Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH:13]4[CH2:19][CH2:18][N:16]([CH2:17][C:7]=3[C:6]=2[CH:5]=1)[CH2:15][CH2:14]4.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23]>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24](/[CH:22]=[CH:23]/[N:9]2[C:10]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][C:6]=3[C:7]3[CH2:17][N:16]4[CH2:15][CH2:14][CH:13]([C:8]2=3)[CH2:19][CH2:18]4)[CH:25]=1
Reactant: C#Cc1cccnc1
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: FC(F)(F)Oc1ccc2c(c1)c1c(n2/C=C/c2cccnc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (140 mg, 0.473 mmol; Example 175) and 3-ethynylpyridine (97 mg, 0.945 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.09-2.18 (m, 4H), 3.03-3.16 (m, 2H), 3.19-3.29 (m, 2H), 3.42-3.49 (m, 1H), 4.25 (s, 2H), 6.86 (d, J=14 Hz, 1H), 7.10 (ddd, J=9, 2, 1 Hz, 1H), 7.28 (d, J=1 Hz, 1H), 7.45 (dd, J=8, 5 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.79 (d, J=15 Hz, 1H), 8.10 (dt, J=8, 2 Hz, 1H), 8.43 (dd, J=5, 2 Hz, 1H), 8.71 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 400 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=4)[C:20](=[O:30])[NH:19][C:18]3=[O:31])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn](Cl)[Cl:33]>C(O)C>[ClH:33].[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=4)[C:20](=[O:30])[NH:19][C:18]3=[O:31])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cc([N+](=O)[O-])ccc12
Reactant: Cl[Sn]Cl
Solvent: CCO
Product: Cl
Product: Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 3 h
Yield: 64 %

Procedure:
To a stirred suspension of 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-nitro-2,4(1H,3H)-quinazolinedione (840 mg) in dry ethanol (30 ml) was added tin(II) chloride (1.90 g) at 80° C. After stirring for 3 hours, the mixture was quenched with 2N potassium hydroxide, diluted with chloroform. The organic layer was decanted and the residue was washed with chloroform. Combined organic layer was dried over magnesium sulfate and evaporated. 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-amino-2,4(1H,3H)-quinazolinedione hydrochloride (546 mg) as a crystal was obtained by recrystallization from 10% hydrogen chloride in methanol.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([OH:16])=[O:15])(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Pyridine (64 μl, 0.80 mmol) was added to an ice cooled mixture of salicylic acid (10 mg, 0.72 mmol) and methylene chloride (10 mL). After 5 minutes, acetic anhydride (10 μl, 1.09 mmoles) was added. The resulting mixture was stirred at room temperature for 4 hrs. The product was extracted with methylene chloride and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 2-acetoxybenzoic acid in 76% yield.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:17])[C@@H:4]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:6][S:7][CH3:8].[ClH:18].O1CCOCC1>>[ClH:18].[NH2:9][C@@H:4]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([NH:2][OH:1])=[O:17].[ClH:18].[OH:1][NH:2][C:3]([CH:4]([NH2:9])[CH2:5][CH2:6][S:7][CH3:8])=[O:17]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NO
Agent: Cl
Solvent: C1COCCO1
Product: CSCCC(N)C(=O)NO
Product: CSCC[C@H](N)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To solid (S)-tert-butyl 1-(hydroxyamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (0.33 g, 1.25 mmol) was added 4 N HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for one hour, and concentrated. The residue was triturated with ether, and dried to provide 1-Hydroxycarbamoyl-3-methylsulfanyl-propyl-amine hydrochloride (S)-2-amino-N-hydroxy-4-(methylthio)butanamide hydrochloride (0.18 g, 80%). MS calcd for (C5H12N2O2S—H)+: 163.1; MS found: (M−H)+=163.0
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:21]([N:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15](=[O:16])[NH2:34])[CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: N
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1CCN(C(=O)C(CCc2cccc(C(N)=O)c2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
A mixture of 85 mg (0.21 mmol) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid, 81 mg (0.42 mmol) of EDC, 57 mg (0.42 mmol), and 2.6 mg (0.021 mmol) of DMAP is stirred in DMF for 2 h at rt. After cooling to −40° C. ˜0.2 mL of NH3 is condensed into the mixture. The resulting solution is sealed and stirred at rt for 10 h. The mixture is concentrated and purified by preparatory TLC (10% MeOH in CH2Cl2) to provide 66 mg (78%) of [3-(3-carbamoyl-phenyl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH2:20]([N:27]1[C:32](=[O:33])[C:31]([CH3:34])=[CH:30][N:29]([CH2:35][CH2:36][CH2:37]Cl)[C:28]1=[O:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:1].[CH2:20]([N:27]1[C:32](=[O:33])[C:31]([CH3:34])=[CH:30][N:29]([CH2:35][CH2:36][CH2:37][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH2:9][CH2:10]2)[C:28]1=[O:39])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)COc1cc(Cl)ccc1N1CCNCC1
Reactant: Cc1cn(CCCCl)c(=O)n(Cc2ccccc2)c1=O
Product: Cc1cn(CCCN2CCN(c3ccc(Cl)cc3OCC(F)(F)F)CC2)c(=O)n(Cc2ccccc2)c1=O
Product: Cl

Procedure:
substituting 1-[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-benzyl-1-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 3-benzyl-1-(3-{4-[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 251°-252° C.; Anal.: Calcd. for C27H30F3ClN4O3.HCl: C, 53.55; H, 5.49; N, 9.25%; Found: C, 53.74; H, 5.26; N, 9.37%;
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C[CH2:11][O:12]C(C1C(=O)CCCC1)=O.[C:22]1(C)[C:23](C)=[CH:24][CH:25]=[CH:26][CH:27]=1>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:11](=[O:12])[N:1]([C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=3)[C:2]2=[N:3][CH:4]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: Cc1ccccc1C
Reactant: Nc1cc(Br)cnc1N
Product: O=c1[nH]c2cc(Br)cnc2n1C1=CCCCC1
Temperature: 25 °C

Procedure:
2,3-Diamino-5-bromopyridine (50 g) and 2-cyclohexanonecarboxylic acid ethyl ester (63.5 ml) were heated under reflux in xylene (2000 ml) for 64 hours. The reaction solution was cooled to room temperature and the precipitated crystals were collected by filtration. The resulting crude crystals were recrystallized from toluene to give the title compound (30 g).
Reaction SMILES: [NH2:1][C@H:2]([C:16]([O:18]CCN(CC)CC)=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:15])[N:8]([C:12]([CH3:14])=[O:13])[C:9]([CH3:11])=[O:10].[NH:26](C(OC(C)(C)C)=O)[C@H:27]([C:34]([N:36]1[CH2:50][CH2:49][CH2:48][C@H:37]1[C:38](ON1C(=O)CCC1=O)=[O:39])=[O:35])[CH2:28][C:29](=[O:33])[O:30][CH2:31][CH3:32].C(OCC)(=O)C>C([O-])(O)=O.[Na+].CC(C)=O>[NH2:26][C@H:27]([C:34]([N:36]1[CH2:50][CH2:49][CH2:48][C@H:37]1[C:38]([NH:1][C@H:2]([C:16]([OH:18])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:15])[N:8]([C:9]([CH3:11])=[O:10])[C:12]([CH3:14])=[O:13])=[O:39])=[O:35])[CH2:28][C:29](=[O:33])[O:30][CH2:31][CH3:32]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CCOC(=O)[C@@H](N)CCCNC(=N)N(C(C)=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N(C(C)=O)C(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 121.8 %

Procedure:
22 g of H-Arg(diAc)-OCH2CH2N(CH2CH3)2 was dissolved in 300 ml of 5% NaHCO3. 24 g of Boc-Asp(OEt)-Pro-OSu in 150 ml of acetone was added into the reaction mixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetate was added into the mixture. The ethyl acetate solution was washed with water (3×100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 ml of dichloromethylene. 200 ml of trifluoroacetic acid was added into the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to yield 32 g of H-Asp(OEt)-Pro-Arg(diAc)*OCH2CH2N(CH2CH3)2.2TFA.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=O)=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([CH2:64][NH2:65])[OH:63]>CN(C=O)C>[OH:63][CH2:62][CH2:64][NH:65][C:26]([C:10]1[C:11](=[O:25])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:13]([CH3:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=2)[CH:9]=1)=[O:28]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Reactant: NCCO
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: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCCO)cn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-(4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1, 70 mg, 0.102 mmol), TBTU (37 mg, 0.115 mmol), DIPEA (40 μL, 0.234 mmol) in DMF (0.5 mL) is stirred for 15 min at room temperature. Ethanolamine (7 μL, 0.116 mmol) is added and the reaction mixture is stirred for 1.5 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 16 mg (34% of theory); ESI mass spectrum: [M+H]+=456; Retention time HPLC: 1.34 min (Z002—005).
Reaction SMILES: Br[C:2]1C=CC=C[C:3]=1[CH2:8][C:9]([O:11][CH2:12]C)=[O:10].[C:14](#[N:17])[CH:15]=[CH2:16].[C:18]([O:22][C:23](=[O:26])[CH:24]=C)([CH3:21])([CH3:20])C>>[C:23]([O:22][C:18]1[CH:20]=[CH:2][C:3](/[CH:16]=[CH:15]/[C:14]#[N:17])=[C:8]([CH:21]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:26])[CH3:24]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C=CC#N
Reactant: CCOC(=O)Cc1ccccc1Br
Product: COC(=O)c1cc(OC(C)=O)ccc1/C=C/C#N

Procedure:
The title compound was prepared according to the procedure outlined in Example 223A substituting Example 227A for ethyl 2-(2-bromophenyl)acetate and acrylonitrile for t-butylacrylate.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:7]N1C(=O)[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2C1=O.[O:19]=O>C(#N)C>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:10]1([OH:19])[CH2:11][CH2:14][CH2:15][CH:16]=[CH:17]1
Reactant: O=O
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1=CCCCC1
Solvent: CC#N
Product: O=C1C=CCCC1
Product: OC1C=CCCC1
Yield: 13 %
Yield: 65 %

Procedure:
To 25 milliliters of acetonitrile were added 1.64 grams (20 millimoles) of cyclohexene, 0.26 gram (1.6 millimoles) of N-hydroxyphthalimide and 0.043 gram (0.12 millimole) of acetylacetonatocobalt Co(AA)2. The resultant mixture was stirred in an oxygen atmosphere at 100° C. for 6 hours. The products in the reaction mixture were analyzed with gas chromatography, and cyclohexene was transformed, with a transformation rate of 90%, into 2-cyclohexen-1-one (selectivity based on cyclohexene 72%, yield 65%) and 2-cyclohexen-1-ol (selectivity based on cyclohexene 14%, yield 13%).
Reaction SMILES: C([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:23][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:24][S:25]([C:28]([F:30])([F:29])[F:31])(=[O:26])=[O:27])=[C:12]([CH:6]([OH:5])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]=1[CH3:22]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C(O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(4-fluoro-3-methyl-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.75 g, 3.76 mmol) in DCM (30 mL) was treated dropwise with TFA (3.0 mL) over 3 min at 23° C. After 16 h, the reaction was diluted with H2O (60 mL) and the system was extracted with DCM (3×20 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated giving the crude desired product (˜1.54 g obtained), which was used in the next reaction. 1H NMR (400 MHz, CDCl3) δ 8.11-8.06 (m, 1H), 7.67-7.64 (m, 1H), 7.61-7.52 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 5.79 (s, 1H), 4.34-4.22 (m, 2H), 2.40 (d, JHF=3.2 Hz, 3H), 1.22 (t, J=7.4 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−122.6 (app. s, 1F), −73.3 (s, 3F).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[Cl-].[NH4+]>CCCCCC.C(OCC)(=O)C.C(COC)OC.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 7.01 ml) was added dropwise to a dimethoxyethane solution (50 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (3.03 g, 10.0 mmol) obtained in Example 5. The temperature of the reaction mixture was raised to room temperature. Then, the reaction mixture was cooled to −78° C. After the addition of t-butyl bromoacetate (1.48 ml, 10.0 mmol), the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was added with a saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then distilled to remove the solvent. The residue thus obtained was subjected to chromatography on a short silica gel column (hexane-ethyl acetate 3:1). The solid thus obtained was recrystallized from hexane, whereby the title compound (3.30 g, 79%) was obtained as a colorless solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH:21]([NH:24][C:25]1[C:26]2[N:27]([C:37]([O:40][CH3:41])=[N:38][N:39]=2)[C:28]2[C:33]([N:34]=1)=[CH:32][C:31]([CH:35]=O)=[CH:30][CH:29]=2)([CH3:23])[CH3:22].CC(O)=O>ClCCCl>[CH:21]([NH:24][C:25]1[C:26]2[N:27]([C:37]([O:40][CH3:41])=[N:38][N:39]=2)[C:28]2[C:33]([N:34]=1)=[CH:32][C:31]([CH2:35][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:30][CH:29]=2)([CH3:22])[CH3:23]
Reactant: COc1nnc2c(NC(C)C)nc3cc(C=O)ccc3n12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1nnc2c(NC(C)C)nc3cc(CN4CCOCC4)ccc3n12
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
Solid sodium triacetoxyborohydride (59 mg) and morpholine (15 μL) were added to a solution of 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carbaldehyde (50 mg) in 1,2-dichloroethane (1.0 mL). The resulting suspension was stirred at 23° C. for 2.5 hrs., and then a portion of AcOH (10 μL) was added. After an additional 2.5 hrs., the reaction mixture was concentrated. The residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Silica gel chromatography afforded isopropyl-(1-methoxy-7-morpholin-4-ylmethyl-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-amine as a white solid. MS (M+H)+=357.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:22][C:21]=2[NH2:31])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH:32](OCC)(OCC)OCC>C1CCN2C(=NCCC2)CC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:17]2[C:18](=[O:19])[C:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[S:22][C:21]=3[N:31]=[CH:32]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc(NC(=O)c2cc(-c3ccccc3)sc2N)ccc1OCCN1CCCC1
Reactant: CCOC(OCC)OCC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2cnc3sc(-c4ccccc4)cc3c2=O)ccc1OCCN1CCCC1

Procedure:
2-Amino-5-phenyl-thiophene-3-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amide [Example E1] (28 mg, 0.064 mmol) was stirred at 95° C. in triethyl orthoformate (5 ml) for 24 h. The mixture was cooled, 4 drops of DBU added and the volatiles removed. The crude product was purified by chromatography on silica gel (eluting with dichloromethane-methanol-aq. ammonia) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O-:14].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: Fc1c(Br)cccc1C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(Br)cccc1C(F)(F)F
Temperature: 150 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzotrifluoride (1.0 g, 4.1 mmol) in methanol (5 ml) was added a solution of sodium methoxide in methanol (30%, 0.73 ml, 4.1 mmol). The mixture was heated under microwave radiation to 150° C. for 10 min. The reaction mixture was poured into water and extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.89 g). MS m/z (rel. intensity, 70 eV) 256 (M+, 87), 254 (M+, 89), 239 (26), 211 (24), 132 (bp).
Reaction SMILES: CC(C)([O-])C.[K+].IP(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]1.[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[C:40]([F:46])[CH:39]=1>C1COCC1>[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:40]([F:46])[CH:39]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCCC1CCC(CP(I)(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C=Cc2ccc(Br)cc2F)CC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Under a nitrogen atmosphere, potassium t-butoxide (30.4 g, 271.0 mmol) was added, at −30° C. or lower, to a THF (500 mL) suspension of iodotriphenyl((4-propylcyclohexyl)methyl)phosphine (73) (143.0 g, 271.0 mmol). The reaction mixture was agitated at −30° C. or lower for 1 hour, and then a THF (100 mL) solution of 4-bromo-2-fluorobenzaldehyde (50.0 g, 246.0 mmol) was added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 500 mL of water, and extracted with 200 mL of toluene three times. Combined organic layers were washed with water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-1-(2-(4-propylcyclohexyl)vinyl)benzene (75) (75.0 g, yield 94.0%) was obtained.
Reaction SMILES: CO[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[H][H].[C:17](OCC)(=[O:19])C>[Pd]>[CH3:17][O:19][C:7]1[N:8]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(OC)nc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC(=O)CCc1cccnc1OC
Yield: 90 %

Procedure:
A suspension of methyl β-(6-methoxypyridin-3-yl)acrylate (3 g, 15.5 mmol) and 1 g of 5% Pd/C in 100 ml of ethyl acetate was hydrogenated under hydrogen (50 psi). After hydrogen uptake had ceased the mixture was filtered through solka floc, the filtrate was concentrated in vacuo to afford 2.7 g (90%) of methyl 3-(6-methoxypyridin-5-yl)propionate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester (2.55 g, 0.009 mol), 1N NaOH (20 ml), water (70 ml), and methanol (70 ml) is heated to reflux for 20 minutes when a clear solution is formed. The reaction mixture is filtered and the filtrate is carefully acidified with 4N HCl (6 ml) to pH 1.0 when a solid pptd. out. The crude 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid is filtered, washed with hot CH30H and dried to give analytical sample. Yield 1.67 g (73%); mp >295° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl([O-])=[O:18].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)cc1OC1CC=CC1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1CC=CC1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
A stirred solution of 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde (1.75 g) in t-butanol (36.5 mL) and 2-methyl-2-butene (9.0 mL) is treated dropwise with an aqueous solution (34 mL) containing sodium chlorite (80% technical grade; 1.0 g) and sodium dihydrogen phosphate (8.75 g). The resulting mixture is further stirred for 5 hours, the layers are separated and the aqueous layer is extracted with t-butyl methyl ether (3×30 mL). The combined organic layers are washed with water (2×15 mL), dried over sodium sulfate and the solvent removed under reduced pressure. The resulting residue is recrystallized from ethyl acetate to give 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.31 g), in the form of a colorless solid, m.p. 171-173° C. [Elemental analysis: C, 66.6; H, 6.0%. calculated: C, 66.7; H, 6.0%].