Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCC(OCc2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC(OCc2ccccc2)C1
Reaction time: 3 h

Procedure:
To a solution of 3-(benzyloxy)cyclopentanol (530 mg) in dichloromethane (8 mL) is added at 0° C. 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-on (Dess-Martin periodinan, 8 mL of a 15% solution in dichloromethane). The mixture is stirred for 3 hours, diluted with dichloromethane, washed with 1 M aqueous NaOH solution and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (petrole ether/ethyl acetate 90:10→40:60) to give the title compound. Yield: 430 mg; LC (method 7): tR=0.90 min; Mass spectrum (ESI+): m/z=191 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][C:3]=1[Cl:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:24][C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)[CH:22]=[CH:23][C:2]=1[NH:1][C:39]([C:34]1[C:33](=[O:42])[N:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[C:37]([CH3:38])=[CH:36][CH:35]=1)=[O:40]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2Cl)c(=O)n1-c1ccc(F)cc1
Yield: 93.6 %

Procedure:
Using N-[6-(4-amino-3-chlorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (160 mg, 0.467 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (150 mg, 0.607 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (161 μL, 0.934 mmol) and HATU (230.8 mg, 0.607 mmol) and in the same manner as in Example 60, the title compound (250 mg, 94%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)[CH:2]=[CH2:3].[Si](I)(C)(C)C>C(#N)C>[CH2:1]([O:4][C@@H:5]1[CH2:6][NH:7][CH2:8][C@H:9]1[NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: C=CCO[C@@H]1CNC[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl rel-(3R,4R)-3-(allyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate (575.6 mg, 1.13 mmol) in acetonitrile (5 mL) at 0° C. was added TMSI (1.3 mL, 9.04 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and room temperature for 3 h. The reaction was quenched by adding HCl (1N, 15 mL). The mixture was extracted from with EtOAc (15 mL×3). The aqueous phase was neutralized with NaOH (1N) to pH=10. DCM/isopropanol (4:1, 10 mL×3) was used to extract from the aqueous layer. The organic layers then were combined, dried over MgSO4, filtered, concentrated under reduced pressure to afford rel-N-(2-{[(3R,4R)-4-(allyloxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide which was used without further purification (115.6 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]34[CH2:22][CH:20]([CH2:21]3)[O:19][C:18](=[O:23])[NH:17]4)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:24].[NH+]1C=CC=CC=1>C1COCC1>[Br:24][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH2:21][CH:20]([CH2:22]2)[O:19][C:18](=[O:23])[NH:17]3)=[CH:12][CH:11]=1)=[O:9]
Reactant: Br
Reactant: O=C1NC2(c3ccc(C(=O)Cc4ccccc4)cc3)CC(C2)O1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C1NC2(c3ccc(C(=O)C(Br)c4ccccc4)cc3)CC(C2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(4-phenylacetyl-phenyl)-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (2.34 g) and pyridinium hydrobromide perbromide (2.22 g) in THF (39 mL) was stirred at rt for 2 hours. The mixture was partitioned between EtOAc and water and the organic phase washed successively with dilute aqueous sodium thiosulfate and brine, dried and concentrated to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[CH2:2]([C:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:23])=[CH:8][CH:9]=2)(=[O:14])=[O:15])[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: Cc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: C#CCCCI
Product: C#CCCCC1(S(=O)(=O)c2ccc(C)cc2)SC(=O)NC1=O

Procedure:
In the manner of Example 100 above, 5-iodo-1-pentyne is reacted with 5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione to give the title compound, mp 226° C., THEORY: C, 53.4, H, 4.48, N, 4.15. FOUND: C, 53.3, H, 4.58, N, 4.13.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[O:70]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(OC(C)C)(C)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[OH:70])/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([OH:53])=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(/C=C/Cn2cnc3cc(O)c(O)cc32)CS[C@@H]2C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)O)=C(/C=C/Cn4cnc5cc(O)c(O)cc54)CS[C@H]23)cs1
Temperature: 25 °C
Yield: 13 %

Procedure:
Diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(E)-(5,6-dihydroxybenzimidazol-1-yl)-1-propen-1-yl]-3-cephem-4-carboxylate (XIb) (125 mg was dissolved in trifluoroacetic acid (TFA, 1.2 ml), stirred at room temperature for an hour and diluted with isopropyl ether to precipitate 63 mg of a crude product. The product was chromatographed on a column of Prep C18 (Waters) with water and 5% acetonitrile in water as eluants. The desired fractions, checked by HPLC*, were combined, concentrated to a small volume and freeze-dried to afford 7 mg (13% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:4][CH2:3]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2ccc3ccccc3n2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in DMSO (50 ml) was treated with 50% sodium hydride dispersion (2 g, 40 mM) and warmed to 80° until a homogenous solution was obtained. After cooling to room temperature, the mixture was treated with a solution of 2-chloroquinoline (6.55 g, 40 mM) in DMSO (10 ml). After 24 hours the mixture was poured on to water (250 ml) and extracted with toluene (3×250 ml). After drying and evaporation of the solvents, the residue crystallised from cyclohexane to give recovered 1-methyl-4-phenyl-4-piperidinol (2.7 g). Chromatography of the mother liquors on Grade III silica, using 3% methanol in chloroform as eluant gave the title compound (3 g) contaminated with a small quantity of 2-quinolone which was removed by crystallisation from cyclohexane. Recrystallisation of the mother liquors from pentane gave the title compound (1.2 g) m.p. 80°-1° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CCN(CC)CC>ClCCl>[CH3:20][S:21]([O:12][CH2:11][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(COS(C)(=O)=O)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of 2,2-bis(3-bromophenyl)propane-1,3-diol (6.0 g, 15.54 mmol) in dichloromethane (50 mL) at 0° C. was added methanesulfonic chloride (27.1 g, 155 mmol) and Et3N (17.3 mL, 124 mmol) to give an orange solution. The reaction mixture was stirred at 0° C. for 1 h, then at 40° C. for 8 h. The reaction was washed with aq. NH4Cl (80 mL). The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried and concentrated. The residue was purified by chromatography (on silica gel column, Petroleum ether: EtOAc=2:1) to afford 3.2 g of the title compound (5.9 mmol, 38%). LC/MS: [M+18]=560. 1HNMR (CDCl3), 400 MHz: δ 2.93 (s, 6H), 4.49 (s, 4H), 7.15-7.48 (m, 8H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:34])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]=[C:18]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22](=[O:29])[NH:21][C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]3=4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:37]([N:21]1[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18](=[CH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)([OH:34])[CH2:10][CH2:11]2)[C:19]2[CH:33]=[CH:32][CH:31]=[CH:30][C:20]1=2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol hydrochloride (Example 39)(300 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 200 mg), benzyl bromide (0.15 ml) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the titled compound (180 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[O:14][C:13]1=[O:21])CC1C=CC=CC=1.C>CO>[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[O:14][C:13]1=[O:21]
Reactant: CN(CCn1c(=O)oc2cccnc21)Cc1ccccc1
Solvent: CO
Product: CNCCn1c(=O)oc2cccnc21
Temperature: 25 °C

Procedure:
In a 1,000-cm3 ground-necked flask, 0.02 mol of 3-[2-(N-methyl-N-benzylamino)ethyl]-3H-oxazolo[4,5-b]pyridin-2-one is dissolved in 250 cm3 of methanol. 0.2 g of palladinized charcoal is introduced and the mixture is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure. After absorption of the theoretical quantity of hydrogen, the reaction medium is filtered. The filtrate is concentrated on a water bath under vacuum and acidified with a stream of gaseous hydrochloric acid. The precipitate obtained is drained, dried and recrystallized.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1(C)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(Br)c1
Yield: 78.5 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 17.3 g (0.1 mole) of 3-bromophenol, 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 19.8 g (70%) of white solid, mp 90°-91.5° C. (benzene).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([S:36]C2CCCCC2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[Na]>CN(C)C=O>[CH:30]1([S:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCC(SC2CCCCC2)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSC4CCCCC4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.2g) and sodium cyclohexylsulfide (0.08g) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—(cyclohexylthiomethyl)-phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 53) (0.199) as colorless crystals.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([S:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O)(=[O:18])[CH3:17].C([O:35][C:36](=[O:44])[CH2:37][NH:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(Cl)Cl.C(#N)C>[C:16]([S:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:38]([CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH2:37][C:36]([OH:44])=[O:35])=[O:24])(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: COc1cccc(C(=O)O)c1SC(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1SC(C)=O
Reaction time: 8 h

Procedure:
N,N'-Dicyclohexylcarbodiimide (10.3 g, 50 mmol) in methylene chloride (80 ml) was added to 2-acetylthio-3-methoxybenzoic acid (11.3 g, 50 mmol) and N-cyclopentylglycine t-butyl ester (10.0 g, 50 mmol) in methylene chloride (300 ml) at 0°-5° C. Overnight stirring was followed by filtration and washing of the filtrate with dilute hydrochloric acid, sodium bicarbonate solution and brine. Dryng and concentration gave a gum which was dissolved in acetonitrile (65 ml), combined with sodium iodide (11.2 g, 75 mmol) and heated to 40°-50° C. Chlorotrimethylsilane (8.1 g, 75 mmol) was introduced and the mixture was heated for 30 minutes, then quenched with water. The organic phase was washed with water, aqueous sodium thiosulfate and brine then concentrated. Aqueous sodium bicarbonate was added to the residue and the resulting solution was washed with methylene chloride and ether, then acidified and extracted with ethyl acetate. The organic portion was dried and concentrated and the residue passed through a silica gel column to provide the amorphous product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 135.6 %

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-L-tyrosine (5.00 g), methyl chloroacetate (1.45 g) and potassium carbonate (1.85 g) in N,N-dimethylformamide (75 ml) was stirred for 20 hours at room temperature. The mixture was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and then brine. After dried over magnesium sulfate, the extract was evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosine (6.40 g), mp. 69°-73° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.[CH3:39][N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>FC(F)(F)CO>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH3:50])[CH3:39])=[O:49])[CH2:48][CH2:47]3)=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=2)=[N:15][CH:16]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(CC(=O)N(C)C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 82.7 %

Procedure:
DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 207 mg, 0.5 mmol) and N,N-dimethyl-2-piperazin-1-ylacetamide (86 mg, 0.50 mmol) in 2,2,2-trifluoroethanol (2.5 mL). The mixture was heated in a microwave at 140° C. for 1 h then cooled to r.t. The mixture was purified directly by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia to provide crude product after concentration of appropriate fractions. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (234 mg, 83%) as an orange foam; 1H NMR: (CDCl3) 2.71-2.78 (4H, m), 2.97 (3H, s), 3.09 (3H, s), 3.11-3.18 (4H, m), 3.26 (2H, s), 3.99 (3H, s), 6.66 (1H, s), 6.97 (1H, td), 7.35-7.42 (1H, m), 7.52 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.56 (1H, d), 8.92 (1H, s), 9.02 (1H, s); m/z: ES+ MH+ 566.52.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([O:26][CH2:27]C)=[O:25])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[C:21]([O:2][CH3:1])[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][N:18]=2)[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1OC
Yield: 82.4 %

Procedure:
To a methanol solution (50 ml) of 1.88 g (34.8 mmol) of sodium methoxide, a methanol solution (40 ml) of 10.1 g (28.0 mmol) of ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-carboxylate (the compound synthesized in Referential Example 63) was added dropwise over 10 minutes. The resultant mixture was stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure and water was added, followed by extraction with chloroform. After drying the chloroform layer with MgSO4, chloroform was distilled off under reduced pressure and the residue was recrystallized from methanol-ethyl acetate to obtain 7.9 g of the above-identified compound (yield: 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]3([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41]3)[CH:37]=[CH:38][CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:38]5[CH:37]=[C:36]([C:40]6([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41]6)[CH:35]=[CH:34][CH:39]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)C1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: [Na+]
Solvent: COCCOC
Product: COC(=O)C1(c2cccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc3C)c2)CC1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (93 mg, 0.26 mmol) was dissolved in 1,2-dimethoxyethane (2.5 mL) in a reaction tube. Methyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (100 mg, 0.33 mmol), aqueous 2 M sodium carbonate (0.25 mL), and (Ph3P)4Pd (15 mg, 0.013 mmol) were added and the reaction mixture was heated at 120° C. for 20 minutes in the microwave. The resulting material was cooled to room temperature, filtered, and evaporated under reduced pressure. The residue was purified by prep LC-MS to yield methyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylate, which was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[O:15][CH2:16][CH2:17][NH:18][C:19]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])#[N:11].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][C:19]([NH:18][CH2:17][CH2:16][O:15][C:14]2[CH:28]=[CH:29][CH:30]=[C:12]([C:10]#[N:11])[CH:13]=2)=[O:20])[CH2:23][CH2:24]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(C(=O)c3ccccc3)CC2)c1

Procedure:
175 mg (1.43 mmol) of benzoic acid, 430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide, 0.22 ml (1.58 mmol) of triethylamine, 213 mg (158 mmol) of 1-hydroxybenzotriazole and 303 mg (1.58 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 10 ml of dimethylformamide at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.