Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[CH3:44][CH:45]([CH3:49])[CH2:46][CH:47]=[O:48]>C1COCC1>[OH:48][CH:47]([C:11]1[C:6]2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:3](=[O:35])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=1)[CH2:46][CH:45]([CH3:49])[CH3:44]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(OC(F)(F)F)c3)cnc21
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 45, step 1, 100 mg, 0.2 mmol) in THF (4 mL) at −78° C. was added LDA (2M in THF, 0.4 mL, 0.8 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (34 mg, 0.4 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (10 mL) then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 51.7% yield) as a solid. LCMS: [MH+-THP] 498 and TR=1.733 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:21]1[CH2:24][CH:23]([OH:25])[CH:22]=1>>[OH:25][CH:23]1[CH2:24][N:21]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:22]1
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: OC1C=NC1
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Yield: 30 %

Procedure:
Prepared in analogy to Example 1 from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A3(b)) and azetin-3-ol. The crude material was purified by flash chromatography (ethyl acetate/n-heptane) to yield the title compound as a white crystalline solid (yield 30%). MS (m/e): 368.0 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:29])[C@H:16]([NH:21]C(=O)OC(C)(C)C)[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][C@H:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](N)C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (crude from above) in dichloromethane (5 mL) was added TFA (5 mL). Upon completion of addition, the resulting solution was allowed to stir at rt. for 2 h. After this time, the solvent was removed by rotary evaporation to provide an oil which was partitioned between dichloromethane and 1 N NaOH. The dichloromethane extract was washed with water, dried over MgSO4 and evaporated to provide (R)-2-amino-1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3,3-dimethylbutan-1-one as an oil (1.09 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C@H:20]([OH:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@@H:9]([C@H:20]([OH:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@@H](O)[C@H](N)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 101.8 %

Procedure:
To (2S,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (3.0 g, 7.5 mmol) in DCM (30 mL) was added TFA (15 mL) and the mixture was stirred at 0° C. After 30 min it was diluted with DCM (100 mL). Saturated aqueous NaHCO3 (100 mL) was added and the two layers were separated. The aqueous layer were extracted with DCM (100 mL×2) and the combined organics were dried over anhydrous sodium sulfate and concentrated to afford crude (2S,3R)-benzyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (2.3 g, quant.) as an oil, which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[OH:11][C@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-amino-2-indanol (2.0 g, 13.4 mmol) is suspended in 100 mL DCM and at RT it is combined with acetic anhydride (1.27 mL, 13.4 mmol). The reaction mixture is stirred for 1 h at RT, once the reaction is complete the solvent is eliminated using the rotary evaporator and the crude product B-1b (HPLC-MS: tRet.=0.81 min; MS (M+H)+=192) is used in the subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([O:24][CH2:23][C:21]1[CH:20]=[CH:19][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:18])=[C:2]([Cl:1])[CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(CO)cc3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(COCc4ccccc4)cc3Cl)c2n1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
To a suspension of methyl 3-(2-chloro-4-(hydroxymethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg) in dimethylformamide (8.0 ml) were added sodium hydride (51 mg) and benzyl bromide (277 mg) under ice-cooling, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. Chloroform and sodium hydrogencarbonate were added to the residue, and the mixture was partitioned. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column (eluent: chloroform:methanol=50:1) to give the objective compound (322 mg) as a pale-yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:7]=3[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[C:5]3[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-(2), 52.01 g, 202 mmol) was dissolved in methanol (150 mL) N,N-dimethylformamide (600 mL), 16% palladium on charcoal (5.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature overnight. After the unsoluble materials were filtered out, the methanol was removed under reduced pressure. Water (2 L) was added to the residue. The precipitated solid was filtered off and dried at 90° C. under reduced pressure to give the titled reference compound (44.02 g) as a pale yellow solid. (Yield 96%)
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2cccc(OCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(Oc1cccnc1)N1CCC(Oc2cccc(O)c2)CC1
Yield: 70.8 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[3-(benzyloxy)phenoxy]-1-piperidinecarboxylate (4.0 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=O)[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[OH-].[K+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=[N:33][NH:32][C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:31])[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1cccnc1
Reactant: O=Cc1c(-c2ccc([N+](=O)[O-])cc2)nc2sc3c(n12)CCCC3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(NN=Cc1c(-c2ccc([N+](=O)[O-])cc2)nc2sc3c(n12)CCCC3)c1cccnc1

Procedure:
Next, 0.33 g of 5,6,7,8-tetrahydro-2-(4-nitrophenyl)-3-formylimidazo[2,1-b]benzothiazole, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed with water and dried, then the solvent was distilled off and the residue was crystallized from methanol to obtain the desired substance in an amount of 0.25 g (yield of 55.6%).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH:10]2[NH:12][CH:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH3:19][N:20]([CH:22]=[O:23])[CH3:21]>>[CH2:1]([CH:5]1[CH2:6][CH:7]2[N:12]([CH2:9][C@@H:10]([CH3:11])[CH2:19][N:20]3[C:21]4[C:6](=[CH:5][CH:1]=[CH:2][CH:3]=4)[CH2:7][CH2:8][C:22]3=[O:23])[C@@H:10]([CH2:9][CH2:8]2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC1CC2CC[C@@H](C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21

Procedure:
Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (107LH63)(0.094 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), NAI (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c4)(0.025 g), HPLC-MS (ammonium acetate) [M+H]+=369.33.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH2:11]([SH:14])[CH2:12][SH:13]>C1C=CC=CC=1>[C:4]1([C:2]2[S:13][CH2:12][CH2:11][S:14][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCCS
Reactant: O=C(CBr)c1ccccc1
Solvent: c1ccccc1
Product: C1=C(c2ccccc2)SCCS1
Reaction time: 48 h

Procedure:
By following substantially the procedure of Example 4, Step A, phenacyl bromide (95.0 g.) and ethane-1,2-dithiol (40.0 ml.) in benzene (500 ml.) is allowed to stand for 2 days at room temperature (until gas chromatography indicates the absence of starting material). Solid by-product is removed by filtration and the filtrate is washed with aqueous sodium bicarbonate solution and water. The product solution is dried over anhydrous sodium sulfate. Solvent is removed by distillation and the residual oil is distilled at reduced pressure to afford 2-phenyl-5,6-dihydro-1,4-dithiin (47.2 g.; b.p. 140°-150° C./0.25 mm.). The product solidifies on standing and is recrystallized from methanol (m.p. 58.0°-59.0° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@@H:10]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:27])[C@@H:10]([C:23]([CH3:24])([CH3:26])[CH3:25])[N:11]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCI
Reactant: COc1cccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 70 °C
Yield: 64.7 %

Procedure:
To a solution of N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester (1.31 g, 3.35 mmol) in DMF (10 ml) is added K2CO3 (1.87 g, 13.4 mmol) followed by 1-iodo-3-methyl butane (1.33 g, 6.69 mmol) and the reaction mixture is heated to 70° C. overnight. The reaction is cooled to room temperature and then poured over 1 N HCl and extracted with Ethyl Acetate. The organics are washed with brine, dried over MgSO4 and concentrated. The crude product is purified by column chromatography eluting with a gradient of 5-40% (Hex-EtOAc) affording the title compound as a colorless oil (1.0 g, 65% yield). Mass spectrum (462.3; M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1>C(Cl)(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([N:5]=[C:1]=[S:2])=[CH:11][N:10]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(Cl)nc1
Yield: 56.9 %

Procedure:
A solution of thiophosgene (3.21 mL, 42.1 mmol) in chloroform (10 mL) was heated at reflux and treated with a solution of 5amino-2-chloropyridine (3.61 g, 28.1 mmol) in chloroform (25 mL) for 40 minutes. The solution was heated an additional 2 hours, the reaction mixture was cooled, and the solids formed were removed by filtration. Concentration of the filtrate provided 2.73 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[OH:11][CH:12]([CH3:16])[C:13](=O)[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[OH:11][CH:12]([CH3:16])[CH:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)[CH3:14]
Reactant: COC(=O)c1csc(N)n1
Reactant: CC(=O)C(C)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1csc(NC(C)C(C)O)n1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Methyl 2-aminothiazole-4-carboxylate (1.0, 6.32 mmol), 3-hydroxy-2-butanone (1.045 ml, 12.01 mmol) and acetic acid (2.278 g, 37.9 mmol) were dissolved in 1,2-dichloroethane. Sodium triacetoxy borohydride (3.75 g, 17.70 mmol) was added and the reaction mixture was stirred overnight. Sodium triacetoxy borohydride (3.1 g) was added in two portions and the reaction mixture was stirred over two nights. 1M NaHCO3 was added slowly and mixture was extracted twice with DCM. DCM phase was dried and evaporated to afford 68.1% of the title product. m/z [230.3+1].
Reaction SMILES: Cl.C([O:6][C:7](=[O:41])[C@@H:8]([NH:10][C:11](=[O:40])[C@H:12]([NH:32]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15](=[O:31])[NH:16][CH2:17][C@@H:18]([OH:30])[CH2:19][P:20]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:22])=[O:21])[CH3:9])(C)(C)C>O1CCOCC1.O>[NH2:32][C@H:12]([CH2:13][CH2:14][C:15](=[O:31])[NH:16][CH2:17][C@@H:18]([OH:30])[CH2:19][P:20]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([OH:22])=[O:21])[C:11]([NH:10][C@@H:8]([CH3:9])[C:7]([OH:41])=[O:6])=[O:40]
Reactant: C[C@H](NC(=O)[C@@H](CCC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)[C@H](N)CCC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
4N HCl in dioxane (5 mL) was added to (S)-2-{(R)-2-tert-butoxycarbonylamino-4-[(R)-3-(cyclohexylmethyl-hydroxy-phosphinoyl)-2-hydroxy-propylcarbamoyl]-butyrylamino}-propionic acid tert-butyl ester (0.351 g, 0.592 mmol) in water (1 mL). The resulting colorless solution was stirred under N2 at rt overnight. The reaction mixture was concentrated in vacuo and the residue was purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (adjusted with HCl pH=3.5) to 100% CH3CN over 20 min at 45 mL/min. The appropriate fractions were combined and lyophilized to give the title compound (0.096 g, 0.220 mmol) as a white solid. 1H NMR (CD3OD, 300 MHz): δ 4.38 (q, J=7.2 Hz, 1H), 4.04 (m, 1H), 3.90 (t, J=6.3 Hz, 1H), 3.35 (dd, J=5.7, 13.2 Hz, 1H), 3.21 (dd, J=5.7, 13.5 Hz, 1H), 2.41 (m, 2H), 2.11 (m, 2H), 1.92 (br d, 2H), 1.77-1.65 (m, 6H), 1.52 (dd, J=6.3, 13.5 Hz, 2H), 1.43 (d, J=7.2 Hz, 3H), 1.37-1.15 (m, 3H), 1.08-1.00 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 42.95. LCMS m/z: [M+H]+=436.25
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccn3)c2c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Following General Procedure C, ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 278 mg, 1.07 mmol) in DMF (15 ml) was added K2CO3 (590 mg, 4.28 mmol) and 2-(bromomethyl)pyridine (914 mg, 5.35 mmol). The reaction was stirred at 60° C. for 5 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].I[CH2:11][CH2:12][C@H:13]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+]>C1COCC1>[CH2:23]([Si:20]([CH2:21][CH3:22])([CH2:25][CH3:26])[O:19][C@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:24]
Reactant: CCOC(=O)[C@H](CCI)O[Si](CC)(CC)CC
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(C(=O)OC)C(=O)OC)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A solution of dimethyl malonate (6.155 ml, 53.72 mmol), (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (10.00 g, 26.86 mmol) and THF (100 mL), dimethyl malonate, (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (10.00 g, 26.86 mmol) was cooled to −78° C. and maintained under N2. To the solution was added sodium hydride (2.149 g, 53.72 mmol, 60% dispersion in mineral oil) portion wise over 5 min and the resulting mixture stirred at −78° C. for 3 h. The reaction was warmed to RT and stirred for 48 h. The reaction was quenched by adding H2O and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (4:1) to afford 4.2 g, (41%) of (S)-4-ethyl 1,1-dimethyl 4-(triethylsilyloxy)butane-1,1,4-tricarboxylate (398).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[C:11]3[CH2:12][CH2:13][C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[Na].[CH2:22](Br)[CH3:23]>C(O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[C:11]3[CH2:12][CH2:13][C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: CCBr
Reactant: Oc1cccc(-c2cc3n(n2)-c2ccccc2CC3)c1
Agent: [Na]
Solvent: CCO
Product: CCOc1cccc(-c2cc3n(n2)-c2ccccc2CC3)c1
Reaction time: 8 h

Procedure:
2.62 Grams (0.010 mole) of the compound of Example 10 is added to a solution of 0.23 g. (0.010 mole) of sodium in 40 ml. of absolute ethanol at room temperature, then 2.2 g. (0.020 mole) of ethyl bromide is added dropwise. The resulting solution is refluxed for seven hours and allowed to stand overnight at room temperature. After dilution with 30 ml. of water and subsequent evaporation of the ethanol, a residue is obtained which is crystallized from methanol. Yield 2.29 g. of the title compound, m.p. 99°-100° C.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[C:28](=[O:34])[CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:35]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:36])[CH2:16]1>CC(C)=O.C(Cl)(Cl)Cl>[O:44]1[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][O:37][C:35]([C@H:24]2[CH2:23][CH2:22][C@H:21]3[C@H:20]4[C@H:29]([C:28](=[O:34])[CH2:27][C@:25]23[CH3:26])[C@:30]2([CH3:33])[C@H:17]([CH2:16][C:15](=[O:14])[CH2:32][CH2:31]2)[CH2:18][CH2:19]4)=[O:36])[CH2:46][CH2:45]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.33 h

Procedure:
Jones reagent (0.4 ml.) was added to a solution of 3α-hydroxy-17β(3'-morpholinopropoxycarbonyl)-5α-androstan-11-one (325 mg.) in acetone (5 ml.). After stirring (20 min.) the reaction mixture was diluted with chloroform and washed with aqueous 10% sodium bicarbonate and water. The chloroform solution was dried, filtered and evaporated to give a gum (238 mg.) which, after purification by preparative thick layer chromatography, afforded the pure title compound; νmax.CHBr3 1703 (-C=O) and 1720 cm-1 (-COOR), (-OH absent).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.CN(C)C=O.[S-2:25].[Na+].[Na+]>C(O)(=O)C>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([SH:25])=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: [S-2]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1ncc2c1ncc1c(S)nc3ncnn3c12
Reaction time: 1 h

Procedure:
5.6 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.) are dissolved in 100 ml. of dimethylformamide. 2 g. of powdered sodium sulfide are added and the mixture is stirred for 1 hour. After this time, the solution is carefully acidified with acetic acid. 8-Ethyl-8H-pyrazolo[3',4':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-5-thiol precipitates and is filtered off.