Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1>>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:59][C@@H:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[CH3:58])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1

Procedure:
(R)-4-Chloro-N-[1-(4-fluororhenyl)ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide. The title compound was prepared from the HATU-mediated coupling of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 3, Step B) and (R)-1-(4-fluorophenyl)ethylamine hydrochloride and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H18ClFN4O3S, 484.1; m/z found, 483 [M−H]−. HPLC (reverse phase): RT=9.95 min. 1H NMR (500 MHz, CDCl3): 11.40 (s, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=7.4, 1.4 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.30-7.27 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.08-7.04 (m, 2H), 6.91 (dd, J=8.4, 2.0 Hz, 1H), 6.11 (br d, J=6.5 Hz, 1H), 5.24-5.20 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=[O:18])=[N:14][C:15](Cl)=[O:16]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]1([CH:7]2[C:8]3[O:12][C:15](=[O:16])[NH:14][C:13](=[O:18])[C:9]=3[CH2:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CC2
Yield: 13.1 %

Procedure:
A solution of 2-phenylcyclopentanone (19.995 g, 125 mmol) and N-(chlorocarbonyl)isocyanate (23.70 g, 225 mmol) was stirred at 58° C. for 1 h and at 130° C. for 45 min. The resulting tarrified reaction mixture was dissolved in ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The product was purified by column chromatography on silica gel to give 7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g, 16.36 mmol, 13% yield) as brownish solid. LC-MS (M+H)+=230.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.34 (1H, br s), 7.35 (2H, t, J=7.3 Hz), 7.27-7.32 (1H, m), 7.18 (2H, d, J=7.3 Hz), 4.20 (1H, t, J=7.6 Hz), 2.82-2.91 (1H, m), 2.61-2.79 (2H, m), 2.11-2.21 (1H, m).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH4+:15].[OH-]>CCO>[NH2:15][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 5.2 mmol) in EtOH (20 mL) was added NH4OH (600 mg, 35.2 mmol) at −78° C. The reaction mixture was then warmed and heated at 100° C. for 3 h in a seal tube. The reaction mixture was concentrated and the crude product was used in next step without further purification. LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:13])[C:10]([N:39]1[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: F[C@@H]1CCNC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
(R)-2-tert-Butoxycarbonylamino-propionic acid (1.0 g, 5.3 mmol), 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide (2.33 g, 12.2 mmol) and hydroxybenzotriazole (1.64 g, 12.2 mmol) were dissolved in DMF (50 ml). (R)-3-Fluoropyrrolidine hydrochloride (1.66 g, 13.2 mmol) and N,N-diisopropylethylamine (2.95 ml, 16.9 mmol) were added and the mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the solution was washed with 10% citric acid solution three times. The organic layer was washed with sodium bicarbonate solution which was then back-extracted with ethyl acetate four times. The combined organic layers were then washed further with lithium chloride solution, sodium chloride solution, and dried over magnesium sulfate. Concentration of the solution gave 1.3 g (94%) of [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[CH3:17][N:18]1[C:22]([S:23][CH3:24])=[N:21][N:20]=[C:19]1[CH2:25][CH2:26][CH2:27][CH:28]=O.[BH4-].[Na+].C(Cl)[Cl:33]>ClCCCl.C(O)(=O)C.O>[ClH:33].[CH3:17][N:18]1[C:22]([S:23][CH3:24])=[N:21][N:20]=[C:19]1[CH2:25][CH2:26][CH2:27][CH2:28][N:11]1[CH2:12][C@H:13]2[C@:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1
Reactant: CSc1nnc(CCCC=O)n1C
Reactant: ClCCl
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CSc1nnc(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)n1C
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (40 mg) and 4-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]butanal (40 mg) in 1,2-dichloroethane (4 ml) sodium borohydride (76 mg) and acetic acid (20 μl) were added and the reaction mixture was stirred overnight at room temperature. Then an additional amount of 4-[4-methyl-5-(methylthio)-4H-1, 2,4-triazol-3-yl]butanal (48 mg), sodium borohydride (76 mg) and acetic acid (20 μl) were added and the stirring continued for 2 days then DCM and water were added to the reaction mixture. The solvent was removed under reduced pressure affording a crude product that was purified by chromatography to give the free base of the title compound. To a solution of this compound in DCM (1 mL) HCL 1N in diethylehter was added (0.12 mL) and the solvent removed under reduced pressure to give the title compound (67 mg) as a slightly hygroscopic solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[O:23])/[C:20](=[CH:24]/[C:25](Cl)=[O:26])/[O:19]1>>[CH3:17][C:18]1([CH3:28])[O:19][C:20](=[CH:24][C:25]([N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:26])[C:21](=[O:23])[O:22]1
Reactant: Fc1ccc(CNc2ccc(F)cc2)cc1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)c2ccc(F)cc2)O1

Procedure:
Acylation of (4-fluorobenzyl)-(4-fluorophenyl)-amine (Pombrik, S. I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 6, 1982, 1289-1294) with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in the preparation of Intermediate 71A gave the title amide as a syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s, CH3), 4.88 (2H, s, NCH2), 5.29 (1H, s, CH), 6.94 (4H, m, aromatics), 7.03 (2H, m, aromatics), 7.19 (2H, m, aromatics). HRMS (MAB N2) calculated for C20H17F2NO4 [M+]: 373.112565: found: 373.112320.
Reaction SMILES: NC1N=C(OCC)C2N=C(C3C=C(NS(C(C)C)(=O)=O)C=CC=3)C=CC=2N=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]3[N:45]=[C:46]([NH2:54])[N:47]=[C:48]([O:51][CH2:52][CH3:53])[C:49]=3[N:50]=2)=[CH:37][CH:36]=1>>[NH2:54][C:46]1[N:47]=[C:48]([O:51][CH2:52][CH3:53])[C:49]2[N:50]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:40][CH:39]=3)[CH:42]=[CH:43][C:44]=2[N:45]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CCOc1nc(N)nc2ccc(-c3ccc(N)cc3)nc12
Agent: CCOc1nc(N)nc2ccc(-c3cccc(NS(=O)(=O)C(C)C)c3)nc12
Product: CCOc1nc(N)nc2ccc(-c3ccc(NS(=O)(=O)CC)cc3)nc12

Procedure:
Then the procedure of propane-2-sulfonic acid [3-(2-amino-4-ethoxy-pyrido[3,2-d]pyrimidin-6-yl)-phenyl]-amide is repeated, except for the use of ethanesulfonyl chloride instead of isopropylsulfonyl chloride and 6-(4-amino-phenyl)-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine instead of 6-(3-amino-phenyl)-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine. The resulting product was characterized by its mass spectrum as follows: MS (m/z) 374.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]([Zn]CC)[CH3:15].O1CCO[CH2:21][CH2:20]1>>[CH2:14]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:20][CH3:21])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1c(Br)cncc1Br
Reactant: CC[Zn]CC
Product: CCOC(=O)c1c(CC)cncc1CC
Temperature: 70 °C
Yield: 54.8 %

Procedure:
To a solution of ethyl 3,5-dibromopyridine-4-carboxylate (5.98 g, 19.35 mmol) in anhydrous dioxane (40 mL) was added at room temperature (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (424 mg, 0.580 mmol). Diethylzinc (3.58 g, 23.8 mL, 28.95 mmol, 15% solution in toluene) was then added dropwise. The reaction mixture was heated at 70° C. for 45 minutes, then cooled to room temperature and quenched with MeOH. The resulting mixture was extracted with ethyl acetate (2×100 mL), washed with water, 0.1 N HCl, and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate in hexane to provide ethyl 3,5-diethylpyridine-4-carboxylate as a pale yellow oil (2.2 g, 54.8% yield); 1H NMR (400 MHz, CDCl3): δ 1.23 (t, 6H), 1.40 (t, 3H), 2.64 (q, 4H), 4.44 (q, 2H), 8.36 (s, 2H), M+208.5; M+180.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#N.[CH2:11]([Mg]Cl)[CH3:12].C1C[O:18]CC1>CC(OC)(C)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:18])[CH2:11][CH3:12])[CH:8]=[CH:9][N:10]=1
Reactant: CC[Mg]Cl
Reactant: COc1cc(C#N)ccn1
Reactant: C1CCOC1
Solvent: COC(C)(C)C
Product: CCC(=O)c1ccnc(OC)c1
Temperature: 0 °C

Procedure:
A stirred suspension of 25.44 g of 2-methoxy-isonicotinonitrile as obtained in Example 1 (189.7 mmol) in 380 mL TBME was cooled to 0° C. and 114 mL ethyl magnesium chloride in THF (2.0 M, 228.0 mmol, 1.20 eq) were added within 45 min. Stirring was continued at 0° C. After 3 h 40 min, additional 5 mL ethyl magnesium chloride in THF (2.0 M, 10.0 mmol, 0.05 eq) were added at 0° C. The reaction was monitored by HPLC. After 4.5 h (<3% area 2-methoxy-isonicotinonitrile), the reaction was quenched at 0° C. by addition of 300 mL water. The resulting suspension was stirred for 16 h at room temperature and was then diluted with 200 mL toluene. The aqueous phase was extracted with 400 mL toluene and the combined organic phases were washed with 500 mL saturated aqueous NH4Cl and 500 mL brine, dried over 50 g Na2SO4 (30 min) and filtered. The filter cake was washed with 100 mL toluene. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the title compound (28.64 g, 91% by weight) was obtained as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:18])([F:17])[F:16].O[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]([CH3:36])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]([CH3:36])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:16])([F:18])[F:17]
Reactant: CCC(C)(Oc1ccc(OCCCO)cc1)C(=O)OC
Reactant: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(O)cc2O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(Oc1ccc(OCCCOc2cc3c(cc2Cl)C(C(F)(F)F)=CC(C)(C)O3)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol (0.66 g, 2.95 mmol), methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate (1.0 g, 2.97 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) in 25 mL THF is added diethyl azodicarboxylate (0.56 g, 3.21 mmol)(slight exotherm) and the reaction mixture is stirred at ambient temperature overnight (16 h). After concentrating under reduced pressure, the residue obtained is chromatographed over silica gel to provide methyl 2-(4-(3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoate (0.99 g).
Reaction SMILES: C[CH:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=O.[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.Cl[CH:17](Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[CH3:17][O:10][C:8]([CH2:7][CH2:2][CH2:3][C:4]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)=[O:6])=[O:9]
Reactant: c1ccoc1
Reactant: CC(CC(=O)O)CC(=O)O
Reactant: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
In 50 ml of toluene were dissolved 7.31 g (0.05 mole) of monomethylglutaric acid, 4.43 g (0.085 mole) of furan and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 9.54 g of 2-(4-methoxycarbonylbutyryl)furan.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Br:19])=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:20].ClC(OCC)=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:20])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:10])=[CH:17][C:18]=1[Br:19]
Reactant: C1COCCN1
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccccc2)cc1Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1Br

Procedure:
This compound was prepared from 4-amino-3,5-dibromo-β-phenyl-cinnamic acid (isomer ratio A:B=1:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c). Melting point of the 1:1 mixture of isomers A and B: 156°-174° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][C@H:26]([CH3:28])[O:25][C@H:24]([CH3:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([N:22]6[CH2:23][C@H:24]([CH3:29])[O:25][C@H:26]([CH3:28])[CH2:27]6)[CH:17]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[cis-2,6-dimethylmorpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (29.0 mg, 0.0449 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixute and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (27.9 mg, 94.7%) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.O[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][N:9]([CH2:12][N:13]3[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]3=[O:21])[CH:10]=[C:4]2[CH:3]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: CCCC1CC(=O)N(CO)C1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cn2cc3cc(Br)cnc3n2)C1
Yield: 7.8 %

Procedure:
A solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (1 g, 1 eq, 5.04 mmol) and 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (1.58 g, 2 eq, 10.08 mmol) in trifluoroacetic acid (20 ml) is refluxed for 4 hours. The reaction mixture is poured on crushed ice, on saturated NaHCO3 aqueous solution, and the aqueous phase is extracted with dichloromethane. The cumulated organic layers are dried over MgSO4, filtered, evaporated under reduced pressure. The crude product is purified by preparative chromatography on silicagel affording 1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one 291 as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([Cl:11])[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26]>C(Cl)Cl>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25](=[NH:26])[O:10][CH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=1[Cl:11]
Reactant: OCc1cc(F)c(Br)cc1Cl
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (3.95 g, 16.49 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.5 mL, 3.34 mmol) in methylene chloride (30 mL) was added trichloroacetonitrile (, 2.50 mL, 24.93 mmol) over 5 min at 0° C., stirring was continued for 4 h at 0° C. After concentrated in vacuo, the residue was purified by column chromatography eluting with 5% ethyl acetate in hexanes to give 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate as a colorless solid (5.80 g, 91%): δ 8.49 (s, 1H), 7.59 (d, J=6.3 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 5.37 (s, 2H).
Reaction SMILES: O1CCOCC1.[ClH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C1(C)C=CC=CC=1>O1CCOCC1.C(O)(=O)C>[ClH:7].[NH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[CH:10]3)=[O:18])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc3[nH]ncc3c2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(NCC1CCNCC1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A 4N-hydrogen chloride-1,4-dioxane solution (0.200 mg, 0.800 mmol) was added to a solution of tert-butyl 4-{[(1H-indazol-5-ylcarbonyl)amino]methyl}piperidine-1-carboxylate (36.0 mg, 0.100 mmol) in a mixture of 1,4-dioxane (0.4 ml) and acetic acid (0.7 ml) at room temperature, and the resulting mixture was stirred for 3 hours while being maintained at room temperature. Toluene was added to the reaction solution and the resulting mixture was stirred while being maintained at room temperature. Then, the resulting slurry was collected by filtration and dried under reduced pressure, and the resulting crude product residue was stirred in methanol (3.0 ml) for 1 hour with heating under reflux while maintaining the temperature. The resulting mixture was concentrated to dryness to obtain N-(piperidin-4-ylmethyl)-1H-indazole-5-carboxamide hydrochloride (29.8 mg, 100%).
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH3:20])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>C(O)(C)(C)C>[CH2:21]([NH:25][C:4]([NH:18][CH2:19][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: CCCCN
Agent: I
Solvent: CC(C)(C)O
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NCC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-ethyl-2-thiopseudourea hydriodide (10 g prepared as described in Example 212), n-butylamine (2.7 g) and t-butanol (75 ml) was heated at 90°-95° C. for 172 hours to yield 1-(n-butyl)-2-(2-morpholinophenyl)-3-ethylguanidine which was converted into its monofumarate salt (m.p. 159°-160° ) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:8][C:9](=[O:24])[CH:10]([C:21](O)=[O:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:8][C:9](=[O:24])[CH:10]([C:21](=[O:22])[NH:49][O:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)O)C(=O)OC(C)(C)C
Reactant: NOCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)NOCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
The residue from stage (d) was stirred in DMF at -15° C. for 1 hour with HOBT (2 equiv) and DCCl (1 equiv). To the mixture was added a precooled solution of O-benzylhydroxylamine hydrochloride (1 equiv) and NMM (1 equiv) in DMF and stirring continued for 48 hour at +4° C. The product was filtered, the filtrate concentrated in vacuo, dissolved in ethyl acetate and acid/base washed in the normal manner. The solution was dried (MgSO4), evaporated in vacuo and the residue used the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[C:5](F)=[N:6][CH:7]=1.[NH3:16]>C(O)C>[NH2:16][C:5]1[C:4]([C:9](=[O:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: N
Reactant: CN(C)C(=O)C(=O)c1cc(Br)cnc1F
Solvent: CCO
Product: CN(C)C(=O)C(=O)c1cc(Br)cnc1N

Procedure:
2-(5-Bromo-2-fluoro-pyridin-3-yl)-N,N-dimethyl-2-oxo-acetamide (948 mg, 3.45 mmol) was treated with saturated ammonia solution in ethyl alcohol (10 mL) in a sealed vial at 50° C. for 1 h. The reaction was complete and the mixture was dried in vacuo and used crude in the next step. MS: m/z 272 (M+H+).