Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:21]C)(=O)[C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:26][CH2:25][CH2:23][OH:24])=[O:21])=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(SSc2ccc(C(=O)OC)cc2)cc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(SSc2ccc(C(=O)NCCO)cc2)cc1
Temperature: 140 °C
Yield: 68.7 %

Procedure:
A mixture of 16.5 g of dimethyl 4,4'-dithiobis[benzoate] [Werbel et al., J. Heterocycl. Chem. 17, 497 (1980)] and 13.0 g of ethanolamine was heated at 140° C. while collecting the methanol which distilled from the reaction. After evolution of methanol had ceased, the reaction mixture was cooled and acidified with dilute hydrochloric acid. The solid product which formed was collected and dried to give 13.3 g of N,N'-bis(2-hydroxyethyl)-4,4'-dithiobis[benzamide], used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[Br:11][C:12]1[S:16][C:15]([S:17]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(Br)s1

Procedure:
Prepared by the method of Example 1 from 5-chloro-3-methoxy-2-pyrazinamine and 5-bromothiophenesulphonyl chloride.
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH2:21][C:19](=[O:20])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[S:17].N1CCCCC1>C(O)C>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:21]2[S:15][C:16](=[S:17])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:19]2=[O:20])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(Nc2ccccc2)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 24, the desired compound was prepared from 440 mg of 2-anilinothiazole-4-carbaldehyde, 412 mg of rhodanine-3-acetic acid, 0.5 ml of piperidine and 10 ml of ethanol. The resulting product was a yellowish-brown powder having the following physical properties.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccc1Sc1ccccc1
Solvent: ClCCl
Product: Cc1cc(CCl)ccc1Sc1ccccc1

Procedure:
Thus obtained 1-hydroxymethyl-3-methyl-4-phenylthiobenzene was dissolved in 100 ml of methylene chloride, and 23.34 ml of thionyl chloride was added while ice-cooling and stirring. After stirring for 1 hour, the reaction mixture was washed with ice water (100 ml×3), and 500 ml of ethyl acetate was added. The mixture was sequentially washed with 5% aqueous solution of sodium hydrogencarbonate (50 ml×4) and saturated brine (100 ml×2), and dried with anhydrous sodium sulfate, concentrated in vacuo, and 1-chloromethyl-3-methyl-4-phenylthiobenzene was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1)C)=[O:4].F[C:22](F)(F)C(NC1C=CC(I)=C(C)C=1)=O>>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:11]([CH3:22])[CH:12]=1)=[O:4]
Reactant: Cc1cc(NC(=O)C(F)(F)F)ccc1I
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1
Product: Cc1cc(NC(=O)C(F)(F)F)ccc1C#CCCCO

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 36, using Intermediate 35 in place of Intermediate 33. ES/MS calcd. for C14H14F3NO2 285.1. Found m/z=286 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[C:15]([OH:20])=[O:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]
Reactant: CCc1cc(=O)c2cc(C(C)CO)ccc2o1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(=O)c2cc(C(C)C(=O)O)ccc2o1

Procedure:
2-(2-Ethyl-4-oxo-4H-1-benzopyran-6-yl)propan-1-ol (3.0g; 0.0129 mol) was dissolved in acetone (20 ml) and Jones Reagent (Example 2) was slowly added until the solution attained a permanent brown colour. Water (100 ml) was added and the mixture was extracted with chloroform (4 × 70 ml). The combined chloroform phases were extracted with saturated sodium bicarbonate solution (4 × 30 ml). The aqueous phases were combined, washed with chloroform (100 ml) and then acidified with concentrated hydrochloric acid. The precipitated product was extracted with chloroform (3 × 100 ml) and the combined extracts dried over magnesium sulphate. After removing solvent, the product was recrystallised from benzene/hexane (1;1) to yield a pale yellow amorphous solid (1.4g) mp 128°-128.5°.
Reaction SMILES: [CH2:1]([N:3]([CH3:10])[CH2:4][CH2:5][C:6]([CH3:9])([NH2:8])[CH3:7])[CH3:2].[C:11](ON1C(=O)CCC1=O)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1COCC1>[CH2:1]([N:3]([CH3:10])[CH2:4][CH2:5][C:6]([NH:8][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:9])[CH3:7])[CH3:2]
Reactant: CCN(C)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
Crude N1-ethyl-N1,3-dimethylbutane-1,3-diamine (1.87 g, 12.9 mmol) was dissolved into THF (100 mL) and cooled in an ice bath. Solid CbzOSu (3.23 g, 1 equiv, 12.9 mmol) was added to the reaction in one portion. The reaction was left to stir at room temperature for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (3.29 g). The crude oil was purified on an ISCO purification system with gradient elution from 15 to 100% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a pale yellow oil (1.81 g, yield: 55.5%). 1H NMR (CDCl3, 400 MHz): δ 1.05-1.09 (t, J=8, 3H), 1.38 (s, 6H), 1.64-1.67 (t, J=6, 2H), 2.22 (s, 3H), 2.39-2.44 (q, J=6.6, 2H), 2.46-2.49 (t, J=6, 2H), 5.07 (s, 2H), 7.16 (bs, 1H), 7.28-7.41 (m, 5H). LRMS (ESI+) for C16H26N2O2 (278.2); Found: 279 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 81.9 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.4 g, 33.5 mmol), 3,4-difluorobenzaldehyde (5.0 g, 1.05 equiv.) and TFA (5.2 mL, 2 equiv.) to give the title compound (7.8 g, 82%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH:19]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:20][N+:21]([O-])=O)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH:19]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:20][NH2:21])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C[N+](=O)[O-])c2cccnc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(CN)c2cccnc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-Nitro-1-pyridin-3-yl-ethyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.92 g, 7.17 mmol) in MeOH (60 ml) was added nickel chloride hexahydrate (1.70 g, 7.17 mmol) and the mixture was cooled in an ice bath. Sodium borohydride (1.08 g, 28.7 mmol) was portionwise added over 30 minutes and the resulting suspension was stirred for further 30 minutes at 0° C. The reaction was quenched with saturated NH4Cl solution (30 ml) and MeOH was removed in vacuo. The aqueous residue was extracted with EtOAc (2×50 ml) and DCM (2×50 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: Cl.[C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:27])=[CH:10][C:11]=2[Cl:26])[NH:6]1)([OH:4])=[O:3].Cl.[C:29]([C@H]1C[C@H](NC(C2C=CC=C(CN)C=2)=O)C2C(=CC(Cl)=CC=2Cl)N1)(O)=O>CS(C)=O>[ClH:26].[CH3:29][O:3][C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:27])=[CH:10][C:11]=2[Cl:26])[NH:6]1)=[O:4]
Reactant: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Reactant: NCc1ccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)cc1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(CN)cc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
This compound was prepared by the method given for Example 82 using trans-2-carboxy-5,7-dichloro-4(4-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride, Example 83, in place of trans-2-carboxy-5,7-dichloro-4(3-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride to give the title compound as a colourless crystalline solid m.p. 238°-240° C. δ (DMSO, 360 MHz), 1.80 (1H, ddd, J=13.0, 12.5 and 4.1 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 3.71 (3H, s, CH3), 4.07 (3H, m, CHACHBHCCHD and CH2NH2), 5.26 (1H, m, CHACHBHCCHD), 6.68 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.95 (1H, s, NH), 7.53 (2H, d, J=8.2 Hz, Ar-H), 7.91 (2H, d, J=8.2 Hz, Ar-H), 8.38 (2H, br s, NH2), 8.73 (1H, d, J=7.2 Hz, NHCO); m/e (CI+ , NH3), 408 (M+1), 15 (100%; Found C, 48.87; H, 4.37; N, 8.95; C19H19Cl2N3O3.1.6 HCl requires C, 48.91; H, 4.45; N, 9.10%.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([NH:7][C:8]([N:10]1[CH:15]([C:16]2[N:17]=[CH:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=2)[C:14]([C:28]#[N:29])=[C:13]([CH3:30])[NH:12][C:11]1=[O:31])=[O:9])[CH3:6]>[Pd].C(#N)C>[CH2:5]([NH:7][C:8]([N:10]1[CH:15]([C:16]2[N:17]=[CH:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:28]#[N:29])=[C:13]([CH3:30])[NH:12][C:11]1=[O:31])=[O:9])[CH3:6]
Reactant: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1ncoc1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1ncoc1-c1ccccc1
Yield: 45 %

Procedure:
Catalytic reduction (10% Pd/C, ammonium formate in refluxing acetonitrile) of the product of Example 99 gave the title compound in 45% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=2[F:22])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc(F)c(-c2cc(C)nc(Cl)n2)c1
Temperature: 80 °C
Yield: 96.6 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine (2.66 g, 16.31 mmol) and (5-ethoxy-2-fluoro-phenyl)boronic acid (2 g, 10.87 mmol) in 1,2-dimethoxyethane (25 mL) and water (15 mL) was added sodium carbonate (3.46 g, 32.62 mmol). This was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium (II) dichloride (0.38 g, 0.54 mmol) was then added and the reaction was heated to 80° C. overnight. The solvent was evaporated and the residue was partitioned between water (300 mL) and EtOAc (300 mL). The organics were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow oil. The material was purified using a Biotage SP4 eluting with 0 to 30% i-hexane/EtOAc and the product containing fractions were collected and the solvent evaporated to give a colourless solid (2.8 g) mainly 2-chloro-4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidine (D16)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc([N+](=O)[O-])c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a mixture of 3-fluoro-4-nitrophenol (2.02 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5.62 g), triphenylphosphine (8.41 g) and THF (60 mL) was added dropwise a toluene solution (1.9 M, 16.9 mL) of diisopropyl azodicarboxylate at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (4.03 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:54]([O:56][CH2:57][CH3:58])=[O:55].C(N(CC)CC)C>ClCCl>[C:54](=[O:55])([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])[O:56][CH2:57][CH3:58]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 30 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.2 g, 0.28 mmol, obtained from the synthetic method described in step 11 of example 1) in dichloromethane (20 mL) were added ethyl chloroformate (0.26 mL, 2.8 mmol), triethylamine (0.78 mL, 5.60 mmol) and 4-dimethyl aminopyridine (cat. 5 mg) in turn at room temperature. The mixture was heated to 30° C. and stirred for 16 hours. The resulting mixture was quenched with 20 mL of saturated ammonium chloride, and then extracted with dichloromethane (40 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 12a as a light yellow solid (73.6 mg, 33.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.44 (s, 1H), 7.39-7.29 (m, 10H), 7.22 (dd, 5H), 7.08 (d, 2H), 6.91 (d, 2H), 6.77 (d, 2H), 5.10 (m, 1H), 4.97 (d, 1H), 4.90 (s, 1H), 4.81 (d, 2H), 4.33 (s, 1H), 4.21 (s, 1H), 4.20-4.09 (m, 2H), 4.07 (s, 1H), 4.04 (d, 2H), 4.00-3.92 (m, 3H), 3.86-3.76 (m, 2H), 3.66 (d, 1H), 1.41 (t, 3H), 1.29 (m, 6H).
Reaction SMILES: [OH-].[K+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)=[O:9].[CH2:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)C>CO>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:25]1[CH2:26][CH2:27][N:22]([CH3:20])[CH2:23][CH:24]=1)=[O:9]
Reactant: CCN1CCC(=O)CC1
Reactant: O=C(Nc1ccc2[nH]ccc2c1)c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccco4)cc23)CC1
Temperature: 0 °C
Yield: 48.3 %

Procedure:
To a solution of 0.868 gm (15.5 mMol) potassium hydroxide in 8 mL methanol were added 1.0 gm (4.42 mMol) 5-(2-furoyl)amino-1H-indole and 0.774 mL 1-ethyl-4-piperidone and the solution was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient and then diluted with ice/water. The resultant precipitate was collected and dried under vacuum. This solid was purified by radial chromatography (2 mm silica), eluting with a gradient of dichloromethane containing 5-7.5% methanol and 0.5-1.0% ammonium hydroxide. The product was then crystallized from ethyl acetate to give 0.715 gm (48.3%) of the title compound as a bright yellow powder.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][N:35]=[N+:36]=[N-:37])[NH:9]1)=[O:7])(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[N:35]([CH2:34][CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31][CH:10]1[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]1([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30])[C:21]#[N:22])=[N+:36]=[N-:37]
Reactant: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 96 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 120b (0.5 g, 0.86 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.54 g, 96%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C1C=CC=CC=1>O>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[NH2:1][C@H:2]([C:7]([O:9][CH2:29][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:8])[CH2:3][C:4]([O:6][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of L-aspartic acid (399 g.; 3.00 moles), benzyl alcohol (1.95 kg.; 18.0 moles), p-toluenesulfonic acid monohydrate (582 g.; 3.06 moles), and dry benzene (1.2 l.) was heated at reflux for 16 hours. The water formed in the reaction (145 ml.) was removed by means of a Dean-Stark trap. The resulting solution was cooled to room temperature, then diluted with benzene (1.2 l.) and ether (3.6 l.). The resulting solid was collected on a filter, washed with ether (7.0 l.), and dried; yield, 1195 g. (82%). The crude product was recrystallized from methanol (1720 ml.) to give 959 g. (80% recovery) of purified (I); m.p., 158°-159.5°; literature m.p., 158°-160°. Additional reactions were carried out to give a total of 4.27 kg. of product suitable for further transformation.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([C:24]4([OH:28])CO[CH2:25]4)[N:19]3[CH2:22]C)=[C:15]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:14]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].ClC1N=C2C(N=C(C3(O)C[N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:48]3)N2C)=C(N2CCOC[C@@H]2C)N=1>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([C:24]4([OH:28])[CH2:25][N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:48]4)[N:19]3[CH3:22])=[C:15]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CN(C(=O)OC(C)(C)C)C1)n2C
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3nc(C4(O)COC4)n(CC)c3n2)cc1
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3nc(C4(O)CN(C(=O)OC(C)(C)C)C4)n(C)c3n2)cc1

Procedure:
This compound (w-2) was prepared in an analogous fashion to (S)-1-ethyl-3-(4-(8-(3-hydroxyoxetan-3-yl)-9-ethyl-6-(3-methylmorpholino)-9H-purin-2-yl)phenyl)urea, using (S)-tert-butyl 3-(2-chloro-9-methyl-6-(3-methylmorpho-lino)-9H-purin-8-yl)-3-hydroxyazetidine-1-carboxylate as the starting material. LC-MS m/z (method A)=567.4 [M+H]+, RT=2.44 min.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][CH2:15][CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[N:19]=[C:18]1[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:13]>CC(O)C>[CH2:12]([O:14][CH2:15][CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[N:19]=[C:18]1[CH2:26][N:27]1[CH2:28][CH2:29][N:30]([CH2:11][CH:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:10])[CH2:31][CH2:32]1)[CH3:13]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Solvent: CC(C)O
Product: CCOCCn1c(CN2CCN(CC(O)COc3ccccc3)CC2)nc2cccnc21
Reaction time: 20 h
Yield: 31 %

Procedure:
A mixture of 1.65 parts of 2-(phenoxymethyl)oxirane, 8.9 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-3H-imidazo[4,5-b]pyridine and 40 parts of 2-propanol was stirred for 20 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.36 parts (31.0%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-α-(phenoxymethyl)-1-piperazineethanol; mp. 102.5° C. (compound 118).