Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Ca+2].[OH-].[CH2:4]([O:6][C:7]([CH:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][S:11]([C:14]([CH3:25])([CH3:24])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:13])=[O:12])=[O:8])[CH3:5].O>C(O)C>[C:19]([O:18][C:17]([NH:16][CH2:15][C:14]([S:11]([CH2:10][C@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:7]([O:6][CH2:4][CH3:5])=[O:8])(=[O:12])=[O:13])([CH3:25])[CH3:24])=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)CNC(=O)OC(C)(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)CNC(=O)OC(C)(C)C
Yield: 49.1 %

Procedure:
A 0.039N calcium hydroxide solution is added while stirring to a mixture of 1.75 g (4.1 mmol) of tert-butyl [2-[[(RS)-2-(ethoxycarbonyl)-3-phenylpropyl]sulphonyl]-2-methylpropyl]carbamate and 70 mg of α-chymotrypsin in 5 ml of ethanol and 250 ml of water in such a manner that the pH value is maintained at 7.5. When calcium hydroxide is no longer consumed, the working-up of the reaction mixture is effected by extracting the aqueous solution twice with 50 ml of ethyl acetate each time. The combined organic phases are washed with 25 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 0.86 g of ethyl (R)-α-[[[2-(1-tert-butoxyformamido)-1,1-dimethylethyl]sulphonyl]methyl]hydrocinnamate as a yellowish oil; MS: 445 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:15])([CH3:14])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(C)(O)Cc2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of (R)-4-acetyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.80 g, CAS 167102-63-8) in THF (40 ml) was cooled under an argon atmosphere to 0° C. and treated dropwise with benzylmagnesium chloride solution (1 M in diethylether, 34.5 ml). The reaction mixture was stirred at r.t. overnight, then quenched with saturated aqueous NH4Cl (50 ml) and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane ->cyclohexane/EtOAc 3:1) to give (R)-4-(1-hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.45 g, 89%) as off-white waxy solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C([Li])CCC.[Cl:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19](F)(F)F)[C:12]=1[NH2:13].O>C(OCC)C>[Cl:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]2[NH:3][CH2:2][CH2:1][N:4]=2)[C:12]=1[NH2:13]
Reactant: Nc1c(Cl)cc(Cl)cc1C(F)(F)F
Reactant: NCCN
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Nc1c(Cl)cc(Cl)cc1C1=NCCN1
Yield: 36.2 %

Procedure:
To a solution of ethylene diamine (1.2 mL, 18 mmol) in ethyl ether (50 mL) at −20° C. was added n-butyl lithium (6.4 mL, 2.5 M in hexanes, 16 mmol). The mixture was stirred at 0° C. for 0.3 hour before the addition of 2,4-dichloro-6-trifluoromethyl aniline (0.92 g, 4.2 mmol). The mixture was stirred at 0° C. for an additional 1.5 hours, at which point water (0.36 mL, 20 mmol) was added and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica gel, 1% to 10% methanol in dichloromethane) to give the title compound of Step A (0.35 g) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea are dissolved in 15 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, 15 ml of ethanol are added to the reaction mixture. Said mixture is neutralized with potassium carbonate under ice-cooling. Then, 150 ml of ethyl acetate are added to the mixture, and insoluble materials are removed by filtration. The filtrate is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. The residue thus obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (5:2:1)). 1.5 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [N:1]1([C:6]([NH2:8])=[NH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15]>>[NH2:17][CH2:16][C:13]1[C:14]([NH2:15])=[N:7][C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][C:12]=1[C:11]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:10]=1[Cl:9]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)N1CCCC1
Product: NCc1c(N)nc(N2CCCC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=337.8 (M+), was prepared from pyrrolidine-1-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.CO.[C].[Pd]>[ClH:1].[NH:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1
Reactant: O=C1CCN(Cc2ccccc2)CCN1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=C1CCNCCN1
Yield: 96 %

Procedure:
1M HCl in ethanol (7.2 mL) and 10% palladium-carbon (0.34 g) were added to 1-benzylhexahydro-1H-1,4-diazepin-5-one (1.490 g) in methanol (10 mL) at room temperature, and the resultant mixture was stirred in a hydrogen atmosphere for 4 hours. After the reaction atmosphere was purged with nitrogen, insoluble matter was removed by filtration. The solvent of the filtrate was evaporated under reduced pressure, and diethyl ether was added to the residue, and then the precipitated solid was recovered by filtration, to thereby give the title compound (1.045 g, 96%).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.Cl.[C:15]([NH2:23])(=[NH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[K+]>O1CCCC1.O>[C:16]1([C:15]2[NH:22][C:2]([CH3:13])=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(Br)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
A solution of 86.6 g (0.307 mol) of the above-mentioned crude 2-bromo-3′,4′-dichloropropiophenone in 120 ml of tetrahydrofuran was added dropwise over 40 minutes into a suspension, under reflux with heating, of 48.1 g (0.307 mol) of benzamidine hydrochloride, 123.4 g (1.23 mol) of potassium bicarbonate in 450 ml of tetrahydrofuran and 110 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 65.3 g (71.3% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCC(CCCN)Oc1cccnc1
Product: CCOC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1

Procedure:
Ethyl 8-amino-5-(3-pyridyloxy)-octanoate is condensed with p-chlorophenylsulfonyl chloride according to methodology previously described to yield ethyl 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoate which is purified by chromatography on silica gel using 7:3 ethyl acetate/hexane as eluent; 1H-NMR (CDCl3): delta 8.26 (br,1H), 8.20 (br,4H), 5.23 (t,1H), 4.28 (m,1H), 4.08 (q,2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[OH:42]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[OH:42])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Compound 37 (1 g, 3 mmol) was dissolved in THF (100 mL). K2CO3 (2 g, 15 mmol) was added followed by 2-amino-5-nitro-phenol (693 mg, 4.5 mmol). The reaction mixture was allowed to stir at room temperature overnight. K2CO3 was filtered off though filter paper. The solvent was removed under reduced pressure. Liquid-liquid extraction was performed using CHCl3 (100 mL) and H2O (50 mL). The organic layer was dried over MgSO4. After MgSO4 was filtered off, the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give compound 39 (786 mg, 55.7% isolated yield). LC-MS (ESI): m/e=471.1 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][C:12]([CH3:16])([CH3:15])[S:11]1.[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[N:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:13][C:12]([CH3:16])([CH3:15])[S:11]1
Reactant: CC(C)CBr
Reactant: CC1(C)CNC(=Nc2cccc(Cl)c2Cl)S1
Product: CC(C)CN1CC(C)(C)SC1=Nc1cccc(Cl)c1Cl

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C1a to afford 2-(2,3-dichlorophenylimino)-5,5dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2,3-dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:27][S:2]([CH3:1])(=[O:4])=[O:3])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.94 ml) was added to a solution of ethyl 3-(4-benzyloxyphenyl)lactate (3.32 g), which is the product of Reference example 1(b), in anhydrous dichloromethane (30 ml). To this mixture triethylamine (2.47 ml) was added dropwise in an ice bath. The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to afford the desired product (3.60 g) as colorless crystals.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O.[Zn]>[CH:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][N:8]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)C(C2CCCCC2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CCN(C(=O)OCc2ccccc2)C(C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Benzyl 2-cyclohexyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (35.25 g, 112 mmol) was dissolved in AcOH (450 ml) and added zinc dust (22.07 g, 337 mmol). The solution stirred at room temperature for 12 hours. The solution was filtered through celite and washed with EtOAc. The solvent was evaporated under reduced pressure and the product was purified by column chromatography on silica gel 30% EtOAc/Hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][C:41]1[CH:42]=[C:43]([CH:48]2[CH2:53][NH:52][CH2:51][CH:50]([NH:54][C:55](=[O:62])[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH2:49]2)[CH:44]=[CH:45][C:46]=1[CH3:47]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:40][C:41]1[CH:42]=[C:43]([CH:48]2[CH2:49][CH:50]([NH:54][C:55]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)=[O:62])[CH2:51][N:52]([C:13]([C:9]3([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:53]2)[CH:44]=[CH:45][C:46]=1[CH3:47]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: Cc1ccc(C2CNCC(NC(=O)c3ccccc3)C2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CCC3)C2)cc1C
Reaction time: 8 h

Procedure:
62 mg (0.3 mmol) of 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid together with 110 mg (0.3 mmol) of HATU and 47 mg (0.4 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 60 mg (0.2 mmol) of N-[-5-(3,4-dimethylphenyl)piperidin-3-yl]benzamide were added. The reaction mixture was stirred overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 54 mg (55% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+].CNCCNC.C(OCC)(=O)C>CS(C)=O.O>[CH3:11][S:12]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1)(=[O:14])=[O:13]
Reactant: COc1cc(Br)ccc1O
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(S(C)(=O)=O)ccc1O
Temperature: 130 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (500 mg, 2.46 mmol), sodium methanesulfinate (1 g, 9.84 mmol), copper(I) trifluoromethanesulfonate benzene complex (124 mg, 0.25 mmol) and N,N′-dimethylethylenediamine (53 μL, 0.49 mmol) in dimethyl sulfoxide (3 mL) was stirred overnight at 130° C. The mixture was allowed to cool to room temperature followed by the addition of ethyl acetate (8 mL) and water (8 mL). The resulting mixture was filtered through Celite pad and to the filtrate was added 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1) to give the title compound as a white crystal (258 mg, yield 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15](Br)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([CH:29]=[O:30])[CH:21]=1>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.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][C:22]=2[CH:29]=[O:30])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)[nH]1
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Cl)cc2C=O)[nH]1
Temperature: 85 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g, 6.32 mmol), 4-Chloro-2-formyl-phenylboronic acid (1.17 g, 6.32 mmol), Pd(PPh3)4 (365 mg, 0.316 mmol), Pd(dppf)C12-DCM (258 mg, 0.316 mmol) K2CO3 (2 M, 6.3 mL, 12.6 mmol) and DME (30 mL) were combined in a round bottom flask. The stirred suspension was degassed for 10 minutes with bubbling N2 then heated to 85° C. After 4 h, the reaction mixture was poured into saturated aqueous NaHCO3. The aqueous phase was extracted 3× with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hexane) to afford the title compound 2-[5-(4-Chloro-2-formyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.85 g, 78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[C:10]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[N:9]2[N:8]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:15][CH:14]1[N:9]2[N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:16]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:10]2[CH2:11][CH2:12][CH2:13]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CCCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21
Solvent: c1ccncc1
Product: CC(=O)OC1CCCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21

Procedure:
A solution of 2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidin-7-ol (0.04 g, 0.12 mmol) and acetic anhydride (0.2 mL) in pyridine (2 mL) at room temperature is stirred for 24 h. The mixture is partitioned between ethyl acetate and water. The organic portion is washed with water and brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (5% methanol/dichloromethane) to yield the title compound, 0.41 g (91%), as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O>CN(C=O)C>[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([N:24]3[CH2:23][CH2:22][CH:21]([NH2:20])[CH2:26][CH2:25]3)=[O:7])=[CH:4][CH:3]=2)=[O:11])[CH2:23][CH2:22]1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Product: NC1CCN(C(=O)c2ccc(C(=O)N3CCC(N)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of terephthaloyl chloride (1.02 g, 5.0 mmol) in DMF (10 mL) under an inert atmosphere of argon is treated dropwise with a solution of 4-(N-Boc-amino)piperidine (2.00 g, 10.0 mmol) over 20 minutes. The reaction mixture is allowed to stir at room temperature for 40 minutes and then TEA (2.09 mL, 15.0 mmol) is added dropwise. A white suspension forms and stirring continues for 2 hours. The resulting mixture is washed with saturated NaHCO3 solution (50 mL) and water (100 mL). The resulting mixture is filtered under vacuum using phase separating paper to afford a white solid. The solid is dried under vacuum at 45° C. to yield the required product. [M+H]+ 531
Reaction SMILES: [C:1](=[N:4][O:5][CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])([CH3:3])[CH3:2].[OH-].[Na+].Cl>>[C:1](=[N:4][O:5][CH:6]([CH3:12])[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)ON=C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=NOC(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The ethyl α-(isopropylideneaminooxy)propionate was added to 5% NaOH solution (1.2 L) at 70° C. After 20 min, the solution was cooled to rt and acidified to pH 2.0 with 5N HCl solution. Then to the solution was added (NH4)2SO4 (500g) and the mixture was extracted with 1:1 benzene:Et2O (2×300 mL). The combined organic extracts were dried over Na2SO4 and concentrated to approximately 200 mL. Petroleum ether (500 mL) was added and the solution was cooled to −20° C. overnight. The recrystallized product was recovered by filtration. 80g of product 2 was recovered as a white solid (37%). 1H NMR (CDCl3): δ 4.64 (q, 1H, J=6.9 Hz, CH), 1.93 (s, 3 H, CH3), 1.90 (s, 3 H, CH3), 1.50 (d, 3H, J=6.9 Hz, CH3); M.p. 59-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=O)[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.[CH3:39][O:40][CH:41]1[CH2:44][NH:43][CH2:42]1.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][N:43]2[CH2:44][CH:41]([O:40][CH3:39])[CH2:42]2)[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:32][CH2:33]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCC=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COC1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCN4CC(OC)C4)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg, 0.076 mmol) was taken up in THF (0.5 mL) and a solution of 3-methoxyazetidine (9.92 mg, 0.114 mmol) in MeOH (0.2 mL) was added, followed by a drop of AcOH and sodium cyanoborohydride (9.54 mg, 0.152 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and washed with water, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOH/DCM; 24 g column). 2-((2-chloro-5-cyano-4-(3-(3-methoxyazetidin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was obtained as a colorless glass.