Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1C=CC([P]([Pd]([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)=CC=1>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 160 °C

Procedure:
To propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) in acetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 1.0% mmol) and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heated to 160° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0088, 30 mg, 46.9%). MS (ESI) [M+H+]+=457.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:5]=[C:4]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCC2)nc1-c1ccc(C)cc1
Yield: 72.3 %

Procedure:
To a solution of methyl 2-(4-methyl-2-(pyrrolidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.090 g; 0.227 mmol) in methanol (3 mL) was added a solution of sodium hydroxide 5N (0.490 mL; 2.45 mmol) and the reaction mixture was heated to reflux for 18 h. The volatiles were removed under reduced pressure, the residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The formed precipitate was collected by filtration and dried under reduced pressure over P2O5 to give 0.058 g (67%) of the title compound as a white solid.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)NC(CN)Cc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>O1CCCC1>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([CH:13]([OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:11]=1
Reactant: CCCCCC[Mg]Br
Reactant: O=Cc1cccc(Br)c1
Solvent: C1CCOC1
Product: CCCCCCC(O)c1cccc(Br)c1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
Hexylmagnesium bromide (2.0M in THF, 3.7 mL, 7.4 mmol) was added to a solution of 3-bromobenzaldehyde (1.50 g, 8.11 mmol) in tetrahydrofuran (10 mL) at −78° C. After 10 min, the reaction was quenched by the addition of 2N hydrochloric acid (30 mL) and the product extracted into ethyl acetate (30 mL). The organic layer was washed with sat'd sodium chloride (25 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 17% ethyl acetate/hexane gave 1.42 g (5.25 mmol, 65%) of product.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([O:32][CH3:33])[CH:19]=2)[OH:17])=[N:11][CH:12]=[CH:13][C:14]=1[OH:15])C1C=CC=CC=1>CO.[Pd]>[OH:17][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:32][CH3:33])[CH:19]=1)[C:10]1[C:9]([OH:8])=[C:14]([OH:15])[CH:13]=[CH:12][N:11]=1
Reactant: COc1cc(C(O)c2nccc(O)c2OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(O)c2nccc(O)c2O)ccc1O

Procedure:
0.9 g of 3-benzyloxy-2-[(4-benzyloxy-3-methoxy-phenyl)-hydroxy-methyl]-pyridin-4-ol is dissolved in 100 ml of methanol and hydrogenated at room temperature in the presence of 0.18 g of palladium on carbon (5%) until 2 mol of H2 per mol of starting material have been taken up. The catalyst is removed by filtration and the flitrate is concentrated by evaporation. Recrystallisation from methanol yields 2-[hydroxy-(4-hydroxy-3-methoxy-phenyl)-methyl]-pyridine-3,4-diol. Colourless crystals, m.p.: from 210° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:10]([CH2:18][CH3:19])=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1.[Li+].[OH-].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:10]([CH2:18][CH3:19])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1CC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Part A: Ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate was obtained according to WO03040107. To a magnetically stirred solution of ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate (5.80 g, 0.0149 mol) in tetrahydrofuran (40 ml) was added a solution of LiOH (0.715 g) in water (40 ml). The resulting mixture was heated at 70° C. for 16 hours. The resulting mixture was allowed to attain room temperature and subsequently treated with concentrated hydrochloric acid (3.5 ml). The tetrahydrofuran was evaporated in vacuo and the resulting mixture was stirred overnight. The formed precipitate was collected by filtration and washed with petrolaum ether (40-60) to give 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid (4.52 gram, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 1.09 (t, J=7, 3H), 2.90 (q, J=7, 2H), 3.70 (br s, 1H), 7.12 (dt, J=8 and 2, 2H), 7.22-7.28 (m, 1H), 7.29-7.38 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][N:9]=[C:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18]>CN(C)C.CC(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([C:17](=[O:18])[NH:16][CH3:15])[N:9]=[C:10]([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: CC(C)=NNC(=O)c1ccc(Cl)cc1
Agent: CN(C)C
Solvent: CC(C)=O
Product: CNC(=O)N(N=C(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10.5 g of 1-p-chlorobenzoyl-2-isopropylidene hydrazine, 2.9 g of methyl isocyanate and 100 ml of acetone were placed in a 200 ml round-bottom flask, and 3 drops of trimethylamine were added thereto. The mixture was stirred at room temperature for one hour. The separated crystalline mass was recovered to obtain 12.7 g (95%) of 1-p-chlorobenzoyl-1-methylcarbamoyl-2-isopropylidene hydrazine as white crystals having a melting point of 119°-123° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[C@@H:19]([F:33])[CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[C@@H:3]([OH:10])[C@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>>[OH:1][C@@H:2]([C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH:23]=[CH:24]2)[C@@H:19]([F:33])[CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[C@@H:3]([OH:10])[C@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6]
Reactant: CC[C@@H](C(C)C)[C@H](O)[C@@H](O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: CC[C@@H](C(C)C)[C@H](O)[C@@H](O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 50.2 %

Procedure:
70 mg of (22S,23S)-22,23-dihydroxy-6α-fluorostigmast-4-en-3-one are treated with DDQ following the procedure described in the Example 6. After purification by silica column chromatography (eluting solvent: hexane/ethyl acetate 8:2) of the obtained crude product, 35 mg of (22S,23S)-22,23-dihydroxy-6α-fluorostigmasta-1,4-dien-3-one are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19]>>[CH2:1]([O:8][C:9]1[C:10]([Cl:19])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1
Product: Clc1ncc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 3-(benzyloxy)-5-bromopyridine N-oxide (2.0 g, 7.1 mmol) in POCl3 (20 mL) was stirred at 100° C. for 7 hours, cooled to room temperature, concentrated, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexane to provide the desired product (1.0 g, 40%). MS (DCI/NH3) m/e 299 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl.[CH3:20][C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:32])[CH2:22][NH:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1([CH3:32])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][CH2:22]1
Reactant: CC(C)(CNC(=O)c1ccccc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: CC1(C)CN=C(c2ccccc2)c2ccccc21
Temperature: 150 °C
Yield: 54 %

Procedure:
1.42 g (10.0 mmol) of P2O5 and POCl3 (4 ml) were added to a solution of 1.27 g (5.0 mmol) of N-(2-methyl-2-phenylpropyl)benzamide in xylene (20 ml) and the mixture was heated at 150° C. for 3 h. After cooling to RT the mixture was concentrated to small volume under vacuum. The residue was made alkaline with a 20% aqueous NaOH solution. It was then extracted with EE and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 634 mg (2.7 mmol) of 4,4-dimethyl-1-phenyl-3,4-dihydroisoquinoline were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:53][C:54]1[CH:55]=[CH:56][C:57]2[O:61][C:60]([C:62](O)=[O:63])=[CH:59][C:58]=2[CH:65]=1>CN(C=O)C.O>[Cl:53][C:54]1[CH:55]=[CH:56][C:57]2[O:61][C:60]([C:62]([N:16]3[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]4/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/4)[CH2:14][CH2:15]3)=[O:63])=[CH:59][C:58]=2[CH:65]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2cc3cc(Cl)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (0.56 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (283 mg), and 5-chlorobenzofuran-2-carboxylic acid (151 mg). The reaction mixture was stirred at room temperature overnight, water was added, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (57 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Sn](CCCC)(CCCC)CCCC.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:33]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1(C)C(C)=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:33]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cccc1F
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cncc(-c2c(F)cccc2F)c1
Yield: 83.8 %

Procedure:
A mixture of (2,6-difluorophenyl)tributyltin (1.18 g, 2.9 mmol), ethyl 5-bromonicotinate (0.69 g, 3 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g) in xylene (10 mL) was heated under reflux for 24 h, then cooled, filtered and evaporated. The residue was chromatographed on silica gel eluted with 20% ethyl acetate/petrol to give the title compound (0.64 g, 84%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccccc2C#N)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 4-methylhomopiperazine.
Reaction SMILES: C([S@]([NH:7][C@@H:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:14]([CH:20]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9])=O)(C)(C)C.Cl.CO>CO>[NH2:7][C@@H:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:14]([CH:20]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9]
Reactant: CCOC(=O)c1cc([C@@H](C)N[S@](=O)C(C)(C)C)ccc1NS(C)(=O)=O
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of ethyl 5-((1R)-1-{[(R)-tert-butylsulfinyl]amino}ethyl)-2-[(methylsulfonyl)amino]benzoate (4.3 g,11 mmol) in methanol (30 ml) was added hydrogenchloride-methanol solution (30 ml). The solution was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The given residue was recrystallized from methanol-diethyl ether. The precipitate was then filtered, washed with diethyl ether and collected to furnish 3.1 g (87% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]3[N:11]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:12](=[O:16])[CH:13]=[C:14]([OH:15])[N:7]3[C:6]=2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[BH4-].[Li+]>C(Cl)(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]3[N:11]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:12](=[O:16])[CH:13]=[C:14]([OH:15])[N:7]3[C:6]=2[C:5](=[O:25])[N:4]([CH3:26])[CH2:3]1
Reactant: Cn1c(=O)c2c(nc3n(Cc4ccc(F)cc4)c(=O)cc(O)n23)n(C)c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CN1CN(C)c2nc3n(Cc4ccc(F)cc4)c(=O)cc(O)n3c2C1=O
Temperature: 100 °C

Procedure:
Reflux a suspension of 395 g (1.06 moles) of 1,3-dimethyl-9-(4-fluorobenzyl)-6-hydroxy-pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, 12.32 g of ammonium sulfate and 350 ml of 1,1,1,3,3,3-hexamethyldisilazane in 4 liters of chloroform until a clear solution is obtained (18-24 hr.). Remove chloroform and excess hexamethyldisilazane under reduced pressure, and treat the residual thick gum with 9.6 liters of dry 1,4-dioxan. While stirring the resultant mixture, cautiously add 70.4 g (3.24 moles) of lithium borohydride in portions under a stream of dry nitrogen. When foaming subsides, heat the mixture to 100° C. for 18 hr. or until all starting material has been consumed (as determined by TLC on silica with chloroform(90)-methanol(10)-acetic acid(1)). Remove a portion of the dioxane under reduced pressure, purge the system with nitrogen as the vacuum is released, allow the residue to cool, and add 3 liters of chloroform with stirring. Add 1.3 liters of water cautiously (because of foaming), followed by 2.3 liters of 3N hydrochloric acid. Stir for one hour; then separate the layers. Extract the aqueous phase with two 1.3-liter volumes of chloroform, and dry the combined extracts over anhydrous sodium sulfate. Filter off the drying agent, and remove solvent from the filtrate under reduced pressure. Dissolve the residual tacky solid in 1.5 liters of boiling acetonitrile, add a small amount of decolorizing carbon, reflux for 15 minutes, and filter through a pad of Celite. Chill the filtrate, and collect the resultant crystals. Wash the crystals with cold acetonitrile, and dry them under vacuum at 50° C. to obtain the title compound, mp 214°-232° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([O:68][CH2:69][CH2:70][OH:71])=[CH:66][CH:65]=1>>[OH:71][CH2:70][CH2:69][O:68][C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1
Reactant: Nc1ccc(OCCO)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCCO)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 41.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 2-(4-aminophenoxy)ethanol (0.082 g, 0.53 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a yellow solid (Yield 0.11 g, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:10][CH2:11][CH2:12][C:13]1[O:17][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:34])[N:21]3[O:26]CC2C=CC=CC=2)=[N:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[OH:26][N:21]1[C:20](=[O:34])[N:19]2[CH2:25][C@H:22]1[CH2:23][CH2:24][C@H:18]2[C:16]1[O:17][C:13]([CH2:12][CH2:11][NH:10][C:9]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:14][N:15]=1
Reactant: CC(C)(C)OC(=O)N=C(NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3O)o1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,5R)-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)ethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (80 mg, 0.136 mmol) in THF (15 mL) was added 10% Pd/C (45 mg) and the mixture was stirred under H2 atmosphere at rt for 1 h. The reaction mixture was filtered and concentrated to afford (2S,5R)-6-hydroxy-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)ethyl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one, which was directly used in the next step. ESI-MS (EI+, m/z): 496.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][O:18][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
Compound 158 (2.27 g, 8.33 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to 0° C. Tosyl chloride (1.91 g, 10.0 mmol) and catalytic DMAP were added, followed by dropwise addition of triethylamine (2.55 mL, 18.33 mmol). The reaction was then stirred at 0° C. for 18 hours. The solvent was rotovapped off (removed under reduced pressure), and the crude material washed with EtOAc and filtered. The solids were washed with EtOAc, and the filtrate washed with 0.5N HCl (20 mL), brine (30 mL), dried over MgSO4, filtered, and rotovapped. The oil was chromatographed on silica eluting with a 5% EtOAc/hexanes gradient to 10% EtOAc/hexanes to give 159 (3.399 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30 Hz, 2H), 3.99 (dd, J=9.65, 3.54 Hz, 1H), 3.89 (dd, J=9.52, 5.37 Hz, 1H), 2.42 (s, 3H), 2.28 (dd, J=14.7, 6.23 Hz, 1H), 2.19-2.14 (m, 1H), 2.10 (dd, J=14.9, 6.35 Hz, 1H), 1.38 (s, 9H), 1.31-1.17 (m, 3H), 1.08-0.81 (m, 2H), 0.79-0.76 (m, 6H); [α]D=−10.1 (c1 in CHCl3).