Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.C(S(F)(F)([F:32])(CC)N)C>ClCCl>[F:32][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:9][O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(O)c2ccccc2F)CC1
Reactant: CCS(N)(F)(F)(F)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 18 g of tert-butyl {trans-4-[2-(2-fluorophenyl)-2-hydroxyethoxy]-cyclohexyl}carbamate in 200 mL of dichloromethane was added over 30 min to a solution of 23 g of diethyl-amino sulfur-trifluoride in 800 mL of dichloromethane cooled to −78° C. under nitrogen atmosphere. The mixture was allowed stir for 1 h at −78° C. then quenched with 100 mL of saturated sodium carbonate. After stirring for 15 min the layers were separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-25% ethyl acetate in hexane gave 12 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.45 (m, 1H), 7.3 (m, 1H), 7.2 (m, 1H), 7.06 (m, 1H), 5.15 (dm, JH-F=48 Hz), 4.18 (br s, 1H), 3.65 (complex m, 2H), 3.42 (br s, 1H), 3.3 (m, 1H), 2.0 (d, 4H), 1.42 (s, 9H), 1.4 (q, 2H), 1.15 (q, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2cccs2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (60.9 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH2Cl2 was added 2-thiophenecarbonyl chloride (97%, 39.2 mg, 1.2 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded thiophene-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 15 (82.1 mg, 98%). LRMS 300 (M-100)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]([OH:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Cl)[N:30]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH:16]([O:27][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[N:30]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(Cl)n2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 56 mg, 1.4 mmol) in DMF (2.3 mL) was added 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.696 mmol) followed by 2,6-dichloropyridine (309 mg, 2.09 mmol). The mixture was heated to 90° C. for 2 h then concentrated in vacuo. Aqueous work-up and purification gave 4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a colourless foam (313 mg, 95%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][C:48]=2[S:50](Cl)(=[O:52])=[O:51])[CH:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:50]([C:48]1[CH:47]=[CH:46][CH:45]=[C:44]3[C:49]=1[N:40]=[CH:41][CH:42]=[CH:43]3)(=[O:51])=[O:52])[C:12](=[O:17])[C:11]2([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)Nc3ccc(Cl)cc32)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)N(S(=O)(=O)c3cccc4cccnc34)c3ccc(Cl)cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
Potassium tert-butoxide (26.6 mg, 0.24 mmol) was added to a solution of 5-chloro-3-(2,4-dimethoxyphenyl)-3-(4-pyridin-4-ylpiperazin-1-yl)-1,3-dihydroindol-2-one (0.10 g, 0.22 mmol) in dimethylformamide (4 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hour. Then 8-quinolinesulfonyl chloride (53.9 mg, 0.24 mmol) was added to the reaction solution while cooling in ice, and the mixture was stirred at room temperature for 12 hours. Water was cautiously added to the mixture, which was extracted twice with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification of the residue on silica gel (mobile phase gradient 0-7% methanol in dichloromethane) afforded 57.0 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1cccs1)c1ccc(-c2ccccc2)cc1
Yield: 54.8 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 4-biphenylcarbonyl chloride (120 mg, 0.55 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave biphenyl-4-carboxylic acid (2-thiophen-2-yl-ethyl)-amide (70 mg, 0.23 mmol, 55% yield) as a grey powder after crystallisation in hexane/EtOAc.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[C:29]([CH3:35])[C:28]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:28]4[C:29]([CH3:35])=[C:30]([CH3:34])[CH:31]=[C:32]([CH3:33])[C:27]=4[CH3:26])(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cc(C)c(C)c(S(=O)(=O)Cl)c1C
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4c(C)c(C)cc(C)c4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,3,5,6-tetramethylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(=O)(O)O.C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5]([CH:6]=[N:20][C:21]([NH2:23])=[N:22]2)=[C:4]([F:11])[CH:3]=1
Reactant: N=C(N)N
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1ncc2c(F)cc(Cl)cc2n1
Temperature: 140 °C
Yield: 62.7 %

Procedure:
To a stirred suspension of 4-chloro-2,6-difluorobenzaldehyde (45 g, 255 mmol) in DMA (360 mL), at room temperature under nitrogen was added guanidine bis(carbonate) (70.0 g, 382 mmol). The mixture was heated to 140° C. for 3 hours. The reaction was then cooled to room temperature followed by addition of 400 mL water with stirring. The mixture was then filtered. The solids were then collected and triturated in 200 mL methanol for 10 minutes, then filtered. These solids were then dried in vacuo to obtain 31.6 g (63%) of 7-chloro-5-fluoroquinazolin-2-amine (82a) as a brown solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:27]([CH2:35][CH3:36])[CH2:28][CH:29]1[CH2:32][CH:31]([CH:33]=O)[CH2:30]1)[CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:33][CH:31]1[CH2:32][CH:29]([CH2:28][CH:27]([CH2:25][CH3:26])[CH2:35][CH3:36])[CH2:30]1
Reactant: CCC(CC)CC1CC(C=O)C1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(CC)CC1CC(C=C(Br)Br)C1
Reaction time: 0.33 h

Procedure:
To a solution of carbon tetrabromide (27.0 g) in methylene chloride (27 mL) was added dropwise a solution of triphenylphosphine (42.8 g) in methylene chloride (85 mL) at ice temperature. The mixture was stirred at ice temperature for 20 min., and then to the mixture was added dropwise a solution of 3-(2-ethylbutyl)cyclobutanecarbaldehyde in methylene chloride at ice temperature. After stirring at ice temperature for 40 min., saturated aqueous sodium bicarbonate (250 mL) was added dropwise to the mixture. The aqueous layer was removed, and the organic layer was washed with water (50 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. To the residue were added hexane/chloroform=1/1 (100 mL), silica gel (50 g) and hexane (300 mL). The mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added hexane (300 mL), and the mixture was filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: hexane) to give the title compound (9.78 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[F:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=1[S:33]([CH3:36])(=[O:35])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[N:6]([C:30]2[CH:29]=[CH:28][C:27]([S:33]([CH3:36])(=[O:34])=[O:35])=[C:26]([F:25])[CH:31]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)c(F)c3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A suspension of tert-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (400 mg, 1.22 mmol), sodium hydride (60 wt % in mineral oil, 58 mg, 1.5 mmol) and DMF (8 mL) was purged with argon and then stirred at room temperature for 20 minutes. To the reaction was added 2,4-difluoro-1-(methylsulfonyl)benzene (351 mg, 1.83 mmol) and then heated at 130° C. for 1 hour. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 321 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.07-8.14 (m, 1H) 7.35-7.47 (m, 3H) 6.01 (s, 1H) 4.57-4.64 (m, 1H) 3.60-3.69 (m, 2H) 3.44-3.55 (m, 2H) 3.26 (s, 3H) 1.93-2.03 (m, 2H) 1.83-1.93 (m, 2H) 1.49 (s, 9H). MS (ESI) 445 (M−56+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.Cl.[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: Clc1cnnc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1Nc1cnnc(Cl)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
3,5-dichloropyridazine (1.6 g, 10.74 mmol), ethyl (cis)-2-aminocyclohexanecarboxylate hydrochloride (CA, 2.454 g, 11.81 mmol), and triethylamine (5.63 mL, 32.2 mmol) were added to DMSO (10.0 ml) and heated for 5 hrs at 120° C. and then allowed to stir at room temperature for 24 hr. Solvents were removed in vacuo. The residue was dissolved in EtOAc and then poured into sat. sodium bicarb. The aqeuous layer was removed and back extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated to an oil. Purification on biotage again (DCM:MeOH, 0-9% B) and concentration afforded the product, I-22a, as a solid (2.207 g, 71.7%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][N:8]2[C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3ccc(Br)cc32)cc1

Procedure:
(17.4 mg, 48%); from 6-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4f, 25.0 mg, 0.086 mmol) and 4-methoxybenzoyl chloride (26 uL, 0.17 mmol); HRMS-FAB+ for C22H21O2N2Br, calculated MH+ : 425.08646; found: 425.08292.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:38])=[C:4]([N:8]([CH2:16][C:17]2[CH:37]=[CH:36][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=3)[O:25][CH2:26][C@H:27]3[NH:31][C:30](=[O:32])[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH2:9]([N:8]([CH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:35]=[CH:34][CH:33]=[C:24]([O:25][CH2:26][C@@H:27]3[CH2:28][CH2:29][C:30](=[O:32])[NH:31]3)[CH:23]=2)=[CH:19][CH:18]=1)[C:4]1[C:3]([CH3:38])=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@@H]3CCC(=O)N3)c2)cc1
Solvent: c1ccncc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@@H]3CCC(=O)N3)c2)cc1
Reaction time: 3 h

Procedure:
The dried product from example 278B was dissolved in anhydrous pyridine (3 mL) at 0° C. for 30 minutes. Then methanesulfonyl chloride (50 μL, 6 mmoles) was injected. The reaction mixture was let to stand at room temperature for 3 hours. Then the reaction mixture was dried in vaccuo, dissolved in CH2Cl2 (4 mL), filtered and dried in vaccuo. The final residue was purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 7.76 (s, 1 H), 7.27 (m, 7 H), 7.20 (m, 1 H), 7.04 (m, 1 H), 6.95 (m, 4 H), 6.71 (m, 1 H), 6.53 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.92 (m, 1 H), 3.82 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.04-2.29 (m, 3 H), 1.80 (m, 1 H); MS (APCI+) m/z 586 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[N:11]([C:17]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:13][C:14]=3[C:15]#[N:16])=[CH:4][CH:3]=1.[OH2:24]>CS(C)=O.ClCCl>[NH2:9][C:10]1[N:11](/[C:17](=[N:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:24])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: O
Reactant: N#Cc1cnn2c(NC3CCCC3)c(-c3ccc(Br)cc3)[nH]c12
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cnn(/C(=N/C2CCCC2)C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A dilute solution of 2-(4-bromophenyl)-3-(cyclopentylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (500 mg, 1.35 mmol) in DMSO (100 mL) was stored at RT for more than 60 days. The yellow DMSO solution was poured into water (1 L) and the organic compound was extracted into ethyl acetate (2×75 mL). The combined extracts were washed with water and brine solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give the crude yellow solid which was not soluble in dichloromethane even at hot condition. Then, after cooling to RT, the solids were collected by filtration and washed with dichloromethane and the 1H NMR of this solid indicated that it is mostly starting material. Whereas, the mother liquor was removed under vacuum and the crude residue was purified using an ISCO (80 g) column eluting with 0-35% ethyl acetate in hexanes. The pure fractions were combined and the solvent was removed under vacuum to obtain 113 mg (21.7% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(4-bromophenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.80 (br m, 8H), 3.63 (p, 1H), 7.72 (s, 1H), 7.78 (d, J=6.1 Hz, 2H), 7.83 (d, J=6.2 Hz, 2H), 8.14 (br s, 2H). LC/MS calcd. for C17H16BrN5O (m/e) 386.25, obsd. 387.2 (M+H, ES+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([N:13]([CH3:33])[C:14](=[O:32])[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([CH3:17])[CH3:16])=[C:9]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:15]([CH3:16])([CH3:17])[C:14]([N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:3]3)=[CH:8][C:9]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:33])=[O:32])[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 620 mg (1.06 mmol) (R)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 6 ml dichloromethane were added 7 mg (0.05 mmol) 4-(N,N-dimethylamino)pyridine, 275 mg (2.13 mmol) N,N-diisopropylethylamine and 158 mg (1.38 mmol) methanesulfonyl chloride at room temperature. After stirring for 18 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 618 mg (88%) of the title compound as an off-white foam.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13].Cl>O>[Cl:10][CH2:11][C:12]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)CCl)C(=O)O
Temperature: 5 °C
Yield: 62.4 %

Procedure:
To a stirring mixture of 2-aminoisobutyric acid (165.8 g; 1.61 mol), sodium hydroxide (64.4 g; 1.61 mol) and 800 mL water, cooled to 5° C., was added chloroacetyl chloride (200 g; 1.77 mol) and then a solution of sodium hydroxide (70.8 g; 1.77 mol) in 143 mL water. The temperature was maintained between 5 to 10° C. during the additions. The reaction mixture was then allowed to warm to room temperature and the solution was acidified with 165 mL of concentrated aqueous HCl. The precipitated solid was filtered and dried under vacuum to afford 180.4 g (62%) of product.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Li].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1C(Cl)=O.Cl>C1COCC1>[O:5]=[C:3]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)[CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)c1cnccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cnccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diethyl malonate (1.25 ml, 1.32 g) in THF (20 ml) under an atmosphere of nitrogen at −60° C. was added nbutyl lithium (2.5 M, 9 ml) dropwise over 15 min, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 min, the reaction was cooled to −78° C., when a solution of pyrazine-2-carbonyl chloride (0.5 g, dark purple solution in THF (10 ml)) was added dropwise over 15 min. The reaction then warmed to −45° C. and stirred for 1 h. The reaction was then poured into 1M HCl solution (35 ml) with stirring. This was transferred to a separating funnel, and extracted with CH2Cl2 (2×150 ml). The combined organic layers were then washed with sat. NaCO3 soln (1×30 ml) and then dried over MgSO4, filtered and concentrated in vacuo to give the product as a brown oil. Yield 0.65 g, 45%.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[CH3:33][N:34]([C@@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)C(=O)OC(C)(C)C>>[CH3:33][NH:34][C@@H:42]1[CH2:46][CH2:45][N:44]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:43]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2cc(N3Cc4cc(-c5cnn(C)c5)ccc4CC3C)nc(N)n2)C1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate. LCMS (M+H)+: m/z=419.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-bromophenol (10 g). To the mixture were added potassium carbonate (10.4 g) and bromopropane (6.0 ml), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-3-propoxybenzene (11.2 g).