Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[C@H:20]([NH:19][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)[C@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-benzeneacetamide hydrochloride (1:1) (CAN 63291-39-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 366.1808 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=O)[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.C(O)(C)C.CCCCCC>C(O)(=O)C.C(O)(C)C.[Pd]>[CH:5]1[C:6]([C@H:7]2[CH2:8][O:9][C:10]3[CH:11]=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=3[CH2:16]2)=[CH:1][CH:2]=[C:3]([OH:19])[CH:4]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [Pd]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1

Procedure:
Daidzein (200 mg, 0.8 mmol) is dissolved in a mixture of glacial acetic acid (20 mL) and isopropanol (20 mL), and is reduced with 10% Pd on charcoal (150 mg) at 55 p.s.i.g. (3.7 atm gauge). At the end of the reaction (2 hours, TLC:isopropanol/n-hexane 1/4) the catalyst is filtered off, and the filtrate is evaporated. The crude residue is purified by chromatography on a silica gel column using as eluent a mixture of isopropanol and n-hexane (1:4 v/v), to give (±) equol as a pure product (160 mg, yield: 82%) crystallized from n-hexane. The product, colorless crystals, is not hygroscopic, is stable in air, and does not decompose during the final filtration procedure. The product of this chemical synthesis was in all respects identical with an authentic sample of (±) equol (racemic equol). FIG. 4 shows the GC-MS analysis of the trimethylsilyl ether derivative of synthesized product as a single pure peak and a mass spectrum that is consistent with the published electron ionization spectrum of the trimethylsilyl (TMS) ether derivative of authentic equol. The molecular ion as expected is at m/z 470 and the base peak at m/z 234. The purified equol product had a purity of greater than 99%, as confirmed by HPLC and mass spectrometry.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(OC(=O)C)(=O)C.[BrH:12].[CH2:13]([N:16]([CH2:29][CH2:30][CH3:31])[CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:28])[C:23]=2[NH2:27])[CH2:18]1)[CH2:14][CH3:15].C(OCC)C>C(Cl)Cl>[BrH:12].[CH2:29]([N:16]([CH2:13][CH2:14][CH3:15])[CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:28])[C:23]=2[NH:27][C:1](=[O:4])[CH3:2])[CH2:18]1)[CH2:30][CH3:31]
Reactant: CC(=O)O
Reactant: CCCN(CCC)C1CCc2c(ccc(O)c2N)C1
Agent: Br
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCCN(CCC)C1CCc2c(ccc(O)c2NC(C)=O)C1
Reaction time: 1 h

Procedure:
10 ml of acetic acid and 0.46 ml of acetic anhydride are added to 1.5 g of 2-dipropylamino-5-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (obtained in accordance with Example 1(d)) in 25 ml of methylene chloride at 0° C. The mixture is stirred for one hour, diethyl ether is added and the solid is recrystallised from ethanol. This gives 1.2 g of a product melting at 244.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](OCC)=[O:15])[CH:11]=[CH:10][C:9]=2[C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])=[CH:4][C:3]=1[O:29][CH:30]1C[CH2:33][N:32]([CH3:35])[CH2:31]1.[NH2:36][C:37]1([C:47]([OH:49])=[O:48])[CH:44]2[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:46][CH:38]1[CH2:39]3)[CH2:43]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:36][C:37]3([C:47]([OH:49])=[O:48])[CH:44]4[CH2:43][CH:42]5[CH2:41][CH:40]([CH2:39][CH:38]3[CH2:46]5)[CH2:45]4)=[O:15])[CH:11]=[CH:10][C:9]=2[C:19]2[C:20]([O:27][CH3:28])=[CH:21][CH:22]=[CH:23][C:24]=2[O:25][CH3:26])=[CH:4][C:3]=1[O:29][CH2:30][CH2:31][N:32]([CH3:35])[CH3:33]
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(OC3CCN(C)C3)c2)n1
Product: COc1cccc(OC)c1-c1ccc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nc1-c1ccc(Cl)c(OCCN(C)C)c1
Yield: 50.5 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 250 mg (0.5 mmol) of ethyl 6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate and 100 mg (0.51 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 160 mg of 2-({[6-{4-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid in the form of white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1)(=[O:12])=[O:11].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]([S:10]([C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1)(=[O:11])=[O:12])[CH2:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(Cc2ccc(F)cc2)c2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 98 %

Procedure:
Phosphazene base 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-Et) (0.61 ml, 1.6 mmol) was added dropwise to a solution of 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole (0.3 g, 1.04 mmol) in THF (2 ml) at room temperature. After 10 minutes 4-fluorobenzyl bromide (0.16 ml, 1.3 mmol) was added dropwise at room temperature and the mixture was stirred for 1 hour. The reaction was quenched by addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated. The organic phase was washed several times with brine, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.05 of Table 27) as a white solid (405 mg, 98% yield).
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=[C:10]([O:16][CH3:17])[C:8]=2[N:9]=1.O>C(O)CO>[CH3:17][O:16][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)OC)sc12
Solvent: O
Solvent: OCCO
Product: C=Cc1ccc(OC)c2nc(N)sc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl ester was dissolved in ethylenglycol/2N KOH (2:1) and stirred at 100° C. for 3 hrs. Then water was added and the mixture was extracted with CH2Cl2, the organic phase was washed with brine and dried over MgSO4. After evaporation the residue was crystallized from CH2Cl2. White crystals (64%); F.p.: 155-159° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:23])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:23])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])(=[O:17])[CH2:8]1)=[O:6]
Reactant: COc1c(F)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(F)c(O)c(F)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
3-(3,5-difluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (453 mg) was dissolved in N,N-dimethylformamide (4 mL), and lithium chloride (559 mg) was added to the solution, and then the mixture was stirred at 100° C. for 16 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) and then crystallized from diethyl ether to obtain the title compound (270 mg) as a colorless crystal.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:10]1([CH3:42])[CH3:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O>CCCCCC.C1C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25])[C:10]1([CH3:41])[CH3:42])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 88.9 %

Procedure:
3β,24-Bis(tert-butyldimethylsilyloxy)-4,4-dimethylchol-5-ene (44 g) is dissolved in a warm mixture of hexane (2 l) and benzene (540 ml). 1,3-Dibromo-5,5-dimethylhydantoin (15.32 g) is added and the mixture is refluxed for 20 min and then cooled rapidly to room temperature, and the insoluble material is removed by filtration. The filtrate is concentrated under reduced pressure and o-xylene (2 l) and quinaldine (84 ml) is added. The mixture is refluxed for 1 hour. After aqueous work-up and trituration with methanol, 3β,24-bis (tert-butyldimethylsilyloxy)-4,4-dimethylchola-5,7-diene (39 g) is isolated. Melting point: 98-106° C. 1H-NMR (CDCl3, 400 MHz): δ=5.9 (1H, m); 5.54 (1H, m); 3.58 (2H, m); 3.35 (1H, m); 0.91 (18H, s); 0.05 (12H, m).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(OCC)(=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]2[C:10](=[O:12])[O:11][C:6](=[O:5])[NH:8]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](Cc2ccc(F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2(S)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (1.5 g, 5.29 mmol) in ethyl acetate (100 mL) under an argon atmosphere was added triphosgene (628 mg, 2.12 mmol). To the solution was added triethylamine (0.8 mL 5.76 mmol,) over 1 min, and the reaction stirred for 72 h at rt. The reaction mixture was filtered, and the filtrate concentrated in vacuo to yield an oily residue. The crude material was crystallised from cold dichloromethane and petroleum ether to give the title compound. δH (CD3OD): 7.20 (2H, m), 7.10 (2H, m), 5.86 (1H, s, (NH)), 4.58 (1H, s), 3.33–3.23 (2H, m), 3.11–3.00 (1H, m).
Reaction SMILES: Br.[CH:2]1([C:5]([CH:7]2[CH2:9][CH2:8]2)=[NH:6])[CH2:4][CH2:3]1.[F:10][B-:11]([F:14])([F:13])[F:12].[NH4+]>CS(C)=O>[F:10][B-:11]([F:14])([F:13])[F:12].[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2
Reactant: N=C(C1CC1)C1CC1
Agent: Br
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of dicyclopropylmethanimine hydrobromide (0.200 g, 1.05 mmol) in 2.0 ml of dimethyl sulfoxide was added 0.232 g (2.10 mmol) of ammonium tetrafluroborate. The mixture was heated with stirring at 100° C. for 2 hours. The solvent was distilled out in vacuo and isobutyl alcohol was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 0.17 g (Yield: 82%) of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)cc1)C1CCN(C2CCNC2=O)CC1
Temperature: 85 °C
Yield: 30.8 %

Procedure:
A 10 mL microwave vial containing methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (0.56 mmol, 100 mg) and (4-chloro-phenyl)-piperidin-4-yl-methanone (0.56 mmol, 125 mg) in DIEA (2.8 mmol, 0.5 mL) was heated to 85° C. for 105 min. The diisopropylethylamine was decanted off and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (53 mg, 31% yield). MS (ESI) m/e 307.3 (M+H+), calculated 306.2; HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.506 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccnc3)cc2)c2ccc3ccccc3c2N1
Yield: 91.8 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 3-pyridinesulfonyl chloride (20 mg, 0.11 mmol) were treated by heating in pyridine (3 mL). A post-treatment was performed in a conventional manner to give N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamide (40 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.[NH2:26][NH2:27]>CCO>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH2:15][CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[OH:23])[NH:27][N:26]=3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)/C=C/c2ccccc2O)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)n1-c1ccc(C2=NNC(c3ccccc3O)C2)cn1
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a suspension of (2E)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-3-(2-hydroxyphenyl)prop-2-en-1-one (0.31 g, 0.97 mmol) in EtOH (8.5 mL) was added hydrazine hydrate (65% solution, 0.146 mL, 1.95 mmol). After stirring for 15 min, the reaction mixture was concentrated to give 2-{3-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-4,5-dihydro-1H-pyrazol-5-yl}phenol as a yellow solid (0.32 g, 99%). LCMS: (FA) ES+ 333.2 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][NH:30][CH2:29][CH2:28][N:27]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:22][CH:21]=1)[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@@H:9]([CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:31][NH:30][CH2:29][CH2:28][N:27]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:24][CH:25]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(C2CNCCN2C(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CCOc1ccc(C2CNCCN2C(=O)OCc2ccccc2)cc1)C(=O)O
Temperature: 0 °C

Procedure:
A solution of 28-4 (1.0 g, 1.8 mmol) in 10 mL EtOAc was cooled to -40° C. and saturated with HCl gas. The solution was warmed to 0° C., then concentrated to give 28-5 as a tan solid. Rf (10:1:1 EtOH/H2O/NH4OH) 0.18.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)#[N:4]>C(O)C>[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6]1)#[N:4]
Reactant: COc1cccc2c1CC(c1ccccc1)C=C2C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2c1CC(c1ccccc1)CC2C#N

Procedure:
Sodium borohydride (6.8 g) is added to a suspension of 6.1 g (23.3 mmol) of 1-cyano-5-methoxy-3-phenyl-3,4-dihydronaphthalene, from Step 1, in 100 mL of absolute ethanol and the reaction mixture is heated at reflux temperature for 1.5 h. The solvent is evaporated under reduced pressure and the residue partitioned between equal volumes of ethyl acetate and 1N aqueous hydrochloric acid solution. The layers are separated and the organic layer is washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C:6]([CH3:29])=[C:7]3[C@@H:22]2[CH2:21][C@H:20]([OH:27])[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1>C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH:5]=[C:6]([CH3:29])[C@@H:7]3[C@@H:22]2[CH2:21][C@H:20]([OH:27])[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: CC1=C2[C@H](C[C@H](O)[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@H]2C1
Solvent: CCOC(C)=O
Product: CC1=C[C@@H]2C[C@H](O)CC[C@]2(C)[C@H]2C[C@H](O)[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@H]3[C@H]12

Procedure:
2-(3α,7ξ,12α-Trihydroxy-7ξ-methyl-24-nor-5β-cholanyl)-4,4-dimethyl-2-oxazoline from Example 6 (2.5 g) was dissolved in a solution of concentrated HCl (2 ml) and methanol (200 ml). The solution was refluxed for 6 hours, diluted with water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness to give methyl ester derivatives of three hydration products. The residue was combined with the unsaturated dihydroxy fraction obtained in Example 7, (total, 2.6 g) and placed on a column of silica gel (150 g) impregnated with 15 g of AgNO3. Elution with increasing proportions of acetone in chloroform yielded two major fractions. Fraction 1, eluted with 7% acetone in chloroform, gave 480 mg of an oily residue. Alkaline hydrolysis of the residue and recrystallizations from ethyl acetate yielded colorless prisms of 3α,12α-dihydroxy-7-methyl-5β-chol-7-en-24-oic acid. Melting point, 160°-163° C. PMR (δ ppm): 0.79 (3H, s, 18--CH3), 0.86 (3H, s, 19--CH3), 1.16 (3H, d, J=6 Hz, 21--CH3), 1.73 (3H, s, 7--CH3), 3.70 (1H, m, 3β--H), 4.13 (1H, m, 12β--H). Fraction 2, eluted with 10% acetone in chloroform, yielded, approximately, a 1:1 mixture of two unsaturated compounds (1.59 g) on AGNO3 -TLC, GLC and GLC-MS. These two compounds were separated on a column of silica gel (150 g) impregnated with 15 g AgNO3 using increasing concentrations of ethyl acetate in benzene. Elution with 35% ethyl acetate in benzene (Fraction 2A), followed by alkaline hydrolysis, afforded 640 mg of 3α,12α-dihydroxy-7-methyl-5β-chol-6-en-24-oic acid. Recrystallization from ethyl acetate gave colorless needles melting at 144°-148° C. PMR (δ ppm): 0.79 (3H, s, 18--CH3), 0.89 (3H, s, 19--CH3), 1.22 (3H, d, J=6 Hz, 21--CH3), 1.69 (3H, s, 7--CH3), 3.70 (1H, m, 3β--H), 4.13 (1H, m, 12β--H), 5.36 (1H, m, 6--H). Fraction 2B, eluted with 40% ethyl acetate in benzene, gave a second compound (450 mg) which, after alkaline hydrolysis, was recrystallized from ethyl acetate to give colorless needles of 3α,12α-dihydroxy-7-methylene-5β-cholan-24-oic acid, mp 199°-202° C. PMR (δ ppm): 0.79 (3H, s, 18--CH3), 1.05 (3H, s, 19--CH3), 1.20 (3H, d, J=6 Hz, 21--CH3), 3.75 (1H, m, 3β--H), 4.16 (1H, m, 12β--H), 4.61 and 4.74 (2H, m, C=CH2).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:11][CH2:10][CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: OCCBr
Reactant: O=Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cnn(CCO)c1
Temperature: 150 °C
Yield: 97 %

Procedure:
Combine 1H-pyrazole-4-carbaldehyde (0.110 g, 1.14 mmol), 2-bromoethanol (0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150° C. for 20 min. Cool to room temperature and filter, washing with acetonitrile. Concentrate filtrate to give 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.155 g, 97%). GC-MS: m/z=140 [M+].
Reaction SMILES: C(N[C:6]1[C:11]2[C:12]([CH3:21])=[N:13][C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:8]2[N:7]=1)CCC.[CH2:26]([CH2:28][NH2:29])[OH:27].CN(C)CCCO>>[NH2:29][CH2:28][CH2:26][O:27][C:6]1[C:11]2[C:12]([CH3:21])=[N:13][C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:8]2[N:7]=1
Reactant: CCCCNc1nc2cc(C)nn2c2c1c(C)nc1c2cnn1CC
Reactant: NCCO
Agent: CN(C)CCCO
Product: CCn1ncc2c1nc(C)c1c(OCCN)nc3cc(C)nn3c12

Procedure:
By substituting the 5-chloro-2,6-dimethyl-8-ethyl-8H pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine obtained in Example 37 in the procedure of Example 21 and substituting ethanolamine for the 3-(dimethylamino)propanol, 5-(2-aminoethoxy)-2,6-dimethyl-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:16][C:9]2[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 1.0 g, 4.6 mmol) was suspended in pyridine (10 ml), and 4-bromobenzoyl chloride (1.1 g, 4.8 mmol) was then added at 0° C. After 1 hour, water (200 ml) was added and the resulting precipitate was collected on a fritted glass funnel, washed with water twice, and then dried under a stream of nitrogen for 3 hours to give analytically pure product 4-bromo-N-(7-morpholinopyrazolo[1,5-a]pyrimidin-5-yl)benzamide (9B, 1.6 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ=11.13 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.01-7.93 (m, 2H), 7.77-7.71 (m, 2H), 7.37 (s, 1H), 6.38 (d, J=2.3 Hz, 1H), 3.88-3.81 (m, 4H), 3.77-3.70 (m, 4H); ESI-MS: m/z 402.2 (M+H)+.