Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.ClC(OCC)=O.[NH3:29]>C(Cl)(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH2:29])=[O:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: N
Reactant: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reaction time: 0.5 h

Procedure:
18 g of trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]-cyclohexyl)cyclohexanecarboxylic acid were dissolved in 600 ml of chloroform while gassing with argon and the solution was treated dropwise at 0° C. while stirring within 3 minutes with a solution of 7.2 ml of ethyl chloroformate in 40 ml of chloroform. The reaction solution was stirred for a further 30 minutes. Ammonia gas was then conducted into the solution during 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes and then extracted twice with 300 ml of water each time. The aqueous phases were back-extracted with 100 ml of chloroform each time. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. Recrystallization of the brown crystalline crude product obtained (19 g) from 800 ml of methylene chloride gave 13 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]-cyclohexyl]cyclohexanecarboxamide as pale brown crystals.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([Cl:17])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1oc(Br)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
To a solution of 2-bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-38) (1.30 g, 5.0 mmol) in CH2Cl2 (25 mL) was added oxalyl chloride (8.5 mL, 10.0 mmol) and DMF (0.019 mL), respectively, at RT under a nitrogen atmosphere. The reaction was stirred for 6 h at RT. The solvent was concentrated, and the residue was dried in vacuo to yield 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) as yellow oil (1.30 g, 96% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([Cl:26])([F:25])[F:24])=[N:21][N:22]=2)[N:19]=1>>[Cl:26][C:23]([F:24])([F:25])[C:20]1[N:18]2[N:19]=[C:14]([N:10]3[CH2:9][CH2:8][N:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:12][CH2:11]3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: c1csc(CN2CCNCC2)c1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(Cc4cccs4)CC3)nn12
Yield: 74 %

Procedure:
A mixture of 1-(thiophen-2-ylmethyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(thiophen-2-ylmethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 74% yield.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39](Cl)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CCNC(=O)c1cn2nc(Cl)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.594 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-β-alanine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (370:30:4). The desired fraction was collected and recrystallized from ethyl ether to yield 0.347 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCCCC1>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CN1CCCCC1
Solvent: CS(C)=O
Product: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(N2CCOCC2)cc1
Reaction time: 24 h
Yield: 92.6 %

Procedure:
To a dimethylsulfoxide (0.5 ml) solution of the 1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene (40 mg, 0.095 mmol) obtained in Example 160 were successively added morpholine (0.012 ml, 0.14 mmol) and 1-methylpiperidine (0.017 ml, 0.14 mmol). The resulting mixture was allowed to stand at 80° C. for 24 hours. The reaction mixture was purified by preparative high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid). The resulting solid was washed with diethyl ether and collected by filtration, whereby the title compound (43 mg, 0.088 mmol, 92%) was obtained as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CC[O:25][CH2:24]C1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(O)=O>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][CH:24]=[O:25])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O=CO
Solvent: O
Product: N/C(=N\OC=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], formic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-(formyloxy)-2-piperidinecarboximidamide as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH4+].[Cl-]>CCOCC.CCCCC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COc1ccccc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccc1OC
Reaction time: 0.75 h

Procedure:
A solution of 27 g of 1-bromo-2-methoxybenzene in 270 ml of ether is cooled to −70° C. under an argon atmosphere, 90 ml of a 1.6 M solution of n-butyllithium in pentane are added dropwise and the mixture is then left stirring for 45 minutes. 78 ml of diethyl oxalate are added rapidly and the mixture is left stirring, while allowing the temperature to return to RT. After stirring for 1 hour at RT, saturated NH4Cl solution is added to the mixture, the phases are separated after settling has taken place, the aqueous phase is extracted with ether, the combined organic phases are washed with water and then with saturated NaCl solution and dried over Na2SO4, and the solvents are evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=87° C. at 2 000 Pa). The resulting product is chromatographed on silica gel, eluting with a DCM/hexane mixture (50/50; v/v) and then with DCM. The product obtained is purified by distillation under vacuum. 13 g of the expected product are obtained; b.p.=110° C. at 3 Pa.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][C:25]=1[CH3:32]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C)c3)CC2)cc1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
A mixture of (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (40 mg, 0.13 mmol) and 4-fluoro-3-methyl benzaldehyde (0.02 ml, 0.16 mmol), NaBH(OAc)3 (84 mg, 0.4 mmol) and CH3COOH (0.076 ml, 1.3 mmol) in DCM (10 ml) was heated at 110° C. (2 cycles of 5 min each) under microwave irradiation. The resulting mixture was purified by SPE-Si (2 g) eluting with a mixture DCM/AcOEt from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D29) (33 mg).
Reaction SMILES: [CH:1]1[C:5]2[C:6](Cl)=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[NH2:11][C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].Cl>C(O)(C)(C)C.CO>[CH3:20][O:19][C:17]([C:13]1[O:14][CH:15]=[CH:16][C:12]=1[NH:11][C:6]1[C:5]2[CH:1]=[CH:2][NH:3][C:4]=2[N:9]=[CH:8][N:7]=1)=[O:18]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: COC(=O)c1occc1N
Agent: Cl
Solvent: CO
Solvent: CC(C)(C)O
Product: COC(=O)c1occc1Nc1ncnc2[nH]ccc12
Yield: 17.9 %

Procedure:
A suspension of 6-chloro-7-deazapurine (100.00 mg; 0.65 mmol), methyl 3-amino-2-furoate (138 mg; 0.98 mmol) and concentrated hydrochloric acid (55 μL; 0.65 mmol) in tert-butanol (2 mL) was microwaved at 75° C. for 3 h. The reaction mixture was diluted with methanol (2 mL) and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid methyl ester (30 mg, 18%) as a white solid. (HPLC: 99%, RT: 5.43 min). 1H NMR (DMSO-d6) 12.03 (br s, 1H), 8.99 (br s, 1H), 8.40 (s, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.38 (dd, J=3.3, 2.2 Hz, 1H), 6.60 (dd, J=3.3, 1.8 Hz, 1H), 3.90 (s, 3H); MS (m/z) 259 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (80 mg, 0.299 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (151 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (151 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (21 mg). MS 394.2 (M+H); UV 201.1, 265.8, 297.2, 358.5 nm; t 0.451 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(Cl)Cl>[CH2:44]([O:43][C:41]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)Cl
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl ester 12 (0.45 g, 1.06 mmol) in CH2Cl2 (20 mL) at 0° C. was added Et3N (0.32 mL, 0.23 g, 2.33 mmol) and ethyl chloroformate (0.115 mL, 0.126 g, 1.16 mmol) and the mixture stirred at ambient temperature for 1 h. The mixture was washed with ice-chilled 0.1 N hydrochloric acid and the organic layer dried (Na2SO4) and evaporated to provide compound 39 as an off-white solid (0.52 g, 99%); 1H NMR (DMSO-d6): δ 0.86 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.40 (q, J=7.5 Hz, 2H), 4.17 (q, J=7.1 Hz, 2H), 6.51 (d, J=16 Hz, 1H), 6.87 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 7.10-7.16 (m, 3H), 7.18-7.22 (m, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.55 (d, J=16 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H); MS, m/z 521 (M+Na)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([N:40]([CH3:44])[C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:45][C:46]([F:51])([CH3:50])[C:47](O)=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([N:40]([CH3:44])[C:28]1[CH:29]=[CH:30][C:31]([NH:32][CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[C:26]([NH:25][C:47](=[O:48])[C:46]([F:51])([F:45])[CH3:50])[CH:27]=1)(=[O:43])[CH3:42]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(F)F)c1
Reaction time: 8 h

Procedure:
HATU (1.44 g, 3.78 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylacetamide (1.00 g, 3.60 mmol) (for preparation, see Example 1, steps B to E) were added to a solution of 2,2-difluoropropanoic acid (0.40 g, 3.60 mmol) and DIPEA (0.75 mL, 4.32 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred overnight. The solvent was concentrated and the crude product was recovered in EtOAc. The organic was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield: 1.00 g (75%); MS (ESI) (M+H)+: 370.2.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[C:22]2=[O:40])=[CH:17][CH:16]=1)C.CO>ClCCCl>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH:23]2[CH2:24][CH2:25][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:13])=[CH:16][CH:17]=3)[C:22]2=[O:40])[CH2:34][CH2:35]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccccc3N3CCN(C)CC3)C2=O)cc1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCCl
Product: CN1CCN(c2ccccc2CC2CCN(c3ccc(C(=O)N4CCOCC4)cc3)C2=O)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Trimethyl aluminum (2 M in toluene, 700 uL, 1.4 mmol) was added dropwise to a solution of morpholine (124 uL, 1.4 mmol) in 1,2-dichloroethane (4 mL) at 0° C. Upon completion of addition, the cold bath was removed and the solution was stirred 30 minutes at 23° C. A solution of 4-{3-[2-(4-methyl-piperazin-1-yl)-benzyl]-2-oxo-pyrrolidin-1yl}-benzoic acid ethyl ester (Example 2, 150 mg, 0.36 mmol) in 1,2-dichloroethane (2 mL) was then added and the solution was heated at 70° C. for ca. 18 hours. The solution was cooled to room temperature, methanol was carefully added to quench excess methyl aluminum species, and the mixture was then treated with sodium sulfate decahydrate (1.5 g). The mixture was stirred rapidly for 3 hours, the salts were filtered off, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (20:1 chloroform-methanol w/1% ammonium hydroxide) to afford 160 mg (96% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 176.28, 170.23, 152.12, 141.26, 135.00, 130.88, 130.52, 128.25, 127.71, 124.54, 120.84, 119.35, 67.14, 67.09, 55.90, 54.36, 52.97, 46.81, 46.36, 44.91, 32.48, 24.58; MS (AP/Cl) 463.2 (M+H)+. The enantiomers were separated by HPLC (60/40 heptane/ethanol; Chiralcel OJ, 10 cm×50 cm; 27.5 mL/min). Approximate retention times: t1=45 minutes; t2=60 minutes.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(O)(=O)C>C1C=CC=CC=1>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:14]=[C:15]([NH:16][C:2]([CH3:10])=[CH:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=CC(=O)OC(C)C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4.33 g (30 mmol) isopropyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 28] (0.037 g) in DCM (1.0 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g), HOBT (0.025 g) and triethylamine (0.026 ml) and the mixture was stirred at room temperature for 5 min. Morpholine (0.012 ml) was added and the resultant mixture stirred at room temperature for 15.5 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract was concentrated under reduced pressure and the residue was partially purified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:5) to give an impure sample of the title compound. This sample was repurified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:8) to give the title compound (0.036 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:29]COCC>CN(C)C=O.[Ag]=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH3:29])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: O=[Ag]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-hydroxy-pyrazolidine-1-carboxylic acid benzyl ester, 28, (2.55 g, 7.91 mmol) is dissolved in dimethylformamide (40 mL). Methyl iodide (1.97 mL, 31.6 mmol) is added followed by silver oxide (3.67 g, 15.8 mmol). The flask is cover with foil and stirred overnight in the absence of light. The reaction mixture is poured into ether (150 mL). The mixture is stirred vigorously at room temperature and filtered through a pad of Celite. The filtrate is washed with water (2×150 mL) and brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.58 g (97% yield) of the desired product as a yellow, clear oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCCC(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using 5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 118.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.88 min, m/z=473.1-474.1 [M+H]+, m/z=471.1-472.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.38 (m, 2H) 1.53-1.61 (m, 1H) 1.79-1.86 (m, 1H) 2.53 (s, 3H) 2.57 (dd, J=12.10, 9.17 Hz, 1H) 2.72 (t, J=10.51 Hz, 1H) 3.35-3.41 (m, 1H) 3.42-3.51 (m, 1H) 3.56-3.63 (m, 1H) 4.73 (d, J=4.40 Hz, 1H) 7.34-7.39 (m, 3H) 7.86 (d, J=8.80 Hz, 2H) 7.90 (dd, J=8.07, 2.20 Hz, 1H) 8.06 (d, J=2.20 Hz, 1H) 8.67 (d, J=1.96 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).