Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br[CH2:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:24]1[N:4]=[C:1]([CH2:2][CH3:3])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:23]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)CBr
Product: CCc1nc(C(C)(C)C)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 1-bromo-3,3-dimethylbutan-2-one: MS (ESI) m/z 372 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[OH-].[Li+].Cl.ClCCl.CO>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][N:14]=[N:15][N:16]=2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Alternately, combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (1.71 g, 7.3 mmol) and an aqueous solution of lithium hydroxide (25 mL, 1 M) in methanol (40 mL). After 18 hours, heat to reflux. After 1 hour, add an aqueous solution of lithium hydroxide (15 mL, 1 M) and continue the reflux. After 15 hours, cool to ambient temperature, acidify with a 1 M aqueous hydrochloric acid solution and extract four times with ethyl acetate and then with dichloromethane. Combine the organic layers, dry over MgSO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromethane/methanol 70/30, dichloromethane/methanol 50/50, dichloromethane/methanol 30/70, and then methanol to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([O:25]CC)=[O:24])=[C:16]2[N:15]=1.[Li+].[OH-]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:16]2[N:15]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 90 °C
Yield: 92.4 %

Procedure:
(R)-ethyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (2.13 g, 5.72 mmol) was suspended in EtOH (28.6 mL) and heated at 90° C. for 20 min (homogeneous). 1M aq. LiOH (11.4 mL, 11.4 mmol) was added and the reaction mixture was heated for 15 hours at 90° C. After cooling, the reaction mixture was concentrated, diluted with water and washed with EtOAc to remove any unreacted starting material. The aqueous layer was then acidified to pH 1 using 2N HCl. After extracting with DCM and EtOAc, the combined organic fractions were dried with MgSO4, filtered and concentrated to afford (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.82 g, 92.4%) as a light yellow solid. MS (apci) m/z=345.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1([C:6]2[S:10][C:9]([NH2:11])=[N:8][N:7]=2)[CH2:5][CH2:4]1.CN(C)[CH:16]=[O:17]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:17]1[CH2:16][CH2:5][CH2:4][C@@H:3]1[CH2:2][N:8]1[N:7]=[C:6]([C:3]2([C:2]([F:1])([F:12])[F:13])[CH2:5][CH2:4]2)[S:10][C:9]1=[NH:11]
Reactant: CN(C)C=O
Reactant: Nc1nnc(C2(C(F)(F)F)CC2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: N=c1sc(C2(C(F)(F)F)CC2)nn1C[C@H]1CCCO1
Temperature: 25 °C

Procedure:
A mixture of Example 1A (0.15 g, 0.7 mmol), Example 1B (0.20 g, 0.8 mmol) and tetrabutylammonium iodide (0.13 g, 0.36 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 95° C. for 16 hr, cooled to room temperature and quenched with 1M NaHCO3 (10 mL). The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 0.2 g (crude) of the title compound. LC/MS (ESI+) m/z 294 (M+H)+.
Reaction SMILES: [F:1][C:2]1([C:16]([F:19])([F:18])[F:17])[O:7][C:6]([F:9])([F:8])[C:5](F)([C:10]([F:13])([F:12])[F:11])[O:4][C:3]1=[O:15].[O-2].[Ca+2].[O:22]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[O:15]=[C:3]1[C:2]([F:1])([C:16]([F:17])([F:18])[F:19])[O:7][C:6]([F:9])([F:8])[C:5]([OH:22])([C:10]([F:12])([F:11])[F:13])[O:4]1
Reactant: O=C1OC(F)(C(F)(F)F)C(F)(F)OC1(F)C(F)(F)F
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C1OC(O)(C(F)(F)F)C(F)(F)OC1(F)C(F)(F)F

Procedure:
Perfluoro(2-oxo-3,6-dimethyl-1,4-dioxane), 314 g (1.01 mol), was added dropwise to a slurry of 56.1 g (1.0 mol) of calcium oxide in 500 ml of water while the slurry was stirred in an ice bath. The resultant mixture was stirred for one hour, heated nearly to reflux for 30 min, and stirred for about 65 h. Upon evaporation of the water, the crystalline residue which remained was treated portionwise with 450 g (3.2 mol) of P2O5. The resultant mixture was heated slowly (exothermic reaction) to 150° and then distilled to give 246 g of crude 2-oxo-6-hydroxyperfluoro(3,6-dimethyl-1,4-dioxane), bp 70°-75° (50 mm); upon redistillation from a small amount of P2O5 208 g (67%) of purified lactol was recovered, bp 71°-73° (50 mm). IR: 2.90 (free OH), 5.51 (fluorolactone C=O), 7.5-10μ (C--F, C--O). NMR: 19F-82.7 (several m, 7, CF3 +part of AB for O--CF2) -113.0 and -115.6 ppm (m, 1CF).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:33][C:34]([CH3:55])([C:45]([O:47]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O>>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:45](=[O:47])[C:34]([CH3:33])([CH3:55])[C:35]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[O:37])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Reactant: CC(C)(C(=O)ON1C(=O)CCC1=O)C(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)C(C)(C)C(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1

Procedure:
Compound 183 was prepared from intermediate 175.1 and bis(2,5-dioxopyrrolidin-1-yl) 2,2-dimethylmalonate (prepared using the methods outlined in example 168) following the procedure outlined in example 175. The crude product was purified by Prep-HPLC with acetonitrile:water (0.05% CF3COOH)(10%-100%). This resulted in 29.5 mg (5%) of a TFA salt of N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.94-7.92 (m, 4H), 7.57 (m, 2H), 7.51-7.49 (m, 4H), 6.87 (m, 2H), 4.83-4.74 (m, 4H), 4.55-4.50 (m, 2H), 3.92-3.87 (m, 2H), 3.67-3.48 (m, 8H), 3.40-3.38 (m, 4H), 3.18 (s, 6H), 3.14-3.00 (m, 4H), 1.41 (s, 6H). MS (m/z): 551 [½M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[C:4]=2[O:3]1.[CH3:20][O:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C)C=O>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH:16][C:23]([N:22]([O:21][CH3:20])[CH3:26])=[O:24])=[CH:14][CH:13]=3)[C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2cccc(Oc3ccc(N)cc3)c2O1
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1ccc(Oc2cccc3c2OC(C)(C)C3)cc1
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
1.5 g of 4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)aniline was dissolved in 20 ml of N,N-dimethylformamide, and 0.8 g of N-methoxy-N-methylcarbamoyl chloride was gradually added to this solution at room temperature. After 1.5 hours, N,N-dimethylformamide was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. After distilling off the solvent, the residual oily substance was purified by silica gel column chromatography by using a solvent mixture of ethyl acetate/n-hexane=1/4 as the developer, to obtain 1.4 g of compound No. 2 as identified in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@:23]([OH:29])([CH3:28])[C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: C[C@](O)(c1ccc(-c2ccc(S(=O)(=O)c3ccccc3)c(Cl)c2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(-c2ccc(S(=O)(=O)c3ccccc3)c(Cl)c2)cc1)C(F)(F)F

Procedure:
(2S)-2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=8.2 Hz, 1H), 8.02-7.81 (m, 4H), 7.79-7.68 (m, 5H), 7.66-7.58 (m, 2H), 1.77 (s, 3H). m/z (ESI, +ve ion) 441.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.58 μM; GK-GKRP EC50 (LC MS/MS)=4.23 μM.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:27][CH3:28])=[C:8]([O:25][CH3:26])[CH:9]=2)[N:4]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:27][CH3:28])=[C:8]([O:25][CH3:26])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(Cl)cc1
Reactant: CCNCC
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(Cl)cc1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(4-chlorophenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 4-(4-chlorophenyl)-2-(N,N-diethylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 82°-83° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9]>>[Cl:4][CH2:5][CH2:6][NH:7][C:8]([NH:3][CH2:1][CH3:2])=[O:9]
Reactant: O=C=NCCCl
Reactant: CCN
Product: CCNC(=O)NCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of ethylamine (2.0M in THF, 2.369 mL, 4.74 mmol) and chloroethylisocyanate (0.50 g, 4.74 mmol) was stirred at RT for 2 h, concentrated to dryness and treated with MeCN. The solid was collected via filtration and dried to afford 1-(2-chloroethyl)-3-ethylurea (460 mg, 65%). 1H NMR (400 MHz, DMSO-d6): δ 6.05 (s, 1 H), 5.96 (s, 1 H), 3.54 (t, J=6.3 Hz, 2 H), 3.30-3.23 (m, 2 H), 3.02-2.93 (m, 2 H), 0.96 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 151.1 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:18]2[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=2)[N:12]=1.O>CN(C)C=O>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:19]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=3)[N:12]=[C:11]([CH2:10][N:3]3[CH2:8][CH2:7][S:6][CH2:5][CH2:4]3)[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: C1CSCCN1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CN2CCSCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
Oily sodium hydride (60%, 0.753 g) was added to a solution of thiomorpholine (1.8 g) in N,N-dimethylformamide (50 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (6.0 g) was added. The resulting mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (7/3, v/v) gave ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-thiomorpholinomethylquinoline-3-carboxylate (1.4 g, 42%) which was then recrystallized from ethanol. Colorless prisms. mp. 148°-149° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30]([S:31][C:32]2[CH:37]=[C:36]3[O:38][CH2:39][O:40][C:35]3=[CH:34][C:33]=2I)=[N:29][C:23]2[C:24]([NH2:28])=[N:25][CH:26]=[N:27][C:22]1=2)[CH3:16].C([O-])(O)=O.[Na+].CN(C=O)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.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:33]2[C:32]([S:31][C:30]3[N:21]([CH2:20][CH2:19][CH2:18][NH:17][CH:15]([CH3:16])[CH3:14])[C:22]4[C:23]([N:29]=3)=[C:24]([NH2:28])[N:25]=[CH:26][N:27]=4)=[CH:37][C:36]3[O:38][CH2:39][O:40][C:35]=3[CH:34]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C(C)(C)C)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 82.4 %

Procedure:
4-tert-Butylphenylboronic acid (15.6 mg, 0.0876 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 25.0 mg (83%) of DZ2-390. 1H NMR (500 MHz, MeOH-d4) δ 8.11 (s, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (s, 1H), 6.06 (s, 2H), 3.93 (t, J=6.9 Hz, 2H), 2.92 (septet, J=6.5 Hz, 1H), 2.61 (t, J=7.3 Hz, 2H), 1.86 (m, 2H), 1.28 (s, 9H), 1.12 (d, J=6.5 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 155.9, 153.3, 151.9, 151.8, 150.9, 150.2, 149.2, 141.9, 138.8, 130.0, 125.9, 120.4, 120.3, 115.4, 112.3, 103.6, 50.6, 44.0, 41.8, 35.4, 31.8, 29.3, 21.1; HRMS (ESI) m/z [M+H]+ calcd. for C28H35N6O2S, 519.2542; found. 519.2545; HPLC: method A Rt=7.43, method B Rt=9.45.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[N:13]=[CH:12][C:11](=[O:15])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:22](OC(=O)C)(=[O:24])[CH3:23].OO>C(O)(=O)C>[C:22]([O:1][C:2]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]2[N:13]=[CH:12][C:11](=[O:15])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:24])[CH3:23]
Reactant: O=c1cnc2c([nH]1)-c1ccccc1C2(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: CC(=O)O
Product: CC(=O)OC1(c2ccccc2)c2ccccc2-c2[nH]c(=O)cnc21

Procedure:
9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazin-3(4H)-one (0.24 g) was stirred with a mixture of acetic acid (3 ml), acetic anhydride (3 ml) and hydrogen peroxide (0.42 ml) at room temperature for 3 weeks. The resulting very complex mixture was evaporated and treated with water resulting in precipitation of 200 mg of a crystalline mixture. Purification on silica gel column using methylene chloride/methanol: (9/1) as eluent resulted in 70 mg of a compound which was recrystallized from ethanol. Yield 40 mg of the title compound. M.p. 220°-223° C. MS showed the molecular ion 318 and a degradation pattern in accordance with the title compound. 1H-NMR (CDCl3 /CD3OD: 9/1, δ): 2.4-2.5 (3H, s), 7.3-7.6 (9H, m), 7.9-8.0 (1H, m), 8.2 (1H, s).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:18])([C:7]([F:17])([F:16])[C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH2:10][OH:11])[CH2:5][OH:6].[CH2:19](I)[CH3:20]>O>[CH2:19]([O:11][CH2:10][C:9]([F:12])([F:13])[C:8]([F:15])([F:14])[C:7]([F:16])([F:17])[C:4]([F:18])([F:3])[CH2:5][OH:6])[CH3:20]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
15.4 g potassium hydroxide was dissolved in 200 ml of deionized water, 62 g of 2,2,3,3,4,4,5,5-octafluorohexane-1,6-diol [prepared essentially as described by I.L. Knunyants, L. Chih-yan and V. V. Shokina, Advances in Chem. (Uspekhi Khimi) 32, Original 1502, Eng. Trans. 461-476 (1963); Translation RSIC-165 (Redstone Information Center)] was added, and the mixture was heated to 90° C. Over a period of one hour, 35.7 g of ethyl iodide was added with rapid stirring to the flask via an addition funnel. The reaction mixture was then heated to reflux for two hours. The reaction mixture was cooled to room temperature, and the bottom product phase (54 g crude product) was split away from the aqueous layer. The crude product was distilled at 92°-100° C. at 5.5 mm Hg (5.5 torr) to give 29.1 g of 6-ethoxy-2,2,3,3,4,4,5,5-octafluorohexanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([NH2:20])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([NH2:20])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc([N+](=O)[O-])ccc21
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Reaction time: 3 h

Procedure:
3-Amino-5-nitroindazole-1-carboxylic acid tert-butyl ester (3 g, 10.8 mmol) was dissolved in MeOH (50 mL) and the solution degassed (3× alternating vacuum/nitrogen purges). Palladium on charcoal 10% w/w (300 mg) was added and the nitrogen atmosphere replace by hydrogen. After 3 hours, the mixture was filtered through a pad of Celite® and the filtrate concentrated to afford the title compound as a highly viscous oil (2.17 g, 81%). 1H NMR (400 MHz, DMSO)1.55 (9H, s), 5.07 (2H, brs), 6.04 (2H, brs), 6.79–6.82 (2H, m), 7.62 (1H, brs). MS (ES+) m/e=249.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:32]1([C@H:38]([NH:40][C:41]([NH2:43])=[O:42])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:31][O:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:43][C:41]([NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])=[O:42])=[CH:3][C:4]=2[N:10]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
6-Chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (133 mg, 0.312 mmol), (R)-1-(1-phenylethyl)urea (115 mg, 0.700 mmol), 1:1 BrettPhos:BrettPhos pre-catalyst (20.5 mg, 0.015 mmol), and cesium carbonate (254 mg, 0.781 mmol) were taken up in 1,4-dioxane (3 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 100° C. for 6 h. The reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (12-100% EtOAc-hexanes) gave (R)-1-(3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C35H31N5O2 [M+1]+ 554. found 554.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[C:11](/Cl)=[N:12]/[OH:13])(C(C)(C)C)(C)C.N#N.[CH:17]#[C:18][CH3:19].C(N(CC)CC)C>C(Cl)CCl.C[C]1[C](C)[C](C)[C](C)[C]1C.C1CC=CCCC=C1.Cl[Ru]>[CH3:19][C:18]1[C:11]([CH2:10][CH2:9][OH:8])=[N:12][O:13][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCC/C(Cl)=N/O
Reactant: C#CC
Agent: Cl[Ru]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Solvent: CCN(CC)CC
Solvent: C1=CCCC=CCC1
Solvent: ClCCCl
Product: Cc1conc1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
A solution of (Z)-3-(tert-butyldimethylsilyloxy)-N-hydroxypropanimidoyl chloride (90 mg, 0.378 mmol) in ClCH2CH2Cl (Volume: 2 mL) at room temperature was purged with N2 for 2 min. Prop-1-yne (0.022 mL, 0.378 mmol) [Condensed at −78° C.] was added as a liquid, followed by chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium (II) (7.17 mg, 0.019 mmol) and triethylamine (0.066 mL, 0.473 mmol). The reaction mixture was stirred at room temperature for 16 h. It was dark brown in color. The mixture was filtered through 0.45 μm membrane. The filtrate was concentrated, diluted with MeOH, and purified with prep HPLC (Waters Xbridge C18 19×100 mm), 20 mL/min flow rate with gradient of 30% B-100% B over 10 minutes Hold at 100% B for 2 min. (A: 0.1% TFA in water/MeOH (90:10), B: 0.1% TFA in water/MeOH (10:90) monitoring at 220 nm. After concentration, 2-(4-methylisoxazol-3-yl)ethanol (35 mg, 0.270 mmol, 71.3% yield) was obtained as light brown liquid. 1H NMR (400 MHz, chloroform-d) δ 8.13 (s, 1H), 4.03 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H), 2.02 (d, J=0.9 Hz, 3H).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(R)-Thiazolidine-4-carboxylic acid (309.9 mg, 2.33 mmol) was dissolved in DMF (10 mL) and distilled water (10 mL). The solution was cooled to 0° C., and DIEA (0.590 mL, 3.39 mmol) was added followed by benzyl chloroformate (0.485 mL, 3.40 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.