Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H]1CCN(C(C2C=CC(OC(F)(F)F)=CC=2)=O)[C@H]1C(NOCC1C=CC=CC=1)=O.COC(=O)C([NH:44][C:45](=[O:63])[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][C:54]#[C:55][C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=C[CH:57]=2)=[CH:48][CH:47]=1)CNC(OC(C)(C)C)=O.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:62]1[CH:59]=[CH:60][CH:61]=[C:56]([C:55]#[C:54][C:53]#[C:52][C:49]2[CH:50]=[CH:51][C:46]([C:45]([NH2:44])=[O:63])=[CH:47][CH:48]=2)[CH:57]=1
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)c1ccc(C#CC#Cc2ccc(N)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(NOCc1ccccc1)[C@H]1[C@H](O)CCN1C(=O)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(C#CC#Cc2cccnc2)cc1
Reaction time: 0.08 h

Procedure:
Resin 1 (142 mg, 0.109 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 3-ethynylpyridine 2 (38 mg, 0.368 mmol) and Et3N (200 μL 1.4 mmol) in DMF (2 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (22 mg, 0.031 mmol) and CuI (25 mg, 0.131 mmol) was added and the resin was agitated for 72 h. The resin was drained, washed with DMF (3×2 mL), DCM (3×2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC (C18 column, CH3CN gradient 5-65%, 0.1% TFA, UV analysis 300 nm, 24 min) and lyophilization of the collected fractions afforded 4.4 mg (11% yield) of N-(2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4-(4-pyridin-3-yl-buta-1,3-diynyl)-benzamide. LRMS (ES+) m/z 364.0 (C20H17N3O4+H requires 364.13); RP-HPLC (300 nm, 24 min run) 11.2 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[H][H]>[Pd].CO>[NH2:8][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:12])[F:13])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)cnc1O
Yield: 99.3 %

Procedure:
A mixture of 3.13 g of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, 40 ml of methanol and 0.85 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for two hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 2.66 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([CH:18]=[O:19])[NH:8][C:7]=1[CH2:20][CH2:21][NH2:22])=O)C.O.[OH-].[Li+].O>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:6]3[C:4](=[O:3])[NH:22][CH2:21][CH2:20][C:7]=3[NH:8][C:9]=2[CH:18]=[O:19])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(CCN)[nH]c(C=O)c1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
A stirred solution of 2-(2-amino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester (257.5 mg, 2.5 mmol), lithium hydroxide monohydrate (840 mg, 20 mmol) in ethanol (95%, 20 ml) was heated to reflux under an argon atmosphere for 3 hours. The mixture was added with cold water (150 ml), stirred for 10 minutes, extracted with a 5 to 1 solvent mixture of dichloromethane and methanol (50 ml×7), washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from dichloromethane and methanol to give 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (170 mg, 26.3%) as a red solid.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC(CSCCO)=CC=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccc(CSCCO)cc2)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 99 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (3.11 g, 9.83 mmol, 1 eq.) in anhydrous THF (100 mL) was treated with phenol (1.29 g, 13.76 mmol, 1.4 eq.), triphenylphosphine (3.61 g, 13.76 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (2.78 g, 2.71 mL, 13.76 mmol, 1.4 eq.) as described. When the reaction was complete, the reaction was worked up and the product purified via silica gel flash chromatography leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester (3.82 g, 99% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc(OC)c(-c3c(Cl)cnn3C)c2)c1
Yield: 27 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Methoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 7.5 mg (27%) of Compound 30 (Note: Compound 30 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=389 (M+H37Cl, 39), 387 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.91 (s, 1H), 1H), 7.49 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.28 (s, 1H), 7.12 (t, J=2 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 6.81 (dd, J1=8 Hz, J2=4 Hz, 1H), 6.37 (dd, J1=8 Hz, J2=4 Hz, 1H), 3.63 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=2[S:6][C:5]1=[NH:18].NC1SC2C=C(OC(F)(F)F)C=CC=2N=1.[Br:34]CCO>C(O)C>[BrH:34].[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:12][C:7]=2[S:6][C:5]1=[NH:18]
Reactant: OCCBr
Agent: N=c1sc2cc(OC(F)(F)F)ccc2n1CCO
Agent: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CCO
Product: Br
Temperature: 20 °C

Procedure:
3-(2-Hydroxyethyl)-2-imino-6-trifluoromethoxybenzothiazoline may be prepared in the following manner: 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2-bromoethanol (10 g) in absolute ethanol (30 cc) are heated for 95 hours to boiling. The mixture is cooled to a temperature in the region of 20° C. The precipitate formed is filtered off and washed with ethyl ether (100 cc). 3-(2-Hydroxyethyl)-2-imino-6-trifluoromethoxybenzothiazoline hydrobromide (6.4 g), m.p. 219° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[C:18]([I:19])=[CH:17][C:5]2[C:6](=O)/[C:7](=[CH:12]\N(C)C)/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>CCO>[NH2:23][C:22]1[N:24]=[CH:12][C:7]2[CH2:8][C:9](=[O:11])[NH:10][C:4]3[CH:3]=[C:2]([Cl:1])[C:18]([I:19])=[CH:17][C:5]=3[C:6]=2[N:21]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C1/CC(=O)Nc2cc(Cl)c(I)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Temperature: 70 °C
Reaction time: 19 h
Yield: 81.9 %

Procedure:
A suspension of (4Z)-8-chloro-4-[(dimethylamino)methylene]-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (9.50 g, 24.3 mmol), guanidine hydrochloride (2.56 g, 26.8 mmol), and potassium carbonate (11.1 g, 80.3 mmol) in EtOH (143) was allowed to stir while heating at 70° C. in a sealed reaction vessel. After 19 h, the reaction mixture was allowed to cool to room temperature then added to water (200 mL) and allowed to stir for 1 h. The resulting tan solid was collected via suction filtration, washed with water, and dried in a vacuum oven to give 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (7.69 g, 82%). LCMS (FA): m/z=387 (M+H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16])=[O:6])[CH3:4].[N:22]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28](O)=[O:29]>CN(C=O)C.CC(O)=O>[N:22]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16])=[O:6])[CH3:4])=[O:29]
Reactant: C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Yield: 54.9 %

Procedure:
After 2.31 g (5.0 mmols) of HCl.H-Ala-Arg(NO2)-CHA was dissolved in 10 ml (15.0 mmols) of 1.5N NEM/DMF, 1.93 g (5.0 mmols) of Z-PyroGlu-SDP was added to the solution at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with 300 ml of AcOH followed by washing 4 times with 100 ml of cold 5% hydrochloric acid and twice with 100 ml of saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate and decoloring with activated charcoal, the AcOEt phase was distilled under reduced pressure. The residue was recrystallized from MeOH/AcOEt/ether to give 18.4 g (54.9%) of Z-pyroGlu-Ala-Arg(NO2)-CHA.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:12]CO)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)([Cl:17])=O.O.C(=O)([O-])O.[Na+].Cl[CH2:26][Cl:27]>>[Cl:17][CH2:2][CH2:3][N:4]([CH2:12][CH2:26][Cl:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Bis(2-hydroxyethyl)benzylamine (1 g) was dissolved in dichloromethane (20 ml), added with thionyl chloride (1.9 ml) with ice cooling and stirred at room temperature for 2.5 hours. The reaction mixture was added with water (10 ml) with ice cooling, and adjusted to pH 7 with saturated aqueous sodium hydrogencarbonate. The layers were separated and the aqueous layer was further extracted with dichloromethane (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain bis(2-chloroethyl)benzylamine (1.090 g).
Reaction SMILES: Cl.CN(C)CCCC(N=C=N)C.[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:22]=1[CH2:23][N:24]([C:27]1[S:28][C:29]([C:32]([OH:34])=O)=[CH:30][N:31]=1)[CH2:25][CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:40]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:22]=1[CH2:23][N:24]([C:27]1[S:28][C:29]([C:32]([NH:49][S:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:48])=[O:47])=[O:34])=[CH:30][N:31]=1)[CH2:25][CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ncc(C(=O)O)s1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ncc(C(=O)NS(=O)(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3--Dimethylaminopropyl)ethylcarbodiimide hydrochloride (0.85 g) was added to a stirred mixture of 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]thiazole-5-carboxylic acid (1 g), benzenesulphonamide (0.35 g), 4-dimethylaminopyridine (0.27 g) and triethylamine (0.225 g) in N,N-dimethylformamide (100 mL) and the mixture was stirred at ambient temperature for 16 hours. Water (30 mL) was added to the reaction mixture which was then extracted three times with ethyl acetate (20 mL each time). The combined ethyl acetate extracts were washed consecutively with aqueous 2N HCL (3×10 mL), aqueous saturated NaHCO solution (3×10 mL) and water (10 mL) and dried. The residue obtained on evaporation of the solvent was filtered through silica using ethyl acetate as eluant. The solvent was evaporated and on trituration with diethyl ether the residue gave 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]-N-(phenylsulphonyl)thiazole-5-carboxamide, yield 0.358 g, mp 140°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.C(N(CC)C(C)C)(C)C.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 25 °C

Procedure:
To a mixture of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (3.0 g, 16.5 mmole) and N,N-diisopropylethylamine (9 ml, 50 mmole) in toluene (150 ml), was added POCl3 (4.7 ml, 50 mmol). The resulting reaction mixture was refluxed for 1.5 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (200 ml) and washed with cold water till pH=6-7. The organic phase was dried over MgSO4, filtrated and concentrated under reduced pressure to yield crude 4,6-dichloro-pyrido[3,2-d]pyrimidine which was not purified but used as such for further reactions.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C[Si](CCOCCl)(C)C.ClC1C2C=CNC=2N=CN=1>C(O)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3].[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Agent: C[Si](C)(C)CCOCCl
Agent: Clc1ncnc2[nH]ccc12
Solvent: CCO
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Reaction time: 0.27 h
Yield: 92.3 %
Yield: 90.8 %

Procedure:
A solution of racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 5.2 g, 12.36 mmol) in a mixture of ethanol and hexanes (1:9 by volume) was injected into preparative HPLC system equipped with the chiral column (30×250 mm) packed with a silicagel based packing coated with cellulose tris(3,5-dimethylphenyl)carbamate (available from Daicel Chemical Industries, Ltd. (Daicel) as “Chiralcel® OD-H” (5 μm)). The chiral column was eluted with mobile phase made by a mixture of ethanol (EtOH) and hexanes in a 1 to 9 volume ratio at a flow rate of 32 mL/min at room temperature. The column elution was monitored by UV at wavelength 220 nm. Under these conditions, baseline separation of the two enantiomers was achieved and the retention times were 16.4 minutes (Peak 1, the undesired (S)-enantiomer (S)-21) and 21.0 minutes (Peak 2, the desired (R)-enantiomer (R)-21), respectively. Each injection was 1.4 mL of feed solution at a concentration of 50 mg/mL and each run cycle was 14 minutes by using stack injections. Total 75 injections were taken for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-21) and Peak 2 (the desired (R)-enantiomer, (R)-21) were collected separately from each injection, and fractions collected for each peak were concentrated under reduced pressure. The residue from each evaporator was further dried under high vacuum to constant weight to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-21, 2.36 g, 2.6 g theoretical, 90.8% yield) from Peak 2 as off-white solids and (S)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((S)-21, 2.4 g, 2.6 g theoretical, 92.3% yield) from Peak 1 as off-white solids.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:8]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:7][CH:6]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:4].[NH2:33][C:34]1[CH:35]=[C:36]([C:40]2[NH:44][N:43]=[N:42][N:41]=2)[CH:37]=[CH:38][CH:39]=1.FC1C=CC=CC=1C1N(C(=O)CNC(=O)NC2C=C(C[C:69](O)=[O:70])C=CC=2)C(C(N2C3C(=CC=CC=3)CCC2)=O)CC1S(C1C=CC=CC=1)(=O)=O>ClCCCl.[Na]>[C:29]([O:28][C:26]([CH:6]1[CH2:7][CH:8]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:69](=[O:70])[NH:33][C:34]1[CH:35]=[C:36]([C:40]2[NH:44][N:43]=[N:42][N:41]=2)[CH:37]=[CH:38][CH:39]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCCc4ccccc43)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CN
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(-c2nnn[nH]2)c1

Procedure:
A The reaction is carried out in a way analogous to that described in Example 16B, but from 2.3 g of tert-butyl (2RS,4SR,5RS)-1-(2-aminoacetyl)-5-(2-fluorophenyl)-4-(phenylsulphonyl)pyrrolidine-2-carboxylate, 0.9 g of N,N'-carbonyldiimidazole and 0.81 g of 5-(3-aminophenyl)tetrazole in 70 cm3 of 1,2-dichloroethane. After treatment, there is obtained 0.6 g of (2RS,4SR,5RS)-5-{3-[3-(2-(2-tert-butoxycarbonyl-5-(2-flurophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl)ureido]phenyl}tetrazole in the sodium salt form [Rf 0.17; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[S:10][C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:38]=[C:39]([C:46](=[O:48])[CH3:47])[CH:40]=[CH:41][C:42]=1[NH:43][CH2:44][CH3:45]>CN(C=O)C.CC#N>[C:46]([C:39]1[CH:40]=[CH:41][C:42]([NH:43][CH2:44][CH3:45])=[C:37]([N:36]=[C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12](=[O:13])[C:11](=[CH:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[S:10]2)[CH:38]=1)(=[O:48])[CH3:47]
Reactant: CCNc1ccc(C(C)=O)cc1N
Reactant: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=CN(C)c2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
A mixture of 3-benzyl-5-[(N-methyl-phenylamino)-methylene]-2-thioxo-thiazolidin-4-one (0.40 g, 1.2 mmol) and methyl p-toluenesulfonate (0.26 g, 1.4 mmol) in DMF (2 mL, anhyd) was heated at 125° C. After 2 h, the reaction mixture was cooled and an aliquot (0.4 mL) of the intermediate was transferred to an oven-dried vial. The intermediate was diluted with MeCN (2 mL, anhyd) and charged with 3′-amino-4′-ethylamino-acetophenone (53 mg, 0.30 mmol). The reaction mixture was warmed to 50° C., charged with TEA (100 μL), sealed and heated at 65° C. After 16 h, the reaction mixture was cooled, concentrated and chromatographed (silica gel, 0:100 to 50:50 EtOAc-Hex) to give the title product (14 mg) as a yellow solid. 1H-NMR (CDCl3): δ 7.92 (1H, s), 7.65 (1H, dd), 7.50 (1H, d), 7.27-7.42 (7H, m), 7.14-7.23 (3H, m), 6.48 (1H, d), 5.12 (2H, s), 4.27 (1H, br s), 3.51 (3H, s), 3.02 (2H, q), 2.45 (3H, s), 1.01 (3H, t); MS (ESI): 485 (MH+).
Reaction SMILES: ClC1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:33])([F:32])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(C1C=CC([NH2:42])=CC=1)(C)(C)C>>[N:42]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]1[CH:19]=[CH:18][C:11]2[C:12]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([S:22]([C:21]([F:32])([F:20])[F:33])(=[O:23])=[O:24])=[CH:30][CH:29]=3)=[N:13][S:14](=[O:15])(=[O:16])[C:10]=2[CH:9]=1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=S1(=O)N=C(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c2ccc(-c3ncccn3)cc21

Procedure:
The title product was prepared using the procedure as described in Example 1C, substituting the product of Example 24A for the product of Example 1B, and substituting 4-trifluoromethanesulfonyl-phenylamine for 4-tert-butylaniline. 1H NMR (300 MHz, DMSO-d6) δ 7.63 (t, J=4.9 Hz, 1H), 8.29 (m, 2H), 8.39 (m, 2H), 8.70 (d, J=8.1 Hz, 1H), 8.86 (s, 1H), 8.95 (dd, J=8.1, 1.4 Hz, 1H), 9.05 (d, J=5.1 Hz, 2H), 11.46 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:28][CH2:27][N:26]=[C:25]1[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:23][N:24]1[CH2:28][CH2:27][N:26]=[C:25]1[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:10](=[O:12])[CH:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:1][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:22])=[CH:31][CH:30]=1
Reactant: CN1CCN=C1c1ccc(N)cc1
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN=C1c1ccc(NC(=O)C(Cc2ccccc2)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of DL-phenylalanine (83 mg, 0.50 mmol) in DMF (6 mL), 4-chlorophenyl isocyanate (77 mg, 0.50 mmol) was added. The mixture was then stirred at room temperature overnight. To the reaction mixture, 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (180 mg, 1.02 mmol) and H2O (1 mL, to solubilize the amine) were added. To the solution, EDC (200 mg, 1.04 mmol) was added. After being stirred at room temperature overnight, the solution was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (96 mg). MS 476.1 and 478.1 (M+H, Cl pattern).