except using 2-(tributylstannyl)thiophene instead of 2-(tributylstannyl)pyridine and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=190-192° C. (CH2Cl2-EtOAc); 1H NMR (360 MHz, CDCl3) δ 1.39 (3H, t, J=7.3 Hz), 4.18 (2H, q, J=7.3 Hz), 5.60 (2H, s), 7.15 (1H, m), 7.29 (1H, t, J=9.4 Hz), 7.38-7.42 (2H, m), 7.46 (1H, d, J=3.6 Hz), 7.66 (1H, m), 7.81 (1H, m), 7.90 (1H, s), 9.56 (1H, s); MS (ES+) m/e 422 [MH]+; Anal. Found C, 57.30; H, 3,71; N, 23.35%. C20H16FN7OS requires C, 57.00; H, 3.83; N, 23.26%.
Reaction SMILES: [S:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(Cl)(=O)C([Cl:20])=O.N#N.CCCCCC>CN(C=O)C.ClCCl.C(Cl)(Cl)Cl>[S:1]([NH:11][C@H:12]([C:14]([Cl:20])=[O:16])[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Reaction time: 2 h

Procedure:
10 g (42 mmol) of N-tosyl-L-alanine and 6 to 7 drops of DMF were dissolved in 100 ml of dichloromethane and 3 ml of oxalyl chloride was added by dropwise under N2 gas. After 2 hrs, reaction mixture was evaporated. The solid residue, so formed, is dissolved in a small amount of chloroform, followed by the addition of purified hexane to obtain a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13](=O)[CH2:14]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=[S:20])([S-:19])[NH2:18].[NH4+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[N:18]=[C:17]([SH:20])[S:19][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=S)[S-]
Reactant: CC(C)(C)OC(=O)NCCSCC(=O)CCl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCc1csc(S)n1

Procedure:
To a stirred solution of 1-(2-t-butyloxycarbonylaminoethylthio)-3-chloropropan-2-one (11.47 g, 42.8 mmol) in methanol (50 mL) was added ammonium dithiocarbamate (4.73 g, 42.9 mmol) at room temperature. After 50 hours the reaction mixture was partitioned between ethyl acetate and water.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=4)=[CH:21][C:14]=3[N:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:32][NH:31][C:29]([C:25]1[CH:24]=[C:23]([O:22][C:20]2[CH:19]=[CH:18][C:15]3[N:16]([CH3:17])[C:12]([NH:11][C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:4][CH:5]=4)=[O:10])=[N:13][C:14]=3[CH:21]=2)[CH:28]=[CH:27][N:26]=1)=[O:30]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(NC(=O)c2ccc(CCl)cc2)n3C)ccn1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(NC(=O)c2ccc(CN4CCN(C)CC4)cc2)n3C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) in tetrahydrofuran was added methylpiperazine (4 eq) and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified on preparative chromatography to yield N-methyl{4-[1-methyl-2-({4-[(4methylpiperazinyl) methyl]phenyl}carbonylamino) benzimidazol-5-yloxy](2-pyridyl)}carboxamide. MS: MH+=512.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1([CH3:35])[CH2:34][O:33][CH2:32][CH2:31][NH:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:28][C:29]1([CH3:35])[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1)=[O:18]
Reactant: O=C(O)c1ccc(C#Cc2cccc(F)c2)cn1
Reactant: CC1(C)COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1C(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
(50 mg, 0.21 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in DMF (0.5 ml) and Hunig's Base (44 μl, 0.31 mmol, 1.2 equiv.), 3,3-dimethylmorpholine (36 mg, 0.25 mmol, 1.5 equiv.) and TBTU (73 mg, 0.23 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone (61 mg, 87% yield) was obtained as a light yellow oil, MS: m/e=339.2 (M+H+).
Reaction SMILES: [NH:1]([C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH3:12])[N:4]=1)[NH2:2].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C.C(OCC)(=O)C>C(O)C>[NH2:21][C:20]1[N:1]([C:3]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH3:12])[N:4]=2)[N:2]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: Cn1nc(NN)cc1C(F)(F)F
Reactant: CCOC=C(C#N)C#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-n2ncc(C#N)c2N)cc1C(F)(F)F

Procedure:
0.85 g (4.72 mmol) 3-Hydrazino-1-methyl-5-trifluoromethylpyrazole and 0.59 g (4.72 mmol) ethoxymethylenemalononitrile in 10 ml ethanol was stirred for 10 hours at room temperature and for 2 hours at 50° C. After addition of 50 ml ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:21][CH2:22][CH3:23])[NH:8][C:9]=1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])([CH3:4])[CH3:3].[C:24]([N:43]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[CH:61]=[CH:60][C:57]([CH2:58]Br)=[CH:56][CH:55]=2)=[N:46][N:45]=[N:44]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:21][CH2:22][CH3:23])[N:8]([CH2:58][C:57]2[CH:56]=[CH:55][C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[C:47]3[N:43]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:44]=[N:45][N:46]=3)=[CH:61][CH:60]=2)[C:9]=1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])([CH3:4])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 48.8 %

Procedure:
Following a procedure similar to that described in Example 61(a), but using 0.85 g of pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in Preparation 22(ii)], 1.52 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.72 g of potassium carbonate, 1.02 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[C:10](O)=[O:11])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[C:10]([Cl:29])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: Cn1nnnc1C(C(=O)Cl)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a solution of dry (0.1 mmHg at 80° C.) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoic acid 3.8 g (11.0 mmoles) in 20 mL of dry methylene chloride was added 4 mL (46.0 mmoles) of purified oxalyl chloride (redistilled over CaH2) in one single portion. The reaction mixture was warmed gradually to reflux temperature for two hours. The mixture was evaporated under reduced pressure to remove volatile solvent, then excess oxalyl chloride was removed under vacuum (20 mmHg) at ambient temperature for 2 hours and under high vacuum (0.1 mmHg) at 50° C. for 16 hours to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:28][CH3:29])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:28][CH3:29])[N:8]([C:37]2[CH:36]=[CH:35][C:34]3[O:30][CH2:31][CH2:32][C:33]=3[CH:38]=2)[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II) acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecular sieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.60 g, 79%) as a pale-yellow liquid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[CH:23]=O.O>O1CCCC1>[CH3:19][C:20]1[CH:21]=[C:22](/[CH:23]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:25]=[CH:26][N:27]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Cc1cc(C=O)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(/C=C/C(=O)OC(C)(C)C)ccn1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (12.4 g, 49 mmol) in tetrahydrofuran (30 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 2.3 g, 57 mmol) and tetrahydrofuran (100 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 2-methylisonicotinaldehyde (5.0 g, 41 mmol) in tetrahydrofuran (20 ml) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:3, v/v) were collected and concentrated to give the titled compound (4.4 g, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3CCC[C@@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3CCC[C@@H]2S(=O)(=O)C1(C)C
Yield: 97.8 %

Procedure:
A solution of tert-butyl-N-((4aS,11bR)-10-nitro-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (125 mg, 0.227 mmol) in THF (2 ml) was hydrogenated in the presence of palladium (10% wt.) on activated carbon (48.2 mg, 0.045 mmol) for 1 h (hydrogen balloon). The mixture was filtered through plug of celite, filter cake was washed with EtOAc, filtrate was concentrated to afford tert-butyl-N-((4aS,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (116 mg, 0.222 mmol, 98% yield), which was used without further purification. LC/MS (ESI+) m/z=522 (M+H).