Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42](Cl)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.C[C:53]([N:55](C)C)=O>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:53]#[N:55])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Zn]
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C#N)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 115 °C

Procedure:
To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (730 mg, 1.0 mmol), was added ZnCN2 (280 mg, 2.4 mmol), Zn (64 mg, 1.0 mmol), DMA (10 mL), and Pd(P-t-Bu3)2 (78 mg, 0.15 mmol). The reaction mixture was heated in a sealed vial at 115° C. for 2 h, then cooled to RT, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCN(CCN2CCOC2=O)CC1

Procedure:
20 G. of 2,10-dichloro-10,11-dihydro-7-methyl-dibenzo[b,f]thiepin are stirred with 41 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and 400 ml. of chloroform at the boiling temperature for 20 hours. The solution is cooled and washed successively with 2N sodium hydroxide and with water. The organic phase is decanted and extracted with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and the oil which separates out is shaken out with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 3-{2-[4-(2-chloro-10,11-dihydro-7-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 161°-163° C.) which is converted into the corresponding dimethanesulfonate (melting point 187°-189° C.) by reaction with methanesulfonic acid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:22](=O)([O-])[OH:23].[Na+].O>CS(C)=O>[OH:23][CH2:22][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C
Yield: 632.5 %

Procedure:
A mixture of methyl 3,5-bis(trifluoromethyl)benzeneacetate (Description 1, 10.0 g, 35 mmol), paraformaldehyde (1.15 g, 38.5 mmol) and sodium hydrogen carbonate (84 mg, 1 mmol) in dimethylsulfoxide (10 mL) was heated at 45° C. for 1 hour, cooled and water (200 mL) was added. The mixture was extracted with ether (2×200 mL) and the combined organic fractions were washed with water (4×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25) to give the title compound as a colorless oil (2.0 g, 10%). 1H NMR (400 MHz, CDCl3) δ 2.27 (1H, t, J 7.0 Hz), 3.76 (3H, s), 3.94–3.99 (2H, m), 4.01–4.15 (1H, m), 7.77 (2H, s) and 7.83 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=O)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:13]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[CH:8]=1)=[O:15]
Reactant: COc1ccc2c(C(=O)O)cn(C)c2c1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Product: CNC(=O)c1cn(C)c2cc(OC)ccc12
Yield: 83.8 %

Procedure:
This material was prepared from 6-methoxy-1-methyl-indole-3-carboxylic acid 16b (515 mg, 2.5 mmole), oxalyl chloride (0.9 ml, 12.6 mmole) and methylamine (7.5 mmole) in a manner as previously described for example 16d to give 457 mg of a pale brown solid (83%). 1H NMR (CD3OD) δ7.83 (1H, d, J=8.7 Hz), 7.51 (1H, s), 6.81 (1H, d, J=2.3 Hz), 6.72 (1H, dd, J=2.3, 8.7 Hz), 3.75 (3H, s), 3.67 (3H, s), 2.80 (3H, s); ESIMS (MH+): 219.05.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O.C([O-])(O)=O.[Na+]>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: Oc1cc(C(F)(F)F)nc2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 25 °C

Procedure:
A mixture of 7-chloro-2-trifluoromethyl-4-quinolinol (4 g, 16.2 mmol) in phosphorus oxychloride (7.55 mL, 81 mmol) is heated at reflux temperature for 3 hours. After cooling to room temperature, ice (200 g) is added, the mixture is neutralized with NaHCO3 and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator. The resulting tan residue is purified by flash chromatography on silica gel (1% ether in hexanes) to give 4,7-dichloro-2-trifluoromethylquinoline as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])[N:4]=1.[CH3:17][S:18]([NH2:21])(=[O:20])=[O:19].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([CH3:16])[C:13]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[O:14])[N:4]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(OC)nc(OC(C)C(=O)O)n1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(OC(C)C(=O)NS(C)(=O)=O)n1
Yield: 58.6 %

Procedure:
To a solution of 1,1-carbonyldiimidazole (1.70 g, 0.0105 mol) in dry tetrahydrofuran (130 ml), 2-(4,6-dimethoxypyrimidin-2-yl)oxypropionic acid (2.28 g, 0.01 mol), prepared as described in Example 1(b) above, in tetrahydrofuran (30 ml) was added dropwise at room temperature (~ 20° C.). The solution was refluxed for 1/2 hour and allowed to cool. Methanesulphonamide (0.95 g, 0.01 mol) Was added in one solid portion and the mixture stirred for 15 minutes before 1,8-diazabicyclo[5.4.0]undec-7-ene (1.52 g, 0.01 mol) in tetrahydrofuran (30 ml) was added dropwise at room temperature (18 20° C.). After a short duration the tetrahydrofuran was removed and the residue acidified with 1M hydrochloric acid solution. The product was extracted with chloroform, backwashed with water and dried. The solvent was removed and the product purified on silica gel eluting with 3% by volume methanol/chloroform to yield the title compound as a solid (1.79 g).
Reaction SMILES: N([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[N:5]([CH3:7])[CH3:6])=O.C[N:13](C)C1C=CC=CC=1.N([O-])=O.[ClH:24]>>[NH2:13][C:10]1[CH:9]=[CH:8][C:4]([N:5]([CH3:7])[CH3:6])=[CH:3][CH:11]=1.[ClH:24]
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccccc1N=O
Agent: Cl
Agent: O=N[O-]
Product: CN(C)c1ccc(N)cc1

Procedure:
In step (a), nitrosodimethylaniline is prepared from dimethylaniline by treatment with nitrite (NaNO2) in aqueous acid (HCl) solution. In step (b), the nitroso compound is reduced to form p-aminodimethylaniline in aqueous acid (HCl) solution using zinc dust. In steps (c), (d), and (e), the p-aminodimethylaniline is oxidized in aqueous acid solution with another molecule of dimethylaniline, and simultaneously a thiosulfonic acid group is introduced; the ring is then closed using manganese dioxide or copper sulfate. More specifically, a clear neutral solution of p-aminodimethylaniline is acidified (H2SO4), and a non-reducing zinc chloride solution is added (ZnCl2 with Na2Cr2O7). Aluminium thiosulfate (Al2(S2O3)3) and sodium thiosulfate (Na2S2O3) are added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated and aerated. Dimethylaniline is added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated, and becomes dark greenish-blue in colour due to the formation of the thiosulfonic acid of Bindschedler green. Manganese dioxide or copper sulfate is added, and the mixture heated, and the dye precipitates from the concentrated zinc chloride solution.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)Nc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and aniline.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.Cl[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([N:18]([CH2:21][CH2:22][N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH2:19][CH3:20])[CH3:16]
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)ncn2CCN(CC)CC

Procedure:
5.4 g (28.4 mmol) of ethyl benzimidazole-5-carboxylate, 9.8 g (56.8 mmol) of N-(2-chloro-1-ethyl)-N,N-diethylamine and 7.9 g (56.8 mmol) of potassium carbonate were heated in 100 ml of dimethylformamide at 100° C. for 4 hours. The mixture was then filtered, the filtrate was concentrated in vacuo, and the resulting residue was purified by chromatography (mobile phase: ethyl acetate/acetone=1/1). 2.6 g of an isomer mixture containing ethyl 3-(2-(N,N-diethylamino)-1-ethyl)benzimidazole-5-carboxylate in addition to the product were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:23][N:24]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: CNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(c1ccccc1)c1cc(Nc2cccc(NC(=O)OC(C)(C)C)c2)ncn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(6-chloropyrimidin-4-ylamino)phenylcarbamate (1.6 g, 5 mmol) and N-methylaniline (1.07 g, 10 mmol) was heated at 120° C. in a sealed tube for 2 hr. The reaction mixture was cooled to RT, mixed with 1 mL of 1N NaOH and 5 mL of DCM, stirred for 30 min, the product was filtered and dried under vacuum to give a solid product. MS (m/z): MH+=392.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[C:37]([I:8])[C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of NIS (147 mg, 0.653 mmol) in DMF (3 mL) was added dropwise to a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (257 mg, 0.634 mmol) in DMF (3.5 mL) at −40° C., and the mixture was stirred and allowed to slowly warm to room temperature (temperature was still <−10° C. after 2 hours, and reaction had progressed to about 20% according to HPLC). After 18 hours HPLC indicated complete consumption of starting material, and only a small amount of diiodo byproduct had formed. The reaction mixture was poured into water (35 mL), stirred for about 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction for several hours to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (253 mg) as a tan solid. LC/MS (ES) m/z=532 [M+H]+.
Reaction SMILES: O.[OH-].[Cs+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([NH2:12])[CH3:11].[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]1[CH2:29][NH:12][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=1)[CH3:11])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: CN(C)c1ccncc1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
To a suspension of crushed and dried 3A molecular sieves (1.0393 g) in DMF (15 mL) was added cesium hydroxide monohydrate (0.6272 g, 3.7 mmol) and DMAP (0.0366 g, 0.3 mmol), and the mixture was stirred at room temperature for 15 minutes. To this was added 1-pyridin-2-yl-ethylamine (0.4168 g, 3.4 mmol) in DMF (10 mL), and was stirred for 30 minutes. Then 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (1.1050 g, 4.1 mmol) was added and the reaction was stirred at room temperature for 19 hours. The reaction mixture was filtered with CH2Cl2, concentrated, and diluted with 1N NaOH (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (4×150 mL). The combined organic layers were washed with brine (1×100 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (33:1:1 CH2Cl2-MeOH—NH4OH) provided 0.7260 g (61%) of 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as an orange oil. 1H NMR (CDCl3) δ 1.47 (d, 3H, J=6.0 Hz), 1.66 (s, 9H), 2.92 (d, 2H, J=31.0 Hz), 4.00-4.07 (m, 1H), 4.13-4.29 (m, 1H), 7.03-7.04 (m, 1H), 7.27-7.33 (m, 3H), 7.48-7.55 (m, 1H), 7.65-7.70 (m, 1H), 7.82-7.86 (m, 1H), 8.48 (d, 1H, J=4.8 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccnc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(O[C@H]2CCNC2)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of 3-((3S)-N-(tert-butoxycarbonyl)-3-pyrrolidinyloxy)pyridine (0.535 g, 2.024 mmol) in dry CH2Cl2 (5 mL, distilled from LiAlH4) was treated drop-wise with trifluoroacetic acid (3 mL, 4.44 g, 38.94 mmol). After stirring 30 min at 0-5° C., the solution was concentrated by rotary evaporation. The residue was acidified with 1 M HCl solution (15 mL) and extracted with toluene (4×25 mL) to remove impurities (triphenylphosphine oxide). At 0-5° C., the aqueous layer was basified with 1 M NaOH solution to pH 12. The mixture was saturated with NaCl and extracted with CHCl3 (8×20 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and briefly dried under high vacuum to give 240 mg (72.3%) of a light-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([C:25]([F:28])([F:27])[F:26])[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C(F)(F)F
Temperature: 45 °C

Procedure:
1,1-Dimethylethyl 4-{[5-methyl-2-nitro-4-(trifluoromethyl)phenyl]amino}-1-piperidine-carboxylate (D57) (3.17 mmol, 1.29 g) was dissolved in ethanol (20 ml) and an aqueous suspension of Raney-Nickel (3 ml) was added at room temperature; the mixture was heated to 40-50° C. and hydrazine monohydrate (15 eq., 48 mmol, 1.5 ml) was added over 20-30 min. The reaction mixture was then cooled to room temperature, filtered through celite and the solvent was evaporated to yield the title compound, 1.1 g, 92%, M+-Boc+H=274.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([OH:17])[C:6]=12.Br[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]3)[C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(CBr)C1
Reactant: Cn1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCC3CCCN(C(=O)OC(C)(C)C)C3)c3c(Br)cnn3c2)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (60.0 mg, 0.205 mmol), tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (114 mg, 0.410 mmol), and NaH (29.5 mg, 0.737 mmol) were suspended in DMF (2 ml), then heated to 60° C. After 2 h, the reaction mixture was quenched with 1 ml of saturated aqueous ammonium chloride, diluted in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine. The combined aqueous layers were extracted with ethyl acetate (1×30 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) afford a yellow oil. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate, filtered and concentrated to afford tert-butyl 3-({[3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](F)[CH:26]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[NH:16][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[C:32]1([C@@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(=O)([O-])O.[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:40][C@H:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:39])[CH:26]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[NH:16][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(F)c2)CC1
Reactant: C[C@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(N[C@@H](C)c3ccccc3)c2)CC1
Temperature: 150 °C
Reaction time: 10 h
Yield: 51.6 %

Procedure:
A mixture of 360 mg (0.85 mmol) of 4-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(2-fluoropyridin-4-yl)-1H-pyrrole [prepared as described in step 73 (ii) above], 3.6 ml (28.3 mmol) of 1(S)-phenylethylamine and 0.36 ml of concentrated hydrochloric acid was stirred at 150° C. for 10 hours. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to give 229 mg (yield 49%) of the title compound as a brown amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](I)[CH3:16]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1cccc(Br)c1=O
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A mixture of 3-bromopyridin-2-ol (1.0 g, 5.75 mmol) in DMF (6 mL) was treated with cesium carbonate (1.87 g, 5.75 mmol) and ethyl iodide (1.38 mL, 17.2 mmol). The mixture was heated at 80° C. for 4 hours. The solvent was concentrated and the residue taken in EtOAc, washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1:2 hexane/ether) to provide 3-bromo-1-ethylpyridin-2(1H)-one (0.905 g, 78% yield) as a yellow oil.