Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[S:23])[N:3]1[C:24]1[CH:25]=[C:26]([C:32]([F:35])([F:34])[F:33])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1.Br[CH:37]([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C1COCC1>[CH:37]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([N:5]3[C:4](=[S:23])[N:3]([C:24]4[CH:25]=[C:26]([C:32]([F:34])([F:33])[F:35])[C:27]([C:30]#[N:31])=[N:28][CH:29]=4)[C:2](=[O:1])[C:6]43[CH2:9][CH2:8][CH2:7]4)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1)([CH3:39])[CH3:38]
Reactant: CC(C)Br
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1
Temperature: 70 °C
Yield: 9.2 %

Procedure:
To a solution of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (50 mg, 0.10 mmol) in anhydrous THF (1 mL) was added 2-bromopropane (20 μL, 0.20 mmol) followed by cesium carbonate (100 mg, 0.30 mmol). The reaction mixture was heated at 70° C. overnight. DMF (1 mL) was added to improve solubility and the reaction was heated at 85° C. for 3 h. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous was extracted further with EtOAc (2×) and the combined organics were washed with water, then brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided 5 mg of 5-(5-(4-((1-isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.04 (d, 1H), 8.30 (d, 1H), 7.13 (d, 2H), 6.99 (d, 2H), 4.37-4.26 (m, 1H), 2.81-2.33 (m, 10H), 2.25-1.74 (m, 5H), 1.00 (d, 6H). LCMS [M+1]+ 544.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[OH:19])[CH:3]=1.CN.[C:22]([BH3-])#[N:23].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH3:22])[C:12]=2[OH:19])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1O
Yield: 61.4 %

Procedure:
4-Chloro-2-(3-formyl-2-hydroxyphenoxy)-benzonitrile (0.30 g, 1.10 mmol), methylamine (2M in methanol, 2.5 mL, 5.0 mmol) and sodium cyanoborohydride (0.10 g, 1.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (35 mL) for 19 h. The solvent was removed in vacuo. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. To the ethyl acetate layer was added fumaric acid (0.12 g, 1.03 mmol) and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[2-hydroxy-3-(methylaminomethyl)phenoxy]-benzonitrile fumarate (256 mg, 58%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][NH:24][C:2]3[C:3]([C:4]([O-:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1.[NH4+:10]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Product: [NH4+]
Reaction time: 16 h
Yield: 96.7 %

Procedure:
A mixture of 2-chloronicotinic acid (10.74 g, 67.5 mmol), 1-(4-pyridyl)piperidine-4-methylamine (8.60 g, 45.0 mmol), and potassium carbonate 15.5 g, 112.6 mmol) in dimethylformide (90 mL) was heated at reflux. After 16 h, the mixture was diluted with methanol, filtered, and concentrated. The residue was dissolved in methanol, acidified with 1 N HCl in ether, heated at reflux for 0.25 h, cooled, and the solid removed by filtration. The filtrate was then treated with 2 M NH3 in methanol until slightly basic, triturated with THF and the resulting solid collected by filtration yielding 10.75 g of the title compound which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][C:35]([OH:37])=[O:36])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.COC(=O)[C@H](CC1C=CC=CC=1)N.Cl.C(N(CC)CC)C>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[K+].[K+].[K+].C(OCC)(=O)C.OCC(CO)O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:38](=[O:39])[C@H:33]([CH2:34][C:35](=[O:36])[OH:37])[NH:32][C:30]([O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: OCC(O)CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Papain (1 g; obtained from J. E. Siebel Son's Co.) was well suspended in 2 ml of 3.0M potassium citrate buffer (pH 5.1), the suspension was then mixed with 2 ml of glycerol. To 100 ml of ethyl acetate, 80 mmole of L-phenylalanine methyl ester hydrochloride and 80 mmole of triethylamine were added and stirred at 25° C. for 40 min then 40 mmole of N-benzyloxycarbonyl-L-aspartic acid was added and stirred for 20 min. The whole ethyl acetate mixture, containing soluble L-phenylalanine methyl ester and N-benzyloxycarbonyl-L-aspartic acid and insoluble triethylamine hydrochloride, w-as subsequently added to the papain suspension. The reaction mixture was stirred at 25° C. for 22 hr then 200 ml of ethyl acetate was added and stirred at 55° C. for 15 min and filtered. As determined by HPLC analysis the yield of the N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester in the filtrate was 85% calculated on the basis of the initial amount of the N-benzyloxycarbonyl-L-aspartic acid. The ethyl acetate solution was then extracted twice with 150 ml of 0.01M phosphate buffer (pH 7.0), then twice with 150 ml of 0.3N hydrochloric acid. The final organic layer was dehydrated with 10 g of anhydrous Na2SO4, then evaporated and vacuum dried to give 17.4 partially purified N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:32]([NH:34][NH:35][CH:36]=O)=O>CN(C=O)C>[N:34]1[N:35]=[CH:36][N:1]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[O:5][CH2:6][C:7]([OH:9])=[O:8])[CH:32]=1
Reactant: Nc1cccc(OCC(=O)O)c1
Reactant: O=CNNC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)COc1cccc(-n2cnnc2)c1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a round bottom flask was added (3-amino-phenoxy)-acetic acid 2 (167 mg, 1.0 mmol, 1.0 eq.), toluene (5.0 mL), DMF (0.5 mL), p-toluene sulfonic acid monohydrate (209 mg, 1.1 mmol, 1.1 eq.), and sym-diformyl hydrazine (96.8 mg, 1.1 mmol, 1.1 eq.). The mixture was refluxed overnight. Upon cooling to RT, the reaction mixture separated out into two layers with product in the bottom brown oil layer and toluene in the clear top layer. The toluene layer was removed; water was added to the brown oil and then extracted with EtOAc 3×. The combined organic layers were then dried with Na2SO4, concentrated via rotary evaporation, and then triturated with ether to give (3-[1,2,4]Triazol-4-yl-phenoxy)-acetic acid 24 as an orange solid (65.0 mg, 30% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 220.1 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 9.10 (s, 2H), 7.48 (m, 1H), 7.39 (t, 1H), 7.31 (dd, 1H), 7.00 (dd, 1H), 4.80 (s, 2H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:31][C:32]1[CH:33]=[C:34]2[C:38](=[N:39][CH:40]=1)[NH:37][CH:36]=[CH:35]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH:37]1[C:38]2[C:34](=[CH:33][C:32]([O:31][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:40][N:39]=2)[CH:35]=[CH:36]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 84.6 %

Procedure:
tert-Butyl 4-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}piperazine-1-carboxylate (2.0 g, 4.42 mmol) was dissolved in N,N-dimethylacetamide (60 ml) and 5-hydroxy-7-azaindole (651 mg, 4.86 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (671 mg, 4.86 mmol) added. The reaction mixture was heated at 85° C. for 3 hours. The mixture was cooled, filtered and concentrated under reduced pressure. Column chromatography of the residue (8-10% methanol/dichloromethane) gave 4-(7-azaindol-5-yloxy)-7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (2.0 g, 85%) as a white solid.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[CH:39]=[C:38](C=O)[CH:37]=[CH:36]5)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:45]1[CH2:49][C:48](=[O:50])[NH:47][C:46]1=[O:51]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[CH:39]=[C:38]([N:47]4[C:48](=[O:50])[C:49](=[CH2:1])[S:45][C:46]4=[O:51])[CH:37]=[CH:36]5)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc2cc(-c3cc4c(c(C56CC7CC(CC(C7)C5)C6)c3)OCO4)ccc2c1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=C1SC(=O)N(c2ccc3cc(-c4cc5c(c(C67CC8CC(CC(C8)C6)C7)c4)OCO5)ccc3c2)C1=O
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of toluene (10 mL), piperidine (10 μL), acetic acid (10 μL), 6-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-2-naphthaldehyde (0.400 g, 0.974 mmol) and 2,4-thiazolidinedione (0.114 g, 0.974 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with toluene and ethanol. The yellow solid was dried under high vacuum to afford 0.344 g (69%) of 6-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-naphthalen-2-yl-methylene-2,4-thiazolidinedione, mp 304–306° (dec). 1H NMR (500 MHz; DMSO-d6): 1.76 (s, 6H), 2.07 (s, 9H), 6.06 (s, 2H), 7.16 (d, J=1.6 Hz, 1H), 7.29 (s, 1H), 7.68 (dd, J=1.0 Hz, J=9.0 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.93 (s, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.17 (s, 1H), 8.19 (s, 1H), 12.5–12.7 (brs, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CCOC(C)=O>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1NC1CCN(Cc2ccccc2)CC1
Yield: 36.6 %

Procedure:
To a solution of 1.64 g 2-chloro-3-nitropyridine and 1.37 g of 1-benzyl-piperidin-4-ylamine in 20 mL THF was added diisopropylethylamine. The reaction was refluxed for 6 hours. The reaction was cooled down, diluted with 50 mL of EtOAc and washed with 30 mL of saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×30 mL of EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 25% EtOAc in hexane, then 50% EtOAc in hexane and 100% EtOAc to give 823 mg of the title compound as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:12]=3[C:8]=2[C:7]([C:22]2[O:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=2)=[CH:6][CH:5]=1.[OH-].[K+]>C(O)C.O1CCCC1.O>[F:32][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:12]=3[C:8]=2[C:7]([C:22]2[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(NS(C)(=O)=O)cc4c23)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2oc3c(OC(F)F)ccc(-c4nc(C(=O)O)co4)c3c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a slurry of ethyl 2-(4-(difluoromethoxy)-8-(methylsulfonamido)dibenzo[b,d]furan-1-yl)1,3-oxazole-4-carboxylate (0.2 g, 0.429 mmol) in ethanol (5 mL) and tetrahydrofuran (3 mL) was added potassium hydroxide (0.256 g, 4.562 mmol) in water (0.5 mL). Then it was stirred at room temperature for 16 hours. The solvent was removed in vacuum. The residue was diluted with water and acidified with 1N HCl until the solid separates out. The solid was filtered and washed with hexane. Yield—98.4%. 1H-NMR (DMSO-d6) δ: 3.09 (s, 3H), 7.40 (s, 1H), 7.48-7.51 (m, 1H), 7.59-7.63 (m, 2H), 7.87 (d, 1H), 8.06 (d, 1H), 8.97-8.99 (m, 2H), 9.81 (s, 1H); HPLC (purity): 99.1%; Mass calculated for C18K2F2N2O7S-438.4, observed—437.0; Rf—0.2 (Dichloromethane:Methanol (8:2)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]([OH:16])=O)([CH2:11]3)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:78]=[CH:77][C:52]([O:53][C:54]2[CH:59]=[CH:58][N:57]=[C:56]3[CH:60]=[C:61]([C:63]4[CH:68]=[CH:67][C:66]([C:69]([N:71]5[CH2:76][CH2:75][O:74][CH2:73][CH2:72]5)=[O:70])=[CH:65][CH:64]=4)[S:62][C:55]=23)=[C:51]([F:79])[CH:50]=1>ClCCl>[F:79][C:51]1[CH:50]=[C:49]([NH:48][C:14]([C:10]23[CH2:11][CH:12]2[CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]3=[O:17])=[O:16])[CH:78]=[CH:77][C:52]=1[O:53][C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[CH:60]=[C:61]([C:63]3[CH:64]=[CH:65][C:66]([C:69]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[O:70])=[CH:67][CH:68]=3)[S:62][C:55]=12
Reactant: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)c3s2)cc1)N1CCOCC1
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (20 mg, 0.085 mmol) in 500 uL of dichloromethane at room temperature under nitrogen was added HOBt (19.5 mg, 0.128 mmol), EDCI (24.5 mg, 0.128 mmol) and DIEA (45 uL, 0.225 mmol). After 15 minutes a solution of (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A, 34 mg, 0.077 mmol) in 500 uL dichloromethane was added by pipet. After stirring overnight, the reaction was diluted to 30 mL with CH2Cl2 and washed 1×30 mL with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto Biotage 12S column and eluted initially with dichloromethane and then after about 100 mL of elution, switched to 2/98 MeOH/dichloromethane. Pure product containing fractions were pooled and concentrated to a white glass (12 mg, 21% yield). LRMS (APCI pos) m/e 667.4 (M+1). 1H NMR: (CDCl3, 400 MHz): δ 10.52 (s, 1H), 8.50 (d, 1H), 7.83 (m, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.54-7.46 (m, 4H), 7.31 (m, 1H), 7.24 (m, 1H), 7.11 (m, 2H), 6.52 (d, 1H), 4.12 (m, 1H), 3.90-3.60 (br m, 8H), 3.78 (d, 1H), 2.81 (m, 1H), 2.05 (m, 1H), 1.39 (m, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28]>CN1C(=O)CCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NCC(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(NCC(N)=O)cc1OCC2
Temperature: 85 °C
Yield: 8 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and glycinamide hydrochloride salt in NMP were heated at 85° C. for 20 h. The reaction mixture was cooled and loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol and appropriate fractions concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% 2M ammonia in methanol in DCM). The solid was recrystallised from methanol to give 404 as a white solid (19 mg, 8%). LCMS: RT=2.14 min, [M+H]+=369. 1H NMR 400 MHz (DMSO-d6) δ: 9.01 (1 H, s), 7.90 (1 H, d, J=0.63 Hz), 7.82 (1 H, s), 7.32 (1 H, br, s), 7.01 (1 H, br, s), 6.11 (1 H, s), 5.97-5.88 (1 H, m), 4.49-4.48 (4 H, m), 3.84 (2 H, d, J=4.26 Hz), 1.48 (6 H, d, J=6.60 Hz)
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.[C-:8]1(C(O)=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH-:16]1[CH:20]=[CH:19]C=C1.[Fe+2:21].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[NH:40][NH2:41]>ClCCl.C1(C)C=CC=CC=1>[C-:6]1([NH:3][C:4]([NH:41][NH:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])=[O:14])[CH:7]=[CH:19][CH:20]=[CH:16]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:21]
Reactant: O=C(O)[c-]1cccc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)NN
Agent: [Fe+2]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1cc[cH-]c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)NNC(=O)N[c-]1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Under ice cooling, 0.6 mL (4.3 mmols) of triethylamine was added to a mixture of 0.5 g (2.17 mmols) of ferrocenecarboxylic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.), 0.47 mL (2.17 mmols) of diphenylphosphorylazide and 4 mL of toluene and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane. The dilution was washed sequentially with a 1% hydrochloric acid aqueous solution and saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the organic layer was filtered and concentrated under reduced pressure to give 4 mL of the toluene solution. To the toluene solution obtained, 2 mL of toluene was added and 0.34 g (3.27 mmols) of ethyl carbazate was added to the mixture while stirring at room temperature. The reaction mixture was heated under reflux for an hour and then diluted with dichloromethane. The dilution was washed sequentially with a 1% hydrochloric acid aqueous solution and saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the organic layer was filtered and then concentrated under reduced pressure. The resulting residue was washed with a hexane-dichloromethane (1:1) mixture to give 0.52 g (72%) of ethyl 3-ferrocenylcarbamoylcarbazate as yellow powders.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:13])[CH2:11][Cl:12])=[CH:4][C:3]=2[O:2]1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>C(O)C>[ClH:12].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:13])[CH2:11][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)N
Reactant: OC(CCl)c1ccc2c(c1)OCO2
Solvent: CCO
Product: CC(C)NCC(O)c1ccc2c(c1)OCO2
Product: Cl

Procedure:
20.5 g. of 1-(3,4-methylenedioxyphenyl)-2-chloroethanol are mixed with 30 g. of isopropylamine and 100 ml. of ethanol and the mixture is refluxed for 8 hours. After cooling, the ethanol and excess amine are removed by distillation under reduced pressure. The residue is extracted with 100 ml. of 1N HCl and the extract is washed twice with 50 ml. of ether. The hydrochloric acid extract is made basic with 1N caustic soda, and the liberated oil is extracted with ether. The ether extract is dried and an etherial hydrochloric acid solution is added. The crystalline hydrochloride settles out of solution and is filtered and dried. Upon recrystallization of the crude crystals from isopropyl alcohol, 6.4 g. of 1 -(3,4-methylenedioxyphenyl)-2-isopropylaminoethanol hydrochloride are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=3)[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:8]=2)[CH:4]=[N:3]1.[OH-].[Na+]>CCO.CCOC(C)=O.[Cl-].[Na+].O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=3)[NH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CCCCO)cc23)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2c[nH]c3ncc(CCCCO)cc23)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To crude azaindole 66 (76 mg, 0.19 mmol) in EtOH (6 mL) was added 10% NaOH (1 mL) and the mixture was stirred in an oil bath (90° C.) for 2 h. The mixture was then cooled to r.t., diluted with AcOEt and saturated brine and partitioned. The aqueous layer was extracted with AcOEt (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residual yellow oil was purified by means of PTLC employing AcOEt as eluent to afford the azaindole 67 (16 mg, 31%); 1H NMR (400 MHz; CDCl3) δ 1.61-1.80 (m, 8H), 2.77 (t, J=7.6 Hz, 2H), 3.67 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 7.34 (d, J=1.9 Hz, 1H), 7.61 (s, 1H), 7.73 (d, J=0.6 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 9.29 (br s, 1H).
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]1=[O:27])=[O:10])C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[C:23]([O:22][C:20]([CH2:19][N:14]1[C:15](=[O:18])[CH:16]=[CH:17][N:12]([CH2:11][C:9]([OH:10])=[O:8])[C:13]1=[O:27])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)OCc2ccccc2)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To ethyl acetate (20 ml) containing 1-benzyloxycarbonylmethyl-3-(tert-butoxycarbonylmethyl)-2,4-dioxopyrimidine (1.2 g) obtained in Example 2 is added a 20% palladium hydroxide (50 mg), and the mixture is stirred at room temperature under hydrogen atmosphere for one hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give the desired 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetic acid (0.7 g) as colorless powder.