Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.C([N:16](CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:13][C:4]1[C:3]([NH:16][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])=[CH:2][CH:12]=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(NC(=O)C(C)(C)C)c1Cl
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
4-Amino-2-chloro-N,N-dimethylbenzamide (1.0 g) and triethylamine (1.21 g) were dissolved in methylene chloride (20 ml) and the solution was cooled to 0°-5° C. 2,2-Dimethylpropionyl chloride (1.21 g) was added dropwise keeping the temperature below 100° C. and the resulting orange solution stirred at 0°-10° C. for 0.5 hour. The organic solution was then washed with aqueous sodium bicarbonate and then water, dried and evaporated to give an orange solid. This was recrystallised from 3:1 ethyl acetate:chloroform to give 2-chloro-(2',2'-dimethylpropionamido)-N,N-dimethylbenzamide as an off-white crystalline solid (1.027 g), m.p. 202°-203° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH:21][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(N)C(=O)OC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(NC(=O)c1ccccc1N)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a mixture of isatoic anhydride (750 mg, 4.60 mmol) and 2-amino-pentanoic acid methyl ester hydrochloride (1.4 g, 8.35 mmol) (prepared according to example C), in DMF (10 mL) is added triethylamine (2.0 mL, 14.30 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the resulting residue is purified by flash chromatography with 35% EtOAc in Hexane as the eluent to afford the desired 2-(2-amino-benzoylamino)-pentanoic acid methyl ester (575 mg, 50%).
Reaction SMILES: [C:1]([CH:3]1[C:11](=O)[C:10]2[N:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)[CH2:5][CH2:4]1)#[N:2].O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[C:3]2[CH2:4][CH2:5][N:6]3[C:10]([C:11]=2[NH:20][N:19]=1)=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]3
Reactant: CCOC(=O)c1cc2n(c1)CCC(C#N)C2=O
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2n(c1)CCc1c(N)n[nH]c1-2
Yield: 78.1 %

Procedure:
To ethyl 7-cyano-8-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate (12 g, 52 mmol) in ethanol a solution of hydrazine monohydrate (6.5 g, 130 mmol) and acetic acid (9 g, 150 mmol) was added. The reaction was refluxed for 62 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and NH3. The organic phase was dried on Na2SO4. 10 g of a pale yellow solid were obtained (yield 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[O:3]1.[Br:18]Br>CC(O)=O>[Br:18][C:5]1[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10]2
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2c(c1)CCC(C)(C)O2
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)c2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
To a solution of ethyl 2,2-dimethylchroman-6-carboxylate (Compound 216, 500 mg, 2.14 mmol) in HOAc (4 mL) was added Br2 (0.11 mL, 2.14 mmol). The reaction mixture was stirred at room temperature overnight and then a stream of air was passed through the reaction mixture to remove the excess Br2. Removal of the solvent under reduced pressure and column chromatography using the residue (EtOAc:hexanes1:9) afforded 741 mg (100%) of the title compound as an oil. 1H NMR δ 8.05 (1H, d, J=2.2 Hz), 7.73 (1H, d, J=2.2 Hz), 4.34 (2H, q, J=7.1 Hz), 2.84 (2H, t, J=6.7 Hz), 1.85 (2H, t, J=6.7 Hz), 1.40 (6H, s), 1.38 (3H, t, J=7.2 Hz). Anal (C14H17BrO3.0.2 H2O) C, H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][NH:34][CH:35]([CH3:37])[CH3:36]>>[C:23]([O:22][C:20]([C:6]1[C:7]([N:34]([CH:35]([CH3:37])[CH3:36])[CH3:33])=[N:8][C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:21])([CH3:25])([CH3:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNC(C)C
Product: CC(C)N(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 92 step A from tert-butyl 6-chloro-4-phenyl-2-(trifluoromethylsulfonyloxy)quinoline-3-carboxylate (prepared in analogy to example 91 step A to C, 100 mg, 0.21 mmol) and N-methylpropan-2-amine (0.213 ml, 2.05 mmol). Pale yellow solid (75 mg, 89%). MS (ESI): 411 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH2:27]([O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:27]([O:34][C:35]1[C:40]([C:2]2[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:5]=[C:6]([C:8]([CH3:10])([CH3:11])[CH3:9])[CH:7]=2)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: CC(C)(C)c1cc(Br)c(C#N)c(C#Cc2ccc(NS(C)(=O)=O)cc2)c1
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: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c(-c2cccnc2OCc2ccccc2)c1
Yield: 64.1 %

Procedure:
step 3—A sealed tube containing 94 (0.290 g, 0.67 mmol), 2-benzyloxy-3-pyridine boronic acid (0.184 g, 0.80 mmol, 141), Pd(PPh3)4 (0.220 g, 0.07 mmol) and Na2CO3 (0.609 g, 2.01 mmol) in MeOH (9 mL) and DCM (3 mL) was irradiated in a microwave reactor at 125° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between DCM and water then the aqueous layer was further extracted with DCM. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 0.230 g (64%) of N-{4-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-2-cyano-phenylethynyl]phenyl}-methanesulfonamide (96) as a light brown solid.
Reaction SMILES: CC(C)[O-].[Li+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1.BrCC(OC(C)C)=O.[C:37](OCC)(=[O:43])[C:38](OCC)=[O:39]>>[OH:39][C:38]1[C:37]([OH:43])=[C:22]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(N(CC(=O)OC(C)C)CC(=O)OC(C)C)cc1
Agent: CC(C)OC(=O)CBr
Agent: CC(C)[O-]
Agent: [Li+]
Product: COc1ccc(-n2c(C(=O)OC(C)C)c(O)c(O)c2C(=O)OC(C)C)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 0.7 %

Procedure:
Lithium isopropoxide (2M in THF) (10.4 mL, 20.8 mmol) was added to a mixture of diisopropyl 2,2′-((4-methoxyphenyl)azanediyl)diacetate (21) (2.69 g, 8.32 mmol) [prepared using the same procedure as Example B step (i) using isopropyl 2-bromoacetate] and diethyl oxalate (1.13 mL, 8.32 mmol), the mixture was stirred at 65° C. for 16 h. A further portion of lithium isopropoxide (2M in THF) (5.2 ml, 10.4 mmol) was added and the reaction stirred at 65° C. for 3 h. The reaction was quenched with acetic acid (5 mL) and the volatiles removed in vacuo, the crude product was took up in EtOAc (100 mL) and partitioned with water (100 mL), the aqueous was washed with EtOAc (2×100 mL) combined organics were washed with brine (150 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a brown oil. The crude product was recrystallised from hot i-PrOH (50 mL), to provide a white solid. The solid was purified by silica gel chromatography (12 g, 0-50% EtOAc in isohexane) to afford diisopropyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-020) (21 mg, 1%) as a white solid: m/z 378 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.62 (s, 2H), 7.12-7.01 (m, 2H), 6.93-6.84 (m, 2H), 4.80 (sept., J=6.3 Hz, 2H), 3.78 (s, 3H), 0.95 (d, J=6.2 Hz, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[O:5][C:6]1[C:11]([F:12])=[C:10]([O:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=2[O:25][CH3:26])[C:9]([F:27])=[C:8]([O:28][C:29]2[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:7]=1.[N:48]#[C:49][NH2:50].Cl>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[O:5][C:6]1[C:11]([F:12])=[C:10]([O:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=2[O:25][CH3:26])[C:9]([F:27])=[C:8]([O:28][C:29]2[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:7]=1)[C:49]([NH2:50])=[NH:48]
Reactant: CCOC(=O)c1ccc(Oc2c(F)c(Oc3cccc(N)c3)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)c(OC)c1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(Oc2c(F)c(Oc3cccc(NC(=N)N)c3)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)c(OC)c1
Reaction time: 4 h

Procedure:
To ethanol (15 mL) was added 4-[[2-(3-aminophenoxy)-6-(5-cyano-2-phenylmethoxyphenoxy)-3,5-difluoropyridin-4-yl]oxy]-3-methoxybenzoic acid, ethyl ester (0.50 g, 0.80 mmol), cyanamide (0.60 g, 14 mmol), and 6 M hydrochloric acid (0.7 mL). After refluxing for 19 hours, cyanamide (0.60 g, 14 mmol) and 6 M hydrochloric acid (0.7 mL) was added and refluxing was continued for 4 hours. The reaction mixture was concentrated in vacuo and purified by HPLC to give 4-[[2-[3-(guanidino)phenoxy)-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoropyridin-4-yl)oxy]-3-methoxybenzoic acid, ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(O)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc(Nc2ccc3[nH]ccc3c2)c([N+](=O)[O-])c1
Yield: 79 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 4-chloro-3-nitrobenzonitrile (0.444 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in absolute ethanol and the reaction was heated at reflux under nitrogen for 3 hours. After evaporation of the solvent, the residue was chromatographed using ether/hexanes [1:1] to afford the title compound (79%) as a red amorphous solid. Mp, decomposes 134° C.; 13C NMR (DMSO-d6) δ146.9, 137.3, 134.8, 131.9, 131.3, 128.9, 128.3, 126.9, 119.8, 118.2, 117.9, 117.2, 112.5, 101.5, 97.4; LRMS (m/z, relative intensity) 278 (M+, 100), 261 (31), 244 (73), 231 (78). HRMS calculated for C15H10N4O2 : 278.0802. Found: 278.0808. Analytical calculated for C15H10N4O2 : C, 64.74; H, 3.62; N, 20.13. Found: 64.84; H, 3.57; N, 20.13.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:8]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[OH:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(CCC(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCc1cc(O)cc(-c2ccc3cc(O)ccc3c2)c1)Nc1ccccc1
Yield: 23 %

Procedure:
The compound is prepared by reaction of 3-[3-methoxy-5-(6-methoxy-naphthalene-2-yl)phenyl]-N-phenylpropionamide (55 mg, 0.13 mmol, 1 eq) with aluminum trichloride (291.3 mg, 2.19 mmol, 12 eq) according to method F. Purification by preparative thin-layer chromatography with hexane/ethyl acetate 1/1 yielded the desired product in a yield of 23%, 17 mg.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:23]=1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Agent: Cl
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCN(Cc3cccnc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine, hydrochloride, preparative HPLC (methode C) (64%, white crystals). HPLC-MS m/z=437.4 (M+1), Rt: 2.38 min.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C([O:14][C:15](=[O:17])[CH3:16])(=O)C>C(Cl)(Cl)(Cl)Cl>[C:5]([O:6][CH:5]([O:14][C:15](=[O:17])[CH3:16])[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH:1]([O:17][C:15](=[O:14])[CH3:16])[O:10][C:1](=[O:10])[CH3:2])[CH:3]=1)(=[O:6])[CH3:4]
Reactant: O=Cc1cccc(C=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC(OC(C)=O)c1cccc(C(OC(C)=O)OC(C)=O)c1
Temperature: 30 °C

Procedure:
Isophtalaldehyde (10.0 g, 0.075 mol) and acetic acid anhydride (16.7 g, 0.164 mol) were mixed under N2 -atmosphere in carbontetrachloride (25 ml). Nafion NR 50 was added and the reaction mixture stirred at 30° C. for several days. During this period additional amounts of catalyst (100 mg) and solvent (5 ml) were added. The catalyst was filtered off and also the reaction mixture was filtered, washing with ether. The crude solid was recrystallized from cyclohexane (540 ml), giving white crystals, m.p. 110-130° C. The yield was 10.3 g, 41% of the theoretical. 1H- and 13C NMR (CDCl3), d (ppm) rel. to TMS: 7.72 (s, 1H, CH(OAc)2), 7.70-7.42 (m, 1+2+1H, Ar-H) and 2.13 (s, 6H, CH3); 168.591 (C=O), 135.908, 128.885, 128.047 and 124.879 (Ar), 89.072 (CH(OAc)2) and 20.717 (CH3).
Reaction SMILES: [Na].Cl.[CH3:3][O:4][C:5](=[O:8])[CH2:6][NH2:7].Cl([O-])(=O)(=O)=O.CN(C)[CH:16]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:18]=[N+](C)C.[CH2:29](O)C>>[C:22]1([C:17]2[CH:16]=[C:6]([C:5]([O:4][CH2:3][CH3:29])=[O:8])[NH:7][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CN
Reactant: CN(C)C=C(C=[N+](C)C)c1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Na]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Yield: 57 %

Procedure:
Sodium metal (900 mg, 41.0 mmol) was added to dry ethanol (150 mL) and allowed to dissolve over 30 min. Glycine methyl ester hydrochloride (3.2 g, 25.0 mmol) and (3-dimethylamino-2-phenyl-prop-2-enylidene)-dimethyl-ammonium perchlorate (5.0 g, 16.0 mmol) were added successively and the reaction mixture heated at reflux for 16 h. Ethanol was evaporated in vacuo, the residue diluted with water and extracted with chloroform. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product obtained was purified by column chromatography over neutral alumina using 10% ethyl acetate in petroleum ether as eluent to afford ethyl 4-phenyl-1H-pyrrole-2-carboxylate (2.0 g, 57%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]=4[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+].Cl>C1COCC1.O>[N:23]1[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][C:22]=1[CH2:21][CH2:20][CH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[CH:11]=[CH:12]2
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CC(=O)O)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of 3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoic acid ethyl ester (83.0 mg, 0.218 mmol) and NaOH (52.0 mg, 1.31 mmol) in THF/H2O (3:1) was stirred at room temperature for 2 days. Aqueous HCl solution (1 N) was added to adjust the pH to 4-5. The crude product was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over Na2SO4. Removal of solvent gave the crude product, which was purified via column chromatography, eluting with 5% methanol in methylene chloride, to give the title compound (65% yield). 1H NMR (CDCl3) δ 9.35 (br, 1H), 7.42 (d, J=8.1 Hz, 1H) 7.27 (m, H), 7.16-7.20 (m, 2H), 6.95 (d, J=7.9 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 6.22 (d, J=7.2 Hz, 1H), 4.91 (br, 1H), 3.40 (m, 2H), 2.56-2.82 (m, 10H), 1.84-2.05 (m, 6H), 0.86 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C25H32N3O2 406.3 (M+H); found 406.4.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:5]=[N:1][NH:2][CH:3]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:19])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CN(CC2CC2)CCN1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(CC2CC2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(cyclopropylmethyl)piperazine (1.2 equiv) to give 195 (M+1 436.0)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:4]=1.C([Li])CCC.[CH2:27]1[O:29][CH2:28]1.O>C1COCC1.C(O)(=O)C>[OH:29][CH2:28][CH2:27][C:4]1[C:5]([NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: C1CO1
Reactant: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1CCO
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A mechanically stirred solution of N-(4-methoxybiphenyl-2-yl)-2,2-dimethylpropionamide (17.91 g, 63.2 mmol) in anhydrous THF at -68° C. was treated dropwise with butyllithium (2.46 M in hexane, 72.0 mL, 177 mmol), stirred 1 h, allowed to warm to -5° C., stirred 1 h, cooled to -78° C., and treated with ethylene oxide (10.0 mL, 8.82 g, 200 mmol) in one portion. The suspension was allowed to warm to room temperature and stirred for 12 h. The suspension was treated with water (50 mL) and glacial acetic acid (2 mL), stirred 10 min, and concentrated in vacuo. The residue was treated with water (500 mL) and Et2O (300 mL), and the layers were separated. The aqueous layer was further extracted with diethyl ether (2×300 mL), the combined organic extracts were washed with saturated sodium bicarbonate (500 mL), brine (500 mL), dried (K2CO3), filtered, and concentrated in vacuo to give a solid. Recrystallization from Et2O/hexanes gave 10.85 g (52%, 2 crops) of the compound as white crystals: 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 9H), 2.00 (br s, 1H), 2.89 (t, J=6 Hz, 2H), 3.85 (s, 3H), 3.91 (t, J=6 Hz, 2H), 6.88 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.26-7.36 (m, 5H), 7.50 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH2:19](O)[CH3:20]>>[O:16]1[CH2:13][C@@H:19]1[CH2:20][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12]
Reactant: O=C1NCCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: [K+]
Product: O=C1NCCc2c(OC[C@H]3CO3)cccc21

Procedure:
A mixture of 2.0 g (12.3 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone, 3.3 g (14.7 mmol) of (R)-glycidal tosylate and 2.03 g (14.7 mmol) of potassium carbonate in 100 ml of ethanol were refluxed until complete (as indicated by TLC). The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The desired product, (R)-3,4-dihydro-5-(2-oxiranylmethoxy)-1(2H)-isoquinolinone, was obtained by chromatography; mp 161°-64° (Rotation=+12.5°).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([O:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Temperature: 150 °C

Procedure:
A mixture of 3-chloro-6-(3-fluoro-4-methoxy-phenyl)-pyridazine (1.0 g, 4019 mmol), phenol (0.26 g, 5.03 mmol) and Cs2CO3 (1.64 g, 5.03 mmol) in 15 mL of DMF (in microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 150° C. for 15 min. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The solid was washed with 50% EtOAc/hexanes to provide the title compound as an off-white solid. MS (ESI pos. ion) m/z: 297.3 (M+H). Calc'd Exact Mass for C17H13FN2O2: 296.30.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=O.N1CCC[C@H]1C(O)=O>CCO>[C:4]([C:3]([C:2](=[O:1])[CH2:6][CH3:7])=[CH:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)#[N:5]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCC(=O)CC#N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCC(=O)C(C#N)=Cc1ccc(C#N)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a 1000 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 3-oxopentanenitrile (23) (21.8 g, 135 mmol, 60%) of, 4-formylbenzonitrile (17.7 g, 135 mmol), L-proline (3.65 g, 27 mmol, 0.2 eq) and 200 ml of EtOH. The mixture was stirred at 22° C. for 16 hours and concentrated to a volume of approximately 120 ml. 100 ml of MTBE was added and the mixture was stirred at 22° C. for about 30 min. The precipitate was collected by vacuum filtration. The solid was washed with 50 ml of MTBE. It was dried in a vacuum oven at 50° C. to give the product 24 as a off white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 8.10 (d, 2H), 7.81 (d, 2H), 3.00 (m, 2H), 1.28 (t, 3H).