Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(COC)OC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:39]([F:50])([F:49])[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CCOC(=O)c1c(-c2ccccc2C(F)(F)F)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 135B (30 mg), 2-(trifluoromethyl)phenylboronic acid (15.3 mg), tetrakis(triphenylphosphine)palladium(0) (3.1 mg) and cesium fluoride (16.3 mg) in dimethoxyethane (1.4 ml) and methanol (0.7 ml) was heated at 100° C. in a microwave reactor (CEM Discover) for 30 minutes and was concentrated. The residue was purified by flash chromatography, eluting with 0%-100% dichloromethane in hexane, to provide ethyl 5-(benzyloxy)-1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J=7.32 Hz, 1H), 7.82 (d, J=7.63 Hz, 1H), 7.69 (t, J=7.32 Hz, 1H), 7.57-7.65 (m, 2H), 7.44-7.56 (m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J=9.00, 2.29 Hz, 1H), 6.85 (d, J=7.93 Hz, 1H), 6.55 (d, J=2.14 Hz, 1H), 4.83-4.98 (m, 4H), 4.05-4.24 (m, 2H), 2.28-2.40 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 120 °C
Yield: 10.8 %

Procedure:
A mixture of 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G (332 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (347 mg), tetrakis(triphenylphosphine)palladium(0) (128 mg), aqueous sodium carbonate solution (2 M, 1.11 ml) and N,N-dimethylformamide (6.0 mL) was heated with microwave irradiation at 120° C. for 1 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (36.0 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].II.[Br:14][C:15]1[CH:16]=[C:17]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[N:23]S(C(C)(C)C)=O)[CH:18]=[CH:19][C:20]=1[F:21]>C(OCC)C.O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:22]2([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=3)[C:30]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1ccccc1C#N
Reactant: COc1ccc(Br)cc1C
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (1.21 g, 6.0 mmol) in diethyl ether (10 mL) was added dropwise to magnesium (0.22 g, 9.0 mmol) and iodine. The resulting mixture was heated to reflux for 2 h and was then allowed to cool to room temperature. The prepared reagent was added to a solution of N-((3-bromo-4-fluorophenyl)(2-cyanophenyl)methylene)-2-methylpropane-2-sulfinamide (Scheme #11 F, 0.82 g, 2.0 mmol) in tetrahydrofuran (20 mL) at 0°. The mixture was stirred at 0° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (20 mL) and was treated with hydrochloric acid (2M in diethyl ether, 2 mL) overnight. The solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and evaporated. Purification by flash chromatography using chloroform:methanol (9:1) afforded 0.53 g (63% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.90-7.74 (m, 1 H), 7.74-7.67 (m, 1 H), 7.59-7.42 (m, 3 H), 7.35-7.21 (m, 2 H), 7.12-7.00 (m, 2 H), 6.97-6.71 (m, 3 H), 3.74 (s, 3 H), 2.06 (s, 3 H); MS (ESI) m/z 425, 427 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](O)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[O:30][CH:34]=[CH:33][N:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncco1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ncco2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and oxazole-2-carboxylic acid (8 mg, 0.07 mmol). Yield 24 mg (69%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]=1.[Br:18]Br.C(N(CC)CC)C>C(OCC)(=O)C>[NH2:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]1[Br:18]
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(CCCN)=CCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=CCCN)C(Br)CO2

Procedure:
To a suspension of 20 g of 4-(3-aminopropyl)-6-methoxy-2H-[1]-benzopyran hydrochloride in 200 ml of ethyl acetate is added 12.5 g of bromine at room temperature. After 15 minutes at room temperature 24 g of triethylamine is added to yield 4-(3-aminopropylidene)-3-bromo-6-methoxy-2H-[1]-benzopyran and the reaction mixture is refluxed for 2 hours. After washing with water and drying the solvent is removed in vacuo. The residue is dissolved in ethanol and acidified with ethanolic hydrogen chloride to afford 9-methoxy-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 285°-286°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH2:23])=[O:22]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:23]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[O:22][CH:2]=2)=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccccn1
Product: CS(=O)(=O)c1ccc(-c2coc(-c3ccccn3)n2)cc1
Temperature: 150 °C
Yield: 3.9 %

Procedure:
The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (500 mg, 1.8 mmol) and pyridine 2-carboxamide (551 mg, 4.51 mmol) was heated to 150° C. for 1 hour. Then the reaction mixture was cooled, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice, and the combined organic layers were washed with water and brine, dried over MgSO4. After concentration, the solid residue was dissolved in methanol and subject to mass-directed HPLC purification to give 21 mg of 2-{4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine. LCMS: m/z 301.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15])=[O:24]
Reactant: Nc1ccc(-c2ccccc2)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc(-c2ccccc2)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g, 1 mmol) and 2-bromo phenyl isocyanate(0.198 g) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56%).EI-MS m/z 383(M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH:27]=O)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:27][N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1C=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.053 g (0.13 mmole) of 4-(3-chloro-phenyl)-2-(6-formyl-5-methoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.46a), 0.030 mL of N-methylpiperazine, 0.050 g of sodium triacetoxyborohydride and 5 mL of dichloromethane was stirred at room temperature for 16 hours. The mixture was partitioned between 50 mL of dilute aqueous potassium carbonate solution and 50 mL of dichlormethane. The organic layer was separated and the aqueous layer was extracted three times with 20 mL of dichloromethane. The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 15:85-20:80) to give 0.016 g of 4-(3-chloro-phenyl)-2-[5-methoxy-6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.46) as a pink solid. MH+/Z=497
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=3)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)c1
Yield: 89.8 %

Procedure:
By the method of Example 1, Step I, 1.0 g (0.0038 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step F) and 1.72 g (0.0076 mole) of methyl 2-(3-chloromethylphenoxy)propionate were reacted in the presence of 0.79 g (0.0057 mole) of anhydrous potassium carbonate in 25 mL of N,N-dimethylformamide, yielding 1.54 g of methyl 2-[3-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]phenoxy]propionate. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 2.44 (s, 3H); 3.76 (s, 3H); 4.78 (q, 1H, JHH =8.0 Hz); 5.04 (s, 2H); 6.76-7.38 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][NH:13][C:14](=[S:15])[NH2:16])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NNC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: NC(=S)NNC(=O)Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 67.8 %

Procedure:
5 g of 4-fluorophenylacetic acid (32.44 mmol, 1 eq.) are placed in 50 mL of dichloromethane with stirring. 3.25 g of thiosemicarbazide (35.68 mmol, 1 eq.), 4.38 g of hydroxybenzotriazole (32.44 mmol, 1 eq.) and 6.22 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.44 mmol, 1.2 eq.) are successively added with continued stirring at room temperature. After 18 hours at room temperature, the dichloromethane is evaporated off. The residue is taken up in ethyl acetate, washed three times with water, once with brine and three times with 1N hydrochloric acid. The organic phase is dried over sodium sulfate and evaporated to give 5 g of 2-[(4-fluorophenyl)acetyl]hydrazinecarbothioamide. M-isobutene+=228.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[S:22](=[O:25])(=[O:24])[CH2:23][C:14]=3[C:13]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[N:12]2)[CH:6]=1)[NH2:4].[C:34](O)(=O)[CH2:35][CH3:36]>CCOC(C)=O>[CH2:35]([C:36]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([N:11]3[C:15]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[S:22](=[O:24])(=[O:25])[CH2:23][C:14]=4[C:13]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[N:12]3)[CH:8]=[CH:9][CH:10]=2)[N:4]=1)[CH3:34]
Reactant: NC(=NO)c1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Reactant: CCC(=O)O
Solvent: CCOC(C)=O
Product: CCc1nc(-c2cccc(-n3nc(C(=O)N4CCOCC4)c4c3-c3ccccc3S(=O)(=O)C4)c2)no1
Temperature: 80 °C

Procedure:
To a solution of N′-hydroxy-3-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzenecarboximidamide (150 mg, 0.32 mmol) in dry EtOAc is added propionic acid (13 μl, 0.32 mmol) under nitrogen followed by TEA (0.13 mL, 0.963 mmol) and propane phosphonic acid cyclic anhydride (0.51 mL, 0.80 mmol) at 0° C. under nitrogen. The reaction mixture is heated to 80° C. for 12 h under nitrogen and concentrated under vacuum. Solid residue is purified by silica gel column chromatography (1.2% MeOH in DCM) to afford the title compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.24-8.22 (d, J=7.4 Hz, 1H), 8.05-8.02 (m, 2H), 7.81-7.77 (m, 2H), 7.64 (m, 1H), 7.57 (m, 1H), 6.93-6.91 (d, J=7.9 Hz, 1H), 4.91 (s, 2H), 3.92-3.90 (m, 2H), 3.67 (m, 4H), 3.61-3.60 (m, 2H), 3.02-3.0 (m, 2H), 1.33-1.29 (t, J=7.6 Hz, 3H). MS (ESI+): 506.0. HPLC (max plot) 97.13%; Rt 4.34 min.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].BrN1C(=O)CCC1=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: NCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCc2ccccc2)c1
Yield: 60.9 %

Procedure:
According to the procedure of Preparation 4 (b), except using tert-butyl 4-fluoro-3-methylbenzoate (6.25 g, 29.7 mmole), N-bromosuccinimide (5.75 g, 32.3 mmole), benzoyl peroxide (375 mg, 1.6 mmole), CCl4 (50 mL), and benzylamine (17 mL, 156 mmole), the title compound (5.70 g, 60%) was prepared as a yellow oil following flash chromatography on silica gel (20% EtOAc/hexanes): MS (ES) m/e 316.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:33][CH3:34])=[C:17]3[N:22]([CH:23]=2)[CH:21]=[CH:20][CH:19]=[C:18]3[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([C:41]([O:43][CH3:44])=[O:42])#[C:36][C:37]([O:39][CH3:40])=[O:38]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[C:35]([C:41]([O:43][CH3:44])=[O:42])[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:21]4[CH:20]=[CH:19][C:18]([CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])=[C:17]([N:22]34)[C:16]=2[CH2:33][CH3:34])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO[Si](C)(C)C(C)(C)C)c12
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3ccc(CO[Si](C)(C)C(C)(C)C)c1n32

Procedure:
2-(4-Benzyloxyphenyl)-8-(tert-butyldimethylsilanyloxymethyl)-1-ethylindolizine, prepared in example 81, step 5, was reacted with dimethyl acetylene dicarboxylate by the general synthetic principle outlined in example 23, step 6, to afford dimethyl 3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate, which was hydrolysed and desilylated by the general synthetic principle outlined in example 23, step 7, to afford 3-(4-benzyloxyphenyl)-4-ethyl-5-hydroxymethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid as yellow crystals in 70% yield. 1H--NMR (DMSO-d6, 200 MHz) δ: 1.32 (t, 3 H); 3.09 (q, 2 H); 5.18 (s, 2 H); 5.19 (s, 2 H); 7.19 (d, 2 H); 7.31-7.58 (m, 7 H); 8.08 (d, 1 H); 8.40 (d, 1 H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:24][C:20]([CH3:21])([CH3:19])[C:22]#[C:23][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12
Reactant: C#CC(C)(C)O
Reactant: Cc1cccc2c1C(=O)N(C)Cc1c(I)ncn1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cc1cccc2c1C(=O)N(C)Cc1c(C#CC(C)(C)O)ncn1-2

Procedure:
5 g (14.2 mmol) of 4,5-dihydro-3-iodo-5,7-dimethyl-6H -imidazo[1,5-a][1,4]benzodiazepin-6-one were heated to boiling under reflux for 4.5 hours with 1.50 g (17.8 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 40 ml of diethylamine. The reaction mixture was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there was obtained 4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5,7-dimethyl -6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 165-167°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:11][CH2:12]2)([OH:9])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1ccnc(Cl)n1)C1CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)(c1ccnc(Cl)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (175 mg, 0.958 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in diethyl ether, 0.380 mL, 1.15 mmol) dropwise. The solution was warmed to room temperature and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 1-(2-chloropyrimidin-4-yl)-1-cyclopropylethanol (115 mg, 0.579 mmol, 60% yield). MS ESI: [M+H]+ m/z 199.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.2, 1H), 7.43 (d, J=5.2, 1H), 3.43 (s, 1H), 1.52 (s, 3H), 1.26 (m, 1H), 0.60 (m, 1H), 0.50 (m, 1H), 0.40 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[CH2:8](Br)[CH:9]=[CH2:10].C(=O)([O-])[O-].[Na+].[Na+].C(C(C)=O)C>CCOCC.[I-].[Na+]>[CH2:10]([CH2:1][NH:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5])[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: CNC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: C=CCCNC(C)(C)C#N
Yield: 48.2 %

Procedure:
A mixture of 2-methylamino-2-methylpropionitrile (14.7 g., 0.15 mole) allyl bromide (18.0 g., 0.15 mole), sodium carbonate (15.9 g., 0.15 mole), sodium iodide (0.2 g., 0.001 mole) and methyl ethyl ketone (200 ml.) was heated under reflux for 40 hrs. The sodium carbonate was filtered off and the solvent was removed from the filtrate in vacuo to give a yellow oil, T.L.C. (Silica, ether), three components RF 0.8, 0.4 and 0.0. The oil was passed through a column of silica 40 × 3.5 cm. using ether as an eluent to give 2-allylmethylamino-2-methylpropionitrile (10.0 g., 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][CH:16]([CH3:22])[CH2:17][CH:18]([NH2:21])[CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:21][CH:18]([CH2:17][CH:16]([CH3:22])[CH3:15])[CH2:19][CH3:20])=[O:13])=[CH:8][C:7]=2[CH:14]=1
Reactant: CCC(N)CC(C)C
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Product: CCC(CC(C)C)NC(=O)c1cc2cc(OC)ccc2o1
Yield: 67 %

Procedure:
Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and 5-methylhexan-3-amine (example 5a). Yield: 67%. 1H NMR (500 MHz, CDCl3): δ 0.96 (m, 9H); 1.39-1.52 (m, 3H); 1.66 (m, 2H); 3.85 (s, 3H); 4.17 (m, 1H); 6.24 (d, 1H); 7.01 (dd, 1H); 7.08 (d, 1H); 7.38 (m, 2H). MS (290, M+H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH:21]([NH2:23])[CH3:22])[CH3:20]>C1(C)C=CC=CC=1>[CH3:20][CH:19]1[CH:21]([CH3:22])[N:23]2[C:11](=[O:13])[C:10]3[C:9]([C:1]2([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:18]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(N)C(C)N
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC1NC2(c3ccccc3)c3ccccc3C(=O)N2C1C

Procedure:
Condense o-benzoylbenzoic acid (22 g.) and 2,3-diaminobutane in toluene (400 ml.) by the procedure of Example 1 to obtain 2,3-dimethyl-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 162°-4° C. (elemental analysis confirms the empirical formula C18H18N2O) and reduce with lithium aluminum hydride as described in Example 1 to obtain 3,4-dimethyl-1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine.