Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([N:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Reactant: COC(=O)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CC[C@H](C(=O)OC)C4)cc3)nc2)cc1
Reaction time: 4 h
Yield: 52 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid INT-22 (2082 mg, 2.75 mmol), methyl (S)-pyrrolidine-3-carboxlate HCl (545 mg, 3.30 mmol), and DIEA (1523 μl, 8.25 mmol) in DMF (6 mL) cooled to 0° C. was slowly added a solution of HATU (1254 mg, 3.30 mmol) in DMF (5 mL) in a drop-wise fashion The reaction mixture was allowed to warm slowly and stirring continued for 4 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in EA (50 mL), dried over MgSO4, evaporated and purified by chromatography (EA/hexane) to provide 932 mg (52%) of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate. LCMS-ESI (m/z) calculated for C40H46N4O6: 678.3. found 679.3 [M+H]+, tR=4.50 min (Method 16).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]Cl.[I-:18].[Na+]>CC(=O)CC>[Cl:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][I:18]
Reactant: COc1ccc(OCCOCCCl)c(Cl)c1
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(OCCOCCI)c(Cl)c1

Procedure:
was prepared from 24.7 g. of the corresponding chloride of part (a) by three hours reflux with 13.5 g. of sodium iodide in 200 ml. of 2-butanone. The crude product was used directly in part (c) below.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.[CH:21](OC)=[O:22]>C1COCC1>[Cl:13][C:14]1[C:19]([CH:21]=[O:22])=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of diisopropylamine (2.6 mL, 18.5 mmol) in THF (18.5 mL) was stirred at −78° C. as a 2.5 N solution of n-butyl lithium (7.4 mL, 18.5 mmol) was added. The solution was stirred at 0° C. for 30 minutes, then cooled to −78° C. for 30 minutes before the addition of 2,4-dichloropyridine (2 mL, 18.5 mmol). The solution was stirred at −78° C. for another 30 minutes before the addition of methyl formate (1.14 mL, 18.5 mmol). The solution was stirred for 30 minutes then was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide 2,4-dichloro-3-pyridinecarbaldehyde (2.18 g, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.54 (d, J=5 Hz, 1H), 7.75 (d, J=5 Hz, 1H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=O)[N:2]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>O>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])[N:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)C=Cc1cc2c(cn1)[nH]c1ccccc12
Yield: 94.7 %

Procedure:
A mixture of 2.0 g of beta-carboline-3-carboxaldehyde, 2.0 g of malonic acid, 40 ml of water-free pyridine and 0.1 ml of piperidine is heated in a steam bath for 4 h. The solvent is evacuated in vacuum and after adding 20 ml of 2-propanol, the precipitate is filtered off. 2.3 g of 3-(3-beta-carbolinyl)-acrylic acid with a m.p. of 240°-260° C. (decomposition) is obtained.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][C:24]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[C:24]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CNC(=NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.25 g, 1.3 mmol) was dissolved in methanol (10 ml), and 3,4-(dibenzyloxy)phenethylamine hydrochloride (0.54 g, 1.5 mmol) and triethylamine (0.15 g, 1.5 mmol) were added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide (0.13 g, 0.3 mmol, yield: 21%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride in methanol (2 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-[ 2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: C[C@@H](O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of (R)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added and a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (249(a)) (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), washed with brine (1×), and the organic layers were dried with sodium sulfate. The solution was concentrated and the product was purified by reverse phase HPLC to afford (R)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (364) (0.129 g, 21% yield) as a light brown solid. 1H-NMR (400 MHz, DMSO)-d6: 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3](NC1C=CC(C2CCNCC2)=CC=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C1(C(Cl)=O)CC1>>[NH:29]1[CH2:28][CH2:27][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:3]([CH:2]3[CH2:18][CH2:1]3)=[O:4])[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: O=C(Cl)C1CC1
Product: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1

Procedure:
Prepared by the procedure for 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide using tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate and cyclopropanecarbonyl chloride: Anal. Calcd for C15H20N2O+0.15CH2Cl2: C, 70.8; H, 7.87; N, 10.9. found: C, 70.9; H, 7.68; N, 11.1; ESMS m/e: 245.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1C(=O)C)[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:22])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(C)cc1C(C)=O
Solvent: ClCCl
Product: CCOc1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The solution of 14.5 g of 1-(2-ethoxy-5-methylphenyl)ethanone in 800 ml of dichloromethane is admixed with 36.8 g of 3-chloroperbenzoic acid and stirred at room temperature over 72 hours. The reaction mixture is concentrated by evaporation, and the residue is admixed with 400 ml of saturated aqueous sodium thiosulphate solution and extracted with tert-butyl methyl ether (2×800 ml). The organic phases are washed successively with saturated aqueous sodium carbonate solution (1×500 ml) and brine (500 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The residue is taken up in 75 ml of methanol, admixed with 25 ml of ammonia solution (25%) and stirred over 30 minutes. The reaction mixture is concentrated by evaporation, admixed with 0.5 M HCl (200 ml) and extracted with tert-butyl methyl ether (600 ml). The organic phase is washed with brine (500 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rt=3.89.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)C.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of 3-bromo-4-fluorobenzaldehyde (50.0 g) in 1,2-dichloroethane (500 mL) is cooled to 0° C. Acetic acid (14.1 mL) and morpholine (23.6 mL) are added slowly, maintaining the temperarture below 4° C. Sodium triacetoxyborohydride (78.3 g) is added all at once, maintaining the temperature below 5° C. The mixture is allowed to warm to rt and stirred for 18 hrs. The reaction is quenched with 1 N NaOH (200 mL) and extracted with CH2Cl2 (500 mL). The organic layer is washed with 1 N NaOH (2×200 mL). The aqueous layers are combined and back-extracted with CH2Cl2 (100 mL). The organic layers are combined and extracted with 0.5 N HCl (5×250 mL). The acidic aqueous layers are combined, and 2 N NaOH is added until the solution is basic (pH=12). The aqueous layer is then extracted with CH2Cl2 (6×100 mL). The organic layers are combined, dried (MgSO4) and concentrated in vacuo to a clear, colorless oil. The crude product is distilled (126° C., 0.3 Torr) to afford 48.9 g (72%) of the title compound as a clear, colorless oil. Physical characteristics: Bp 126° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ 7.62, 7.35-7.29, 3.56, 3.45, 2.34; 13C NMR (75 MHz, DMSO-d6) 8 157.3, 136.1, 133.3, 129.8, 116.2, 107.7, 66.1, 60.9, 53.0; IR (liq.) 2855, 2807, 1495, 1455, 1348, 1257, 1244, 1118, 1009, 862 cm−1; MS (ESI+) m/z 274 (M+H)+. Anal. Calcd for C11H13BrFNO: C, 48.20; H, 4.78; N, 5.11; Br, 29.15. Found: C, 48.04; H, 4.79; N, 5.11; Br, 28.18.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:30]([Si:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][O:15][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO)C(=O)c1cccnc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.69 g (0.0133 mole) of 1-(t-butyldimethylsilyloxy)-3-nicotinoylhexan-2,6-diol, 2.18 g (0.032 mole) of imidazole in 12 ml of dimethylformamide is added at once 4.38 g (0.0159 mole) of t-butyldiphenylchlorosilane, the mixture is stirred at room temperature overnight, diluted with 30 ml of ethyl acetate and washed with water (2×10 ml) and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (2:3) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[Cl-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][Zn+]>C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cccc(C[Zn+])c1
Reactant: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1nc(Cc2cccc(Cl)c2)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (1.46 g, 3.33 mmol), 3-chlorobenzylzinc chloride (0.5 M in tetrahydrofuran, 6.8 ml, 3.40 mmol), tetrakis(triphenylphosphino)palladium(0) (384 mg, 0.33 mmol), and tetrahydro-furan (10 ml) were combined and stirred for 18 hours at 50° C. The reaction was quenched with saturated, aqueous ammonium chloride, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 10% ethyl acetate in hexanes) to give 436 mg (30%) of 2,2-dimethyl-propionic acid 5-bromo-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.88 (s, 1H), 7.24-7.18 (m, 4H), 6.41 (s, 2H), 4.25 (s, 2H), 1.18 (s, 9H); MS: m/z 436.1, 438.1 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][P:9](=O)([O:18]CC2C=CC=CC=2)[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:33]1([CH2:39][O:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][C@H:48]([OH:66])[C:49]([N:51]2[CH2:65][CH2:64][CH2:63][C@H:52]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])=[O:50])=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][P:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:66][C@@H:48]([CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41]([O:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:42])[C:49]([N:51]2[CH2:65][CH2:64][CH2:63][C@H:52]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])=[O:50])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=P(CCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NCCCC[C@H](OP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of (2-phenylethyl)phosphonic acid, dibenzyl ester (1.48 g., 4.04 mmole, 1.5 eq.) in dry benzene (15 ml.) is treated with phosphorus pentachloride (952 mg., 4.57 mmole, 1.7 eq.) and the solution is heated at 75° (oil bath) for 2.5 hours under argon. The mixture is evaporated to dryness (0.5 mm of Hg.), taken up in benzene (10 ml.), and evaporated. This procedure is repeated twice. The clear residue is taken up in dry methylene chloride (15 ml.), 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.26 g., 2.69 mmole, 1.0 eq.) is added, the mixture is cooled to 0° (ice-bath), then treated with triethylamine (0.56 ml., 4.04 mmole, 1.5 eq.) and dimethylaminopyridine (49 mg., 0.40 mmole, 0.15 eq.), stirred at 0° for 15 minutes, and then at room temperature for one hour. The mixture is partitioned between 5% potassium bisulfate and methylene chloride. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and evaporated to a yellow oil. The crude oil is purified by flash chromatography (LPS-1 silica gel) eluting with hexane:acetone (7:3). Product containing fractions are pooled and evaporated to give 916 mg. of 1-[(S)-2-[[(2-phenylethyl)(phenylmethoxy)phosphinyl]oxy]-6-[[((phenylmethoxy)carbonyl]amino]-1-oxohexyl]-L-proline, phenylmethyl ester as a clear, colorless oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCCN(CC)C3)c2n1
Reaction time: 5 h

Procedure:
N2-Butyl-9-[(1-ethyl-3-piperidinyl)methyl]-8-methoxy-9H-purine-2,6-diamine (120 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 5 hours the reaction mixture was stripped, quenched with water then made basic with 1M aq potassium carbonate. The resulting solid was filtered, washed and dried to give the title compound as a crystalline solid, yield 86 mg.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:3]1=2.Cl.O>C1(C)C=CC=CC=1>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2
Yield: 15.8 %

Procedure:
To 172 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo [b,f]-thiepin-3-yl)-propionate in 1 ml of toluene were added a small amount of zinc-amalgam, 0.5 ml of conc. hydrochloric acid and 0.4 ml of water and the mixture was refluxed for 4 hours. After cooling, the mixture was filtered and the filtrate was extracted with benezene. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow oil, which was subjected to thin-layer chromatography and there was obtained 26 mg of ethyl 2-(10,11-dihydro dibenzo[b,f]thiepin-3-yl)-propionate as pale yellow oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][S:88]([N:91]1[CH2:95][CH2:94][CH2:93][CH:92]1[C:96]([OH:98])=O)(=[O:90])=[O:89]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:96]([CH:92]1[CH2:93][CH2:94][CH2:95][N:91]1[S:88]([CH3:87])(=[O:89])=[O:90])=[O:98])[CH2:19][CH2:18]2
Reactant: CS(=O)(=O)N1CCCC1C(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C3CCCN3S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1-(methylsulfonyl)pyrrolidine-2-carboxylic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 705.5 (M+H)+, 2.04 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.88 (s, 1H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.10 (dd, J=3.1, 8.8 Hz, 1H), 3.60 (ddd, J=3.5, 7.0, 10.2 Hz, 1H), 3.40 (dt, J=6.4, 9.6 Hz, 1H), 2.96 (s, 3H), 2.62-2.52 (m, 2H), 2.42 (dd, J=8.2, 11.6 Hz, 1H), 2.31 (dddd, J=3.2, 3.4, 6.4, 9.7 Hz, 1H), 2.21-2.16 (m, 1H), 2.16-2.10 (m, 1H), 2.03 (tdd, J=3.2, 6.6, 13.0 Hz, 1H), 1.99-1.89 (m, 2H), 1.82-1.75 (m, 1H), 1.75-1.72 (m, 1H), 1.70 (s, 3H), 1.69-1.66 (m, 1H), 1.58-1.46 (m, 6H), 1.46-1.29 (m, 5H), 1.28-1.22 (m, 1H), 1.14 (d, J=13.1 Hz, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.93 (s, 6H).