Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].C(Cl)(=O)C(Cl)=O.[NH4+:29].[OH-]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C:11]([NH2:29])=[O:13])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: [NH4+]
Reactant: CC(C)(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)CN(CC(N)=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2-dimethylpropyl)glycine (1.13 g, 3.58 mmol) in CH2Cl2 (10 mL) at 0° C. was added oxalyl chloride (0.33 mL, 3.76 mmol), followed by DMF (0.01 mL, 0.2 mmol). The resulting solution was stirred 5 min in the cooling bath, 20 min at rt and 1 h at reflux under N2. After cooling to rt, the solution was slowly poured into NH4OH (10 mL of a 30 wt % solution) at 0° C., stirred 30 min, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was recrystallized from IPA/hexanes, affording 0.642 g of the title compound as a colorless, amorphous solid. The mother liquor was concentrated and purified by flash chromatography (EtOAc/hexanes), affording an additional 0.241 g of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.9, 2.6 Hz, 1H), 5.70 (bs, 1H), 5.59 (bs, 1H), 4.12 (s, 2H), 3.38 (s, 2H), 1.03 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=O.[NH3:25]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][N:25]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10]=2[CH:20]=1
Reactant: N
Reactant: O=C(c1ccccc1F)c1cc(Br)ccc1-c1ccccc1CBr
Solvent: CCO
Product: Fc1ccccc1C1=NCc2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C

Procedure:
The solution of 5.4 g of 2-(o-bromomethylphenyl)-5-bromo-2'-fluorobenzophenone in 10 ml of ethanol is added slowly to the solution of 150 ml of saturated ethanolic ammonia while stirring at room temperature. After 2 days the mixture is evaporated, the residue taken up in methylene chloride and the solution washed with aqueous sodium carbonate. The organic layer is dried, evaporated and 5 g of the residue chromatographed on 50 g of silica gel, using first toluene, then toluene-diethyl ether (9:1) as the eluent. The later fraction is evaporated and the residue crystallized from hexane to yield the 9-bromo-7-(o-fluorophenyl)-5H-dibenz[c,e]azepine melting at 104°-105°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH2:20](C1C=CC=C2C=1NC=C2)[CH3:21]>>[CH2:20]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2)[CH3:21]
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: CCc1cccc2cc[nH]c12
Product: CCc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-ethyl-1H-indole.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:23][C@@H:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25](O)=[O:26]>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:25](=[O:26])[CH:24]([OH:23])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 12.7, 18.9, 22.8, 25.2, 25.4, 33.9, 34.8, 53.0, 56.8, 60.5, 63.3, 79.0, 107.5, 131.2, 171.8, 174.8; MS m/z 422.4 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.[OH-].[Na+].O1CCOCC1.Cl>C(OCC)(=O)C.O>[OH:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]=13)[O:7][C:6]([CH2:5][CH2:4][C:3]([OH:23])=[O:2])([CH3:22])[CH2:15][CH2:14]2
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCC3C1
Reaction time: 5 h
Yield: 73.3 %

Procedure:
1.0 gram (3.16 mmol) of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester, prepared as described in Example 13, was mixed with 20 mL of 2N NaOH and 20 mL of dioxane, the mixture was stirred for 5 hours and was acidified with dilute HCl. Water and ethyl acetate were added and the organic layer was separated, washed and dried over MgSO4. After the removal of solvents, the residue was further purified by flash column chromatography on silica gel (3:2 ethyl acetate/hexane) to afford 700 mg of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.29 (s, 1H), 4.70 (s, 1H), 3.52-3.46 (d, 2H), 2.69-2.55 (m, 2H), 2.52-2.47 (m, 2H), 2.00-1.64 (m, 8H), 1.43-1.15 (m, 5H); MS: 302 (M+H+, 73%), 325 (M+Na+, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[N:6]=[CH:5]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[N:6]=[CH:5]2)[OH:29]
Reactant: COc1ccccc1-n1ncc2cc(Br)ccc21
Reactant: CC(C=O)c1ccc(Cl)cc1Cl
Product: COc1ccccc1-n1ncc2cc(C(O)C(C)c3ccc(Cl)cc3Cl)ccc21

Procedure:
In analogy to Example 186, 5-bromo-1-(2-methoxy-phenyl)-1H-indazole was reacted with 2-(2,4-dichloro-phenyl)-propionaldehyde to give 2-(2,4-dichloro-phenyl)-1-[1-(2-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-ol which was oxidized to 2-(2,4-dichloro-phenyl)-1-[1-(2-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-one and converted further to the title compound. Colorless solid. MS (m/e)=495.1 [M+H+].
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.C1C(CO)=CC=C(O)C=1.BrC(C)C(OCC)=O.OCC1C=CC(OC(C)C(O)=O)=CC=1>C(O)C>[O:8]([CH2:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: CC(Oc1ccc(CBr)cc1)C(=O)O
Agent: CC(Oc1ccc(CO)cc1)C(=O)O
Agent: CCOC(=O)C(C)Br
Agent: OCc1ccc(O)cc1
Solvent: CCO
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
2.3 g. of sodium is dissolved in 250 ml. of absolute ethanol; 9.4 g. of phenol and 28.6 g. of the ethyl ester of 2-(p-bromomethylphenoxy)-propionic acid [obtainable by reacting p-hydroxybenzyl alcohol with ethyl 2-bromopropionate to the ethyl ester of 2-(p-hydroxymethylphenoxy)-propionic acid and subsequent reaction with SOBr2 ] are added thereto, and the mixture is refluxed for 3 hours and evaporated. The usual working-up procedure yields the ethyl ester of 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: C=O.[CH2:3](NCC)C.[CH2:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>CO>[CH2:22]([O:21][P:17]([C:8]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH2:3])(=[O:24])[O:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCNCC
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC

Procedure:
Paraformaldehyde (104.2 g) and diethylamine (50.8 g) are combined in methanol (2 1), warmed until clear, then treated with methylene bisphosphonic acid, tetraethyl ester (190.09 g) and refluxed for 18 hrs. The sample is then concentrated, methanol added, the methanol removed by heat and reduced pressure, toluene is added and removed by heat and reduced pressure. The residue is dissolved in toluene (1 1), treated with p-TSA (0.5 g) and refluxed through a Dean Stark trap for 18 hrs. The sample is concentrated under reduced pressure with heat, dissolved in methylene chloride washed twice with water, dried with magnesium sulfate, and concentrated under reduced pressure with heat. The sample is purified by distillation at reduced pressure to give the title compound, bp=140° (0.6 torr); MS (m/e) 300, 285, 273, 255, 245, 227, 217, 199, 192, 181, 163, 153 and 135; IR (neat) 2984, 2934, 2909, 1651, 1580, 1479, 1444, 1392, 1254, 1166, 1098, 1042, 1025, 974, 855, 813 and 800 cm-1 ; NMR (CDCl3) 7.1, 6.7, 4.1 and 1.3 δ.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-(1,1-dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH-H2O in 6 ml of reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with 1M HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]([CH2:41][CH2:42]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[O:34]([CH2:41][CH2:42][O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: OCCOc1ccccc1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCCOc2ccccc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 200 using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) and 2-phenoxyethanol. A colorless powder (78 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[N:21]=[C:15]2[NH:16][C:17](=[O:20])[CH2:18][CH:19]=[C:14]2[N:13]=1.[H][H].[ClH:25].O>CN(C)C=O.[Pd]>[ClH:25].[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[N:21]=[C:15]2[NH:16][C:17](=[O:20])[CH2:18][CH:19]=[C:14]2[N:13]=1
Reactant: [H][H]
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C1=NC2=CCC(=O)NC2=N1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cc(N)ccc1C1=NC2=CCC(=O)NC2=N1

Procedure:
An amount of 1.7 gm of 2-(2-dimethylamino-4-nitro-phenyl)-4H-imidazo[4,5-b]pyridin-5-one is dissolved in 20 ml of dimethylformamide and mixed with 0.2 gm of 10% palladium/charcoal. The mixture is hydrogenated for three hours with hydrogen at ambient temperature under 5 bars of pressure. The mixture is filtered off from the catalyst, the mother liquor is mixed with 100 ml each of ether and of ethyl acetate, and finally 3 ml of etheral hydrochloric acid are added. The precipitate is recrystallized from methanol. After drying over phosphorus pentoxide and potassium hydroxide, a product is obtained which contains 1.5 mol of hydrochloric acid and 0.5 mol of water to 1 mol of base.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42](COCCOC)[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C>ClC(Cl)C.FC(F)(F)C(O)=O>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[NH:42][N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COCCOCn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1C
Agent: CC[SiH](CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1ccn[nH]1
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of the 4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (265 mg, 0.376 mmol) prepared in Example 155h and triethylsilane (0.50 mL) in dichloroethane (5.0 mL), trifluoroacetic acid (5.0 mL) was added at room temperature, and the reaction solution was stirred for 4 hours. The reaction solution was concentrated, then methanol (15 mL) and 6 M hydrochloric acid (5.0 mL) were added to the residue, and the reaction solution was stirred for 5 hours under heated reflux. To the reaction solution, an aqueous sodium hydrogencarbonate solution (50 mL) was added, followed by extraction five times with a dichloromethane/methanol (10:1) mixed solvent (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=10:1) to yield the title compound (125 mg, 71%) as a colorless solid.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=3[NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:6]=1.[O:29]=[S:30]1(=[O:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:15]=1)[NH:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][N:33]3[CH2:34][CH2:35][S:30](=[O:36])(=[O:29])[CH2:31][CH2:32]3)[CH:6]=1)=[CH:19]2
Reactant: COC(=O)Cc1cccc(-c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)c1
Reactant: O=S1(=O)CCNCC1
Product: O=S1(=O)CCN(CCc2cccc(-c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)c2)CC1

Procedure:
2-[3-(7-Tetrahydropyran-4-ylamino-5-chloro-1H-indol-2-yl)-phenyl]-acetic acid methyl ester prepared in Example 132 and 1,1-dioxo-thiomorpholine were reacted according to the same procedures as Example 32 and Steps A and B of Example 36 sequentially to give the title compound.
Reaction SMILES: [ClH:1].[O:2]=[C:3]([CH2:5][N:6]([C:8](=[NH:10])[NH2:9])[CH3:7])O.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)Cl>[ClH:12].[CH3:7][N:6]([CH2:5][C:3]([Cl:1])=[O:2])[C:8]([NH2:9])=[NH:10]
Reactant: CN(CC(=O)O)C(=N)N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CN(CC(=O)Cl)C(=N)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Creatine hydrochloride (1.85 g., 0.01 mole) in methylene chloride (50 ml.) was treated with phosphorous pentachloride (2.06 g., 0.01 mole) at room temperature. The mixture was stirred overnight at room temperature and the acid chloride product filtered off, washed with methylene chloride and dried.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]([CH3:27])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]2[N:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:11]2[C:10]1=[O:26])(C)(C)C.C1COCC1>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:6][CH:7]([CH3:27])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]2[N:15]=[C:16]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[C:11]2[C:10]1=[O:26]
Reactant: CC(CN1CCn2nc(COc3ccccc3)cc2C1=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)CN1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
(Rac)-5-[2-(tert-butyl-diphenyl-silanyloxy)-propyl]-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.13 mmol) was dissolved in a 1M solution of TBAF in THF (0.13 mL, 0.13 mmol). The mixture stirred at room temperature for 16 hours. Then the solvent was evaporated in vacuo to yield a yellow crude that was purified by flash column chromatography (silica; MeOH in DCM from 0/100 to 10/90) to yield (rac)-5-(2-hydroxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (20 mg, 51% yield) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][OH:17].B(F)(F)F.[CH3:23]COCC>C(OC)(OC)OC>[O:1]1[CH:23]=[N:18][C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][OH:17])=[N:2]1
Reactant: CCOCC
Reactant: N=C(CCCn1c(CO)nc2ccccc21)NO
Agent: FB(F)F
Solvent: COC(OC)OC
Product: OCc1nc2ccccc2n1CCCc1ncon1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
1H NMR (DMSO) δ 1.97-2.06 (m, 4H), 4.27 (t, 2H, J=7.4 Hz), 4.72 (s, 2H), 5.44 (br s, 2H), 5.64 (br s, 1H), 7.18 (t, 1H, J=7.5 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.5 Hz), 8.83 (s, 1H); MS m/e 249 (MH+); [1-(3-[1,2,4]Oxadiazol-3-yl-propyl)-1H-benzoiidazol-2-yl]-methanol A suspension of N-hydroxy-4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyramidine, 203, (500 mg, 2.01 mmol) in trimethyl orthoformate (5 mL) in the presence of BF3.OEt2 (50 μL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 100° C. for 15 min while stirring, resulting in the dissolution of all the material. The reaction was repeated 5 times. The 6 batches were combined and concentrated in vacuo. The residue was treted with 1M HCl (15 mL) and THF (15 mL) and left overnight. Concentration followed by trituration from dichloromethane and recrystallization from isopropyl alcohol and methanol afforded [1-(3-[1,2,4]oxadiazol-3-yl-propyl)-1H-benzoimidazol-2-yl]-methanol (2.28 g, 73%) as a white solid:
Reaction SMILES: [OH-].[K+].Cl[CH2:4][C:5]#[N:6].[CH:7]1([NH:13][C:14]2[C:19]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]4)[O:22][N:21]=3)=[CH:18][N:17]=[C:16]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:15]=23)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCCC1>[CH:7]1([NH:13][C:14]2[C:19]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][C:27]5([O:30][CH:4]5[C:5]#[N:6])[CH2:26][CH2:25]4)[O:22][N:21]=3)=[CH:18][N:17]=[C:16]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:15]=23)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: N#CCCl
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(=O)CC4)C3)cnc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC5(CC4)OC5C#N)C3)cnc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Benzyltriethyl ammonium chloride (23 mg, 0.00001 mole) was added to a mixture of 50% potassium hydroxide solution and tetrahydrofuran (10 ml) and the mixture was cooled to 0° C. Chloroacetonitrile (0.020 ml, 0.00026 mole) and 3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-one (100 mg, 0.00025 mole) (example 25) in tetrahydrofuran were added to the reaction mixture. It was stirred for about 4 hours at room temperature and water was added. The reaction mixture was extracted with ethyl acetate, organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Yield: 67.2 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.24 g, 5.06 mmol) and phenyl chloroformate (1.90 mL, 15.0 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (1.24 g, 3.40 mmol, 67%). 1H NMR (300 MHz, DMSO-d6) δ 9.96 (br s, 1H), 7.44-7.06 (m, 9H), 6.31 (s, 1H), 3.81 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.Cl>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Yield: 97.3 %

Procedure:
To a suspension of 110 mg of 10o in 1 ml of dioxane, was added 75 μl of anisole and 500 μl of 4N HCl in dioxane. After 1 hr the reaction mixture was diluted with 10 ml of sat. NaHCO3 and the product was extracted with ethyl acetate. The organic layer was washed once with sat. NaCl, dried and concentrated. The residue was triturated with diethyl ether, to provide 90 mg of 10q as white crystalline material. Mp: 250-252° C.; Rf 0.60 (CH2Cl2/methanol 8/2);