Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=[C:32]2[NH2:42]>O1CCOCC1.O>[NH2:42][C:32]1[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=1
Reactant: CC(C)(C)Nc1nc(N)c2cccc(Br)c2n1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(N)nc(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 49.6 %

Procedure:
Argon was bubbled into a slurry of potassium carbonate (Mallinkrodt; 0.140 g, 1.016 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium (ii) (Aldrich; 0.018 g, 0.025 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.133 g, 0.51 mmol), 8-bromo-N2-(tert-butyl)quinazoline-2,4-diamine (484b; 0.075 g, 0.254 mmol) in 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and heated to 80° C. for 30 min. The reaction was adsorbed onto 1 g silica gel and dried in vacuo. The material was treated with purified by silica gel chromatography (12 g column) using 0-100% (90/10 (DCM/2.0 M NH3/MeOH) in DCM). The product-containing fractions were concentrated to afford (R)-2-(4-amino-2-(tert-butylamino)quinazolin-8-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.044 g, 0.126 mmol, 49% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (1H, s), 7.97 (1H, dd, J=7.6, 1.2 Hz), 7.83 (1H, d, J=8.0 Hz), 7.59 (1H, s), 7.32-7.47 (2H, m), 7.02 (1H, t, J=7.7 Hz), 6.76 (1H, d, J=1.2 Hz), 6.47 (1H, br. s.), 4.56 (1H, q, J=6.7 Hz), 1.49 (9H, s), 1.41 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 351.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:44])[C:18]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:19])=[O:12])=[C:5]([CH3:45])[CH:4]=1)=O.C(O)(=O)C.[NH2:50][CH2:51][C@@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CO>[Si:54]([O:53][C@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[CH2:51][NH:50][CH2:1][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:44])[C:18]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:19])=[O:12])=[C:5]([CH3:45])[CH:4]=1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: Cc1cc(NC(=O)CCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To the stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-formyl-2,5-dimethylphenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (˜0.748 mmol) in DCM from the previous reaction was added 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (0.295 g, 0.748 mmol) in 1:1 MeOH:DCM (3.0 mL). The resulting mixture was stirred at room temperature for 30 min and then sodium triacetoxyborohydride (0.476 g, 2.24 mmol) was added and stirring was continued at room temperature for 4 h. Aqueous NaOH (1 M, 3 mL) and DCM (3 mL) were added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-15% MeOH in DCM) to give the title compound (420 mg, 60% yield) as a yellow solid.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)C1C=CC=CC=1>CCCCCC.C1COCC1>[CH:34]1([C:32]2([CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[CH:29][CH:28]=3)[O:33][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 6 using 11.6 g (99.9 mmol) of methyl acetoacetate, 4.19 g (105 mmol) of NaH (60% dispersion in oil), 64.0 mL (102 mmol) of 1.6M n-butyl lithium in hexane, 16.1 g (49.9 mmol) of 3-(4-benzyloxy-phenyl)-1-cyclohexyl-propan-1-one (prepared in Example G) and 550 mL of THF. After addition of the ketone, the reaction was stirred for 120 minutes at 0° C., then 1 hour at room temperature. The reaction was quenched with acetic acid (12 mL) and worked up in the usual manner. The crude product was carried on without further purification.
Reaction SMILES: N1C2C(=CC(O[CH:12]([CH2:22][CH3:23])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14])=CC=2)C=CC=1.[Br:24]C(CC)C(Br)=O.C(N(CC)CC)C.O>ClCCl>[Br:24][CH:12]([CH2:22][CH3:23])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14]
Reactant: CCC(Br)C(=O)Br
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC#CC(C)(C)NC(=O)C(Br)CC
Temperature: 3 °C

Procedure:
The product from Step 3 (5.0 g) was dissolved in dry dichloromethane (200 ml), cooled to 3° C. with stirring then 2-bromobutyryl bromide (6.25 g) was added followed by dropwise addition of dry triethylamine (10.93 ml), maintaining the reaction at 5° C. The suspension, which had formed during the reaction, was stirred at ambient temperature for 1 hour then water was added. The organic phase was separated, washed with water, dried over magnesium sulphate then evaporated under reduced pressure. The residue was fractionated by chromatography (silica; hexane/diethyl ether, 3:1 by volume) to give the required product, 5.2 g, as a colourless solid, m.p. 79–81° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17].[H][H]>[Ni].C(O)C>[NH2:14][C:11]1[CH:10]=[C:7]2[C:8](=[O:9])[N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:17])[C:6]2=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCO
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N(CCO)C2=O

Procedure:
N-(2-Hydroxyethyl)-4-nitrophthalimide (30.0 g.), ethanol (300 ml.), and Raney nickel (3.0 g.) are mixed and hydrogenated at 100° C. and 1500 psi. until hydrogen uptake ceases. The hot solution is filtered to remove the Raney nickel and the solvent evaporated to yield 4-amino-N-(2-hydroxyethyl)-phthalimide, the amine which melts at 171°-173° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@@H](N)C1C=CC=CC=1.[CH3:25][C:26]([CH:28]=C)=[O:27].C1(C=CC(O)=CC=1)O.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C@:10]([CH3:16])([CH2:15][CH2:25][C:26](=[O:27])[CH3:28])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: C=CC(C)=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)CC[C@]1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
1-Benzyl-3-methyl-piperidin-4-one (15.0 g, 73.89 mmol) was dissolved in toluene (150 mL) and (R)-(+)-α-methylbenzylamine (11.4 mL, 88.67 mmol) was added. The contents were heated to reflux for 20 h (Dean-Stark trap) and then cooled to room temperature. The resultant colorless oil was dissolved in THF and methylvinylketone (7.40 mL, 88.67 mmol) and hydroquinone (150 mg, catalytic) were added and the contents were stirred in the dark. After 2 days 1N HCl (90 mL) was added and the contents stirred at ambient temperature for 30 min, the organics were extracted with diethyl ether (100 mL), washed with water, dried with MgSO4, concentrated and purified by flash chromatography (CH2Cl2 100% to 20% EtOAc in CH2Cl2) to afford 6.51 g of ((R)-1-benzyl-3-methyl-3-(3-oxo-butyl)-piperidin-4-one as a colorless oil. LC-MS (Method A): RT=0.32 min, (M+H)+ 274.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][O:29]CC3C=CC=CC=3)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(F)(F)F.CCOCC.C(S)C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][OH:29])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCO2
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CO)CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
Using the same reaction conditions and workup as described for the prepaqration of Example 7A, 1-benzyloxymethyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.27 g, 0.515 mmol) was reacted with BF3.OEt2(1.94 mL, 15.45 mmol) and ethane thiol (0.3 g, 5.15 mmol). The resulting mixture was stirred at room temperature for 3 days. Purification by preparative HPLC afforded 60 mg of the product (26% yield).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1)#[N:16]>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: N#Cc1ccc2sc(S)nc2c1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: N#Cc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Yield: 74 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 2-mercaptobenzo[d]thiazole-5-carbonitrile (14) as the nucleophile to yield 32 as a white solid (74%): MS m/z: 366 (M+H)+. Anal. Calcd. For, C19H15N3OS2: C, 62.44; H, 4.14; N, 11.50; S, 17.55. Found: C, 62.47; H, 4.36; N, 11.35; S, 17.65.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:29])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:37]1([CH2:40][NH:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38]1>C(O)C>[CH:37]1([CH2:40][N:41]([CH2:42][CH2:43][CH3:44])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:29])=[O:9])[CH:3]=2)[CH2:39][CH2:38]1
Reactant: CCCNCC1CC1
Reactant: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCCC(=O)OCC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of ethyl 4-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate (Intermediate 35, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give ethyl 4-(4-(6-((cyclopropyl methyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate which was used directly without any further purification. The residue was dissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:32]=2)[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Reaction time: 0.42 h
Yield: 98.8 %

Procedure:
(S)-(1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (1.07 g, 1.90 mmol) was dissolved in CH2Cl2 (4.5 mL) and treated with TFA (4.5 mL). The reaction was stirred for 25 minutes, then concentrated in vacuo. The residue was dissolved in EtOAc (175 mL) and solution was washed twice with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated in vacuo to give 0.87 g (99%) of the desired product as a pale oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27].CC(C)([O-])C.[K+].C1COCC1.CS(C)=O>CS(C)=O.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:22]2[C:21]([Cl:20])=[CH:33][C:25]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1-benzhydrylazetidin-3-yl)methanol (40.4 mg, 0.159 mmol) and 5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide (43.0 mg, 0.159 mmol) in DMSO (0.80 mL) at rt was added potassium tert-butoxide in 1:10 THF-DMSO (0.38 mL, 0.93 M). The mixture was stirred at rt for 1 hr. LCMS showed major product. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine (1×), dried (Na2SO4). After filtration and concentration, the crude was purified with HPLC (55.7 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1.[O:7]=[S:8](=[O:10])=[O:9].[CH3:11][C@@H:12]([C@@H:19]1[C@:36]2([CH3:37])[C:23](=[C:24]3[CH:33]([CH2:34][CH2:35]2)[C@:32]2([CH3:38])[C@H:27]([CH2:28][C@@H:29](O)[CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[C:21](=[O:22])[CH2:20]1)[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>C(O)(C)(C)C>[S:8]([O-:22])([O-:10])(=[O:9])=[O:7].[CH3:18][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:19]1[C@:36]2([CH3:37])[C:23](=[C:24]3[C@H:33]([CH2:34][CH2:35]2)[C@:32]2([CH3:38])[C@H:27]([CH2:28][C@@H:29]([N+:4]4[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=4)[CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[C:21](=[O:22])[CH2:20]1)[CH3:11])[CH3:17].[CH3:18][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:19]1[C@:36]2([CH3:37])[C:23](=[C:24]3[C@H:33]([CH2:34][CH2:35]2)[C@:32]2([CH3:38])[C@H:27]([CH2:28][C@@H:29]([N+:4]4[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=4)[CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[C:21](=[O:22])[CH2:20]1)[CH3:11])[CH3:17]
Reactant: O=S(=O)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)C3CC[C@@]21C
Reactant: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H]([n+]5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 141 %

Procedure:
Pyridine-sulfur trioxide (5.0 g) was added to 5α-cholest-8(14)-en-3β-ol-15-one (2.0 g; 5.0 mmol) in dry chloroform (50 ml; ethanol-free; dried over Linde molecular sieve, type 3A). The resulting mixture was stirred at room temperature for 3 hours. The excess reagent was removed by filtration, washed with a small volume of chloroform, and the filtrate was cooled to -40° C. in a dry ice-acetone bath and filtered through Hyflo Super-Cel (Johns-Manville Corp.). Hexane was added to the chloroform filtrate until a cloudiness appeared whereupon cooling to 0° C. gave a white precipitate. This material was collected by filtration and placed in a vacuum desiccator for 100 hours at room temperature to remove all traces of solvent. The product, 5α-cholest-8(14)-en-15-one-3β-yl pyridinium sulfate (2.4 g; 86% yield), had the following structural formula as confirmed by i.r., n.m.r., and m.s. analyses: ##STR55##
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]([C:8](=[CH2:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCl>[CH2:12]([O:11][C:9]([CH:8]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:19][PH:1](=[O:2])[OH:3])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[PH2]O
Reactant: C=C(CC(C)C)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(C[PH](=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A vigorously stirred mixture of 17.6 g (0.27 mol) of crystalline phosphinic acid and 43.6 g (0.2 mol) of benzyl 2-isobutylacrylate in 400 ml of dichloromethane was cooled to 0° C. and treated dropwise with 53.4 g (0.53 mol) of triethylamine while maintaining the temperature at below 5° C. After completion of the addition, a solution of 56.0 g (0.52 mol) of trimethylsilyl chloride in 100 ml of dichloromethane was added while stirring vigorously and maintaining the temperature at 10°-12° C. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 24 hours. The mixture was then treated with 200 ml of water and 30 ml of 10% sulfuric acid. The organic phase was separated and washed with 200 ml of saturated sodium chloride solution. The combined aqueous extracts were re-extracted with 100 ml of dichloromethane and the organic phase was washed with 100 ml of sodium chloride solution and added to the previously obtained dichloromethane extracts. After drying over anhydrous sodium sulfate, the dichloromethane was removed by evaporation to give 59.2 g of [(RS)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid in the form of a colorless oil. (b) The compound prepared in the preceding paragraph was dissolved in 600 ml of ethyl acetate. Thereafter, 25.0 g of S(-)-α-methylbenzylamine were added and the solution was left to crystallize for 24 hours. The crystalline salt was collected by filtration and dried to give 34.0 g of a white solid which was recrystallized overnight from a mixture of 120 ml of ethanol and 48 ml of ethyl acetate. The solid was collected and dried to give 21.3 g of a crystalline salt which was recrystallized overnight from a mixture of 120 ml of ethanol and ethyl acetate. There were obtained 16.8 g of [(R or S)-2-[benzyloxy)carbonyl]4-methylpentyl]phosphinic acid S(-)-α-methylbenzylamine salt in the form of white crystals of melting point 137°-138° C. and [α]20/589=-8.9° (c=5% in ethanol).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:25]=O)=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:25][NH:6][CH3:5])=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1
Reactant: Cn1cc(C=O)c2ccc(F)cc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cc(F)ccc12
Yield: 35 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 6-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.11 g, 35%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: O1CCOCC1.Cl.C(OC([NH:15][CH2:16][C:17]([NH:19][C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:18])=O)(C)(C)C>CO>[NH2:15][CH2:16][C:17]([NH:19][C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A 4 M HCl dioxane (38 mL) solution was added to a methanol (60 mL) solution of (R)-3-[N-(tert-butoxycarbonyl)glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (5.39 g, 14.7 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and a 2 M solution (80 mL) of NaOH was added. The mixture solution was extracted with dichloromethane (80 mL×3), and the extracts were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO2, ethyl acetate/ethanol/triethylamine=90:5:5) to afford (R)-3-(glycylamino)-1-(4-chlorobenzyl)pyrrolidine (3.374 g, 86%) 1H NMR (CDCl3, 270 MHz) δ 1.77 (dd, J=1.3 and 6.9 Hz, 1H), 2.20-3.39 (m, 2H), 2.53 (dd, J=3.3 and 9.6 Hz, 1H), 2.62 (dd, J=6.6 and 9.6 Hz, 1H), 2.78-2.87 (m, 1H), 3.31 (s, 2H), 3.57 (s, 2H), 4.38-4.53 (br, 1H), 7.18-7.32 (m, 4H), 7.39 (br, s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][C:24]#[N:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:23]([CH2:24][NH:25][C:18](=[O:20])[C@H:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[NH:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)#[N:22]
Reactant: N#CCN
Reactant: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)NCC#N
Reaction time: 36 h
Yield: 55 %

Procedure:
To a solution of N-(1-phenyl-1H-tetraazol-5-yl)-L-leucine (100 mg, 0.36 mmol), aminoacetonitrile hydrochloride (62 mg, 0.68 mmol) and PyBOP (230 mg, 0.44 mmol) in DMF (3 mL) was added triethylamine (0.2 mL, 1.4 mmol). The solution was stirred 36 h, then partitioned between ethyl acetate and pH 3 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (60% to 90% ethyl acetate/hexanes) gave 62 mg of N1-(cyanomethyl)-N2-(1-phenyl-1H-tetraazol-5-yl)-L-leucinamide. MS (+APCI): 313.9 [M+1]+.