Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH2:19]=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][O:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: COc1ccc(Nc2ccccc2)c(C(=O)O)c1
Reactant: C=O
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)OCN2c1ccccc1
Temperature: 0 °C
Yield: 83 %

Procedure:
A mixture of 15.0 g (0.062 mole) of 5-methoxy-2-(phenylamino)benzoic acid and 75 ml of 37% aqueous formaldehyde solution in 75 ml of ethanol was heated on the steam bath for 75 minutes. The mixture was cooled and added to 400 g ice/water. The crude oxazine product was filtered, stirred in 75 ml of 5% aqueous sodium bicarbonate, and refiltered to yield 13.0 g (83% yield) of the product, mp 99.5°-101° C. A sample recrystallized from hexane was analytically pure, mp 100°-102° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=O)#[N:2].[OH-].[Na+].Cl.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[NH:19])OC)=[CH:14][CH:13]=1>CO.CCOC(C)=O>[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[N:19]=[C:4]([CH2:3][C:1]#[N:2])[NH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: N#CCC(=O)NN
Reactant: COC(=N)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1nc(-c2ccc(F)cc2)n[nH]1
Yield: 47 %

Procedure:
2-Cyanoacetohydrazide (172 mg, 1.74 mmol) and NaOH (66 mg, 1.66 mmol) were added to a solution of methyl 4-fluorobenzimidate hydrochloride (300 mg, 1.58 mmol) in dry MeOH (5 mL) and the mixture was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 20-25% EtOAc in petroleum ether) to yield 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile (150 mg, yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.04-7.99 (m, 2H), 7.39-7.33 (m, 2H), 4.11 (s, 2H). MS (ESI) m/z: Calculated for C10H7FN4: 202.07. found: 203.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1)=[O:4].[C:14]1([CH2:20][CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH2:20][CH2:21][NH:22][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
N,N'-Carbonyldiimidazole (16.2 g, 0.1 mole) was added portionwise under nitrogen to 1,4-benzenedicarboxylic acid monomethyl ester (18 g, 0.1 mole) in dry dichloromethane (250 ml) and stirred for 1 hour. Benzeneethanamine (12.1 g, 0.1 mole) was added and the reaction stirred for 3 hours. The solution was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and water, dried and evaporated. The residue, on trituration with ether, afforded the sub-title compound (23.8 g) as a white solid mp 148°.
Reaction SMILES: [C:1](=[O:26])([O:3][C@@H:4]([C:19]1[S:20][CH2:21][C:22](O)([CH3:24])[N:23]=1)[CH:5]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[NH2:2].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1](=[O:26])([O:3][C@@H:4]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1)[CH:5]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[NH2:2]
Reactant: CC1(O)CSC([C@H](OC(N)=O)C(c2c[nH]c3ccccc23)C(C)(C)C)=N1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1csc([C@H](OC(N)=O)C(c2c[nH]c3ccccc23)C(C)(C)C)n1
Reaction time: 1 h

Procedure:
A solution of tert-butyl-(1R)-1-(4-hydroxy-4-methyl-4,5-dihydrothiazol-2-yl)-2-(1H-indol-3-yl)ethyl carbamate (7.12 g, 18.9 mmol) in toluol (150 mL) was mixed with sodium sulphate (9.00 g) and stirred for 1 h with reflux. The mixture was filtered, the filtrate concentrated to low volume in a vacuum and the residue purified by flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/cyclohexane (1:2).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])[CH3:25]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)(CO)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=356.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[CH3:17][N:18]1[CH:22]2[CH2:23][C:24]([CH2:26][CH:19]1[CH2:20][CH2:21]2)=[O:25]>O1CCCC1>[OH:25][C:24]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:23][CH:22]2[N:18]([CH3:17])[CH:19]([CH2:20][CH2:21]2)[CH2:26]1
Reactant: Brc1ccc2ccccc2c1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1C2CCC1CC(O)(c1ccc3ccccc3c1)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A solution of 5.0 gm (24.1 mMol) 2-bromonaphthalene in 80 mL tetrahydrofuran was cooled to -78° C. To this solution was then added 15.8 mL (25.3 mMol) n-butyllithium (1.6M in tetrahydrofuran) followed by a solution of 4.03 gm (29 mMol) 3-tropinone in 35 mL tetrahydrofuran. The reaction mixture was stirred at -78° C. for 2 hours and was then allowed to warm gradually to room temperature. The reaction mixture quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was extracted well with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing from 2-10% methanol and 30% dichloromethane saturated with ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 3.2 gm (50%) of 3-hydroxy-3-(naphth-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Yield: 95 %

Procedure:
0.26 g (0.5 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-4-cyclohexylpiperidine-4-carboxylate is diluted in 4 mL of DCM and 1 mL of trifluoroacetic acid, and the solution is stirred for 2 hours at room temperature and then quenched by adding aqueous 1N NaOH solution and extracted with dichloromethane. The organic phase is dried and then evaporated. 200 mg of ethyl 1-[(R)-2-amino-3-(4-chlorophenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 95%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (3R,4S)-pyrrolidine-3,4-diol (313 mg, 3.03 mmol) in a mixture of DIPEA (0.883 mL, 5.06 mmol) and iPrOH (2.53 mL) was subjected to MW irradiation at 140° C. for 30 min. The RM was treated with 0.5 M aq. HCl (30 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3, brine and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=462.1-464.0 [M+H]+, m/z=460.1-462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.61 (dd, J=11.13, 4.28 Hz, 2H) 3.84 (dd, J=10.76, 4.89 Hz, 2H) 4.10 (d, J=3.42 Hz, 2H) 4.96 (d, J=3.91 Hz, 2H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=8.80 Hz, 2H) 8.34 (s, 1H) 8.67 (s, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Br-:34].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([Br:34])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(Br)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.9 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (1.01 g) was dissolved in CH2Cl2 (40 mL) under N2 and tetrabutylammonium tribromide (1.21 g) was added and the mixture was stirred at room temperature overnight. More tetrabutylammonium tribromide (0.55 g) was added and the mixture was stirred for 1 day. The mixture was then washed with water (25 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: hexane and AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-bromophenyl)-L-phenylalanine methyl ester (1.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH3:29])=[O:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:26](=[O:27])[O:28][CH3:29])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 63 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 1.1 eq of methyl chloroformate in dioxane/water (2:1) in the presence of sodium acetate (2.5 eq). The crude product is recrystallized from isopropyl ether:cyclohexane to give pure [[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]methyl]hydroxycarbamic acid, methyl ester (63%); mp 113°-114° C.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)#[CH:10].O>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:12][CH:13]=1
Reactant: Nc1ccccc1I
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCNCC
Product: Cc1ccc(C#Cc2ccccc2N)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
To 2-iodoaniline (2.19 g, 10.0 mmol) in diethylamine (40 ml) were added 4-ethynyltoluene (1.16 g, 10.0 mmol), bis(triphenylphosphine) palladium(II) chloride (702 mg, 1.00 mmol) and copper iodide (190 mg, 1.00 mmol) successively, and the mixture was stirred for 6 hours at 50° C. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (1.80 g, 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:15])[N:4]2[C:16]([CH3:21])([CH3:20])[NH:17][C:18](=[O:19])[C:3]=12.[CH3:22][S-:23].[Na+]>CN(C)C=O>[CH3:20][C:16]1([CH3:21])[N:4]2[C:5](=[O:15])[C:6]([NH:8][C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)=[CH:7][C:2]([S:23][CH3:22])=[C:3]2[C:18](=[O:19])[NH:17]1
Reactant: CC1(C)NC(=O)c2c(Cl)cc(Nc3ccncn3)c(=O)n21
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Nc2ccncn2)c(=O)n2c1C(=O)NC2(C)C
Temperature: 110 °C

Procedure:
To a vial was added 8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1,5-dione (1, 0.30 g, 0.98 mmol) in dimethylformamide (5 mL). Sodium thiomethoxide (0.14 g, 1.96 mmol) was added at room temperature, the vial was sealed and heated at 110° C. for 36 h. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with 10% methanol in dichloromethane. The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated it to dryness. Solids were precipitated by the addition of ice, filtered and dried. The solid material was subjected to preparative HPLC to afford 3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 82) as a yellow solid. Yield: 0.060 g, 19%; MS (ESI) m/z 318.42 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.66 (s, 1H), 8.92 (s, 1H), 8.84 (s, 1H), 8.45 (d, J=6.0 Hz, 1H), 7.47 (d, J=6.4 Hz, 1H), 2.47 (s, 3H), 1.80 (s, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].C1(C)C=CC=CC=1.[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:29])[C:24](OCC)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC>[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([OH:29])[C:24]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)C1CCCC1

Procedure:
3-Quinuclidinol (3.8 g., 0.030 mole) and about 0.05 g. of sodium were refluxed in 50 ml. of toluene, in a flask equipped with a reflux head, until all the sodium reacted. Then, ethyl α-cyclopentyl-α-phenylethynylglycolate (5.4 g., 0.02 mole) in 35 ml. of solvent was added dropwise over an hour period. No temperature drop was noted in the reflux head. The reaction mixture was refluxed for about 18 hours and then about 40 ml. of solvent was distilled from the reaction flask over a four hour period. The reaction mixture was cooled, and dry 20°-40° petroleum ether was added. A tarry solid formed and was filtered. The solid was treated with hot hexane to yield 3.2 g. (45%) of crude product melting about 115° C. The pure compound, m.p. 137°-39°, was obtained by recrystallization from hexane.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Cu](C#N)[C:36]#[N:37]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:36]#[N:37])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Temperature: 170 °C
Yield: 48.1 %

Procedure:
A solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (6 g, 10.6 mmol) in DMF (20 mL) at room temperature was deoxygenated by bubbling nitrogen gas through the solution for 10 minutes. Copper cyanide (CuCN) (1.14 g, 12.8 mmol) was added to the reaction mixture and it was heated to 170° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed twice with saturated aqueous ammonium chloride solution and then washed with brine. It was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 320 g) (eluted over a gradient 5-25% ethyl acetate and hexane) to give 2.59 g (95%) of the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3H) 4.82 (s, 2H) 4.9 (s, 2H) 7.6 (dd, 1H) 7.7 (s, 2H) 7.8(s, 2H) 7.8 (dd, 1H). MS (ES+) Calc: 508.1, Found: 509.2 (M+1).
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:30]1([NH:36][N:37]=[C:38]([C:42](Cl)=[O:43])[C:39](Cl)=[O:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[O:43]=[C:42]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:39](=[O:40])[C:38]1=[N:37][NH:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Solutions of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino)-acetamide(3.00 g) in THF (30 mL) and 2-(phenyl-hydrazono) propandioyl dichloride (1.89 g) in THF (30 mL) were added concomitantly dropwise with stirring in an ice/methanol bath over a 30 minute period. After complete addition, the solution was allowed to warm to room temperature and stirred over night. The solvent was evaporated under reduced pressure and the resultant oil taken into ethyl acetate (250 mL), washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.28 g) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28].O>C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:28]#[C:27][CH2:26][OH:29])=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(I)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: O
Product: COc1cc(C#CCO)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg) from Example No. 117, copper (I) iodide (57 mg), and bis(triphenylphosphine)-palladium (II) chloride (35 mg) are suspended in diethylamine (15 mL). Propargyl alcohol (70 μL) is added and the mixture is allowed to stir at rt for 16 h. The reaction mixture is poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer is washed with saturated aqueous ammonium chloride (3×10 mL) and brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography (dichloromethane/methanol, 50/1; 33/1; 25/1; 20/1) to afford 289 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:26][C:9]2[N:10]=[C:11]([NH2:25])[N:12]=[C:13]([C:14]([C:16]3[CH:24]=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)=[O:15])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:27][Mg]Br>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:26][C:9]2[N:10]=[C:11]([NH2:25])[N:12]=[C:13]([C:14]([C:16]3[CH:24]=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)([OH:15])[CH3:27])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C(=O)c3ccc4c(c3)OCO4)nc(N)nc2s1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C(C)(O)c3ccc4c(c3)OCO4)nc(N)nc2s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-Amino-4-(benzo[1,3]dioxole-5-carbonyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (example 312) (100 mg) was dissolved in anhydrous THF under a nitrogen atmosphere before methyl magnesium bromide (3.0M solution in diethyl ether, 5 equiv.) was added. The solution was stirred at 40° C. overnight before being partitioned between 10% aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to yield a crude product that was purified by preparative TLC to give the desired compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:16][NH:17][C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[N:22]([CH3:30])[C:21]=1[CH3:31])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:30][N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[C:25]([O:29][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=34)[CH:24]=2)[C:20]([C:18]([NH:17][CH3:16])=[O:19])=[C:21]1[CH3:31]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)C)sc34)ccc12
Yield: 72.5 %

Procedure:
This material was prepared by the reaction 7-chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide 33a (0.077 g, 0.32 mmole) and 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.070 g, 0.32 mmole) and Cs2CO3 (0.104 g, 0.32 mmole) in a manner as previously described for example 1 to give a pale yellow solid (0.098 g, 73%). 1H NMR (300 MHz, CD3OD) δ8.38 (1H, d, J=5.5 Hz), 7.75 (1H, d, J=8.7 Hz), 7.66 (1H, s), 7.28 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz), 3.61 (3H, s), 3.21 (6H, m), 2.87 (3H, s), 2.56 (3H, s). ESIMS (MH+): 423.05.