Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Cl:28][C:29]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:30]=1[NH2:31]>C(OCC)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:31][C:30]1[CH:32]=[CH:33][C:34]([Br:36])=[CH:35][C:29]=1[Cl:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.2 g, 10 mmol) was dissolved in 150 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (2.8 mL, 34 mmol) followed by the dropwise addition of oxalyl chloride (1.5 mL, 17 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for 1 hours, then at ambient temperature for two hours. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 100 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 2-chloro-4-bromoaniline (1.8 g, 8.5 mmol). The reaction was allowed to warm to ambient temperature and stirred over the weekend. Concentrated reaction, redissolved in 250 mL EtOAc, washed with 10% citric acid (3×100 mL), water, (2×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with an automated system with gradient of 0-60% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a yellow solid. (2.7 g, 79%) APCI (AP−): 401.0, 403.0, 405.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:36]([CH:33]4[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]4)=[O:37])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
Under an inert atmosphere was combined ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (7.0 g, 23.14 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5.3 g, 23.14 mmol), EDCI (4.43 g, 23.14 mmol), HOBT (3.13 g, 23.14 mmol), and triethylamine (65 mL, 46.3 mmol) in dichloromethane (140 mL). The mixture was stirred at room temperature for 48 h then concentrated in vacuo. The residue was taken-up in EtOAc (150 mL) and washed with water (100 mL), 1N NaOH (30 mL), and brine (30 mL), then dried (MgSO4). The solution was filtered, and concentrated. This was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (10.0 g), which was deprotected with 10 mL trifluoroacetic acid as described herein to afford {4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone 39 (6.5 g ), [M+H]+=450.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]3[CH:23]=2)=[CH:8][CH:7]=1.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])[C:25]([NH:24][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]3[CH:23]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:2][OH:1])=[O:31]
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc3)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of 1,1-dimethylethyl [(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]carbamate (1.08 g, 2.54 mmol) and 4M HCl in 1,4-dioxane (8.0 mL, 32 mmol) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness redissolved in DMF (25 mL), and to this solution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) and pentafluorophenyl 3-chloro-4 [(1-methylethyl)oxy]benzoate (0.963 g, 2.54 mmol). The mixture was stirred for 3.0 h at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) as a pale yellow powder.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([NH:36][CH2:37][C:38]([OH:40])=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[CH:41]1[C:49]2[C:48]3[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:47]=3[O:46][C:45]=2[CH:44]=[CH:43][C:42]=1[NH2:55]>>[O:40]=[C:38]([NH:55][C:42]1[CH:43]=[CH:44][C:45]2[O:46][C:47]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C:48]=3[C:49]=2[CH:41]=1)[CH2:37][NH:36][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 46.5 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-glycine (0.24 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl [2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.20 g). MS (ESI) m/z 359 ([M+H]+); MS (ESI) m/z 357.2 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]12[CH2:16][CH2:15][C:12]([C:17](OC)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].O>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]([C:9]12[CH2:14][CH2:13][C:12]([CH2:17][OH:18])([CH2:11][CH2:10]1)[CH2:15][CH2:16]2)[C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CCC(N(Cc3ccccc3)C(=O)OC(C)(C)C)(CC1)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C12CCC(CO)(CC1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of methyl 4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate (2.70 g, 7.23 mmol) in THF (24 mL) at about 0° C. was added lithium borohydride (0.350 g, 14.46 mmol). The reaction mixture was warmed to ambient temperature and stirred for about 16 h. The reaction was cooled to about 0° C. and water (15 mL) was carefully added. The reaction mixture was warmed to ambient temperature and was diluted with EtOAc (20 mL). The layers were separated and the organic layer was washed with brine (2×20 mL), dried over anhydrous Na2SO4, filtered and concd under reduced pressure to provide tert-butyl benzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate (2.31 g, 92%) as an off white sticky foam: LC/MS (Table 1, Method b) Rt=2.67 min; MS m/z: 346 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cccnc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2cccnc2c1Cl
Yield: 28.5 %

Procedure:
A solution of 4-hydroxyl-[1.5]naphthyridine-3-carbonitrile (1.0 g, mmol) in 20 ml POCl3 was refluxed for 3 hrs. After cooling, the solvent was removed by rotary evaporation. The residue was treated with ice-water mixture, made basic by NH4OH, and extracted with CH2Cl2. Removal of the solvent gave 4-chloro-[1,5]naphthyridine-3-carbonitrile (285 mg, 28.5%). This was heated at reflux with 3-bromoaniline (3 eq) in the presence of pyridine HCl salt (350 mg) in ethoxyethanol for 3 hrs under argon. After cooling, the solvent was removed by rotary evaporation. The residue was partitioned between ice-water and ethyl acetate, made basic with (NH4OH), extracted with ethyl acetate. The combined extracts were washed (brine) and dried (Na2SO4), and concentrated. The residue was triturated with ether. The title compound was collected and washed with ether, and dried. mass spectrum (electrospray, m/e): 326.9 (M+H); IR cm-1: 3372, 2209; H-NMR δ (DMSO-d6): 7.36-7.90 (3H, m, C4′ C5′-H and C6′ Hs in bromoaniline), 7.64 (1H, s, C2′-H), 7.94 (1H, dd, C7-H), 8.36 (1H, dd, C8-H), 8.66 (1H, s, C2-H), 8.98 (1H, dd, C6-H), 10.47 (1H, bs, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16](I)[C:17]([NH2:20])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1cc(Cl)cnc1N
Temperature: 25 °C
Yield: 45.8 %

Procedure:
Mixture of 5-chloro-2-methoxyphenylboronic acid (5.0 g, 26.8 mmol), 5-chloro-3-iodopyridin-2-amine (6.83 g, 26.8 mmol), sodium carbonate (8.53 g, 80.5 mmol in 50 mL of water), Pd(PPh3)4 (621 mg, 2 mol. %) and 100 mL of toluene was refluxed overnight under N2. reaction mixture was cooled down to room temperature, organic layer was separated and concentrated in vacuum. The residue was subjected to column chromatography on silica gel with hexane/ethyl acetate gradient mixture as eluent, providing 3.3 g (46% yield) of 5-chloro-3-(5-chloro-2-methoxyphenyl)pyridin-2-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.O1CCCC1>[Pd](Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(C)(C)CC2=O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)OC(C)(C)C=C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
A mixture of 2.1 g (10 millimoles) of 7-methoxy-2,2-dimethyl-4-chromanone, 50 ml of tetrahydrofuran, 20 ml of water, 2.66 g (15 millimoles) of palladium chloride and 4.2 g (0.11 mole) of sodium tetrahydro borate is stirred at 0° C for 20 minutes and thereafter at 5° C. for a further 4 hours. The reaction mixture is filtered, the filtrate extracted twice with 50 ml of chloroform each. The solvent is distilled off, the residue taken up in 50 ml of toluene and distilled in the presence of anhydrous potassium hydrogen sulfate for 20 minutes. The reaction having been completed the organic phase is washed twice with 20 ml of water each and the solvent is removed. The crude product is purified by column chromatography. Thus 1.75 g of the desired compound are obtained in the form of a colorless oil, yield 85 %.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:24]4[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=4)[CH:18]=[O:19])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc3cc(-c4cccc(C=O)c4)ccn3n2)cc1
Yield: 65.2 %

Procedure:
The procedure described in stage 2.4 is followed, starting with 0.157 g (0.54 mmol) of 5-bromo-2-(p-tolyl)pyrazolo[1,5-a]pyridine obtained in stage 8.3, 0.098 g (0.65 mmol) of 3-formylphenylboronic acid, 0.535 g (1.64 mmol) of caesium carbonate and 0.045 g (0.055 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in 5 ml of a 9/1 mixture of tetrahydrofuran and water. After chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.110 g (65%) of the expected product is obtained in the form of a beige powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Br:9][C:10]1[CH:11]=[C:12]([CH3:21])[CH:13]=[C:14]2[C:19]=1[N:18]=[C:17](Cl)[CH:16]=[CH:15]2.C(OCC)(=O)C>O1CCCC1.CCCCCC.C(OCC)(=O)C.O>[Br:9][C:10]1[CH:11]=[C:12]([CH3:21])[CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:16]=[CH:15]2
Reactant: OCC(F)(F)F
Reactant: Cc1cc(Br)c2nc(Cl)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c2nc(OCC(F)(F)F)ccc2c1
Yield: 88.6 %

Procedure:
To 0.8 g of 60% sodium hydride (oil dispersion) stirring in 20 ml of tetrahydrofuran at room temperature, 2.5 ml (34.3 mmol) of 2,2,2-trifluorethanol was added dropwise. An exotherm occurred and to the resulting solution 1.7 g (6.7 mmol) of 8-bromo-2-chloro-6-methyl-quinoline was added followed by heating at reflux for 7 h. Ethyl acetate (200 ml) and excess water was added and the organic layer separated and washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo to give an oil. Silica gel column chromatography (20:1 followed by 10:1 hexane/ethyl acetate) afforded 1.9 g of 8-bromo-6-methyl-2-(2,2,2-trifluoroethoxy) quinoline, m.p. 61°-62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25]([OH:27])=O)[N:19]([CH3:28])[C:18]=4[CH:29]=3)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1.C([N:35](CC)CC)C.ClC(OCC)=O.N>CC(C)=O>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25]([NH2:35])=[O:27])[N:19]([CH3:28])[C:18]=4[CH:29]=3)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Agent: CCOC(=O)Cl
Agent: N
Solvent: CC(C)=O
Product: Cn1c(C2CC2C(N)=O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (150 mg) and triethylamine (0.139 ml) in acetone (2 ml) was added ethyl chloroformate (0.096 ml) at 0° C. The mixture was stirred at 0° C. for 1 h and then NH3 solution (0.101 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/EtOAc) to give the title compound (125 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:12]I.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=c1[nH]cc(Br)c2occc12
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2occc2c1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 7-bromo-5H-furo[3,2-c]pyridin-4-one (250 mg, 1.17 mmol) in DMF (5 mL) cooled to 0° C. was added HNa (56 mg, 1.4 mmol, 60% dispersion in mineral oil) in three portions. After stirring at room temperature for 45 min, MeI (87 μL, 1.4 mmol) was added drop wise over five minutes. The reaction was allowed to warm up to rt stirred for 2 h. It was then cooled to 0° C. followed by addition of sat. aq. NH4Cl (5 mL) drop wise. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound. LCMS: 227.9 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O.CCOCC>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:4])[CH3:5]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (66 mg, 140 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (320 mg, 216 μL, 2.8 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo then the residue was dissolved in dichloromethane (2 mL), methanol (0.5 mL) and ammonium hydroxide (0.3 mL). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo and triturated with ether and water. The yellow precipitate was collected by filtration and washed with water then ether to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methylpyridin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (31 mg, 91.1 μmol, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.38 (s, 1H), 9.86 (s, 1H), 8.39 (s, 1H), 8.12 (d, J=2.5 Hz, 1H), 8.04 (d, J=3.3 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54 (dd, J=8.6, 2.3 Hz, 1H), 5.06 (s, 1H), 3.58 (s, 2H), 2.25 (s, 3H), 1.39 (s, 6H); MS (EI/CI) m/z: 341.1 [M+H].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[CH3:9])(O)=O.S(Cl)(Cl)=O.S(N)([NH2:29])(=O)=O>S1(CCCC1)(=O)=O>[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[CH3:9])#[N:29]
Reactant: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: O=S1(=O)CCCC1
Solvent: O=S(Cl)Cl
Product: Cc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 97.8 %

Procedure:
By the method of Example 5, Step C, 117.0 g (0.3451 mole) of 4-carboxy-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole was reacted with 205.3 g (1.73 moles) of thionyl chloride and 45.1 g (0.47 mole) of sulfamide in 390 mL of sulfolane, yielding 108 g of 4-cyano-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]=[C:54]=[O:55])=[C:49]([C:56]([F:59])([F:58])[F:57])[CH:48]=1>O1CCCC1>[C:37]([CH2:36][C:12]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:54]([NH:53][C:50]3[CH:51]=[CH:52][C:47]([F:46])=[CH:48][C:49]=3[C:56]([F:58])([F:57])[F:59])=[O:55])[CH2:5][CH2:6]2)[CH2:13]1)#[N:38]
Reactant: O=C=Nc1ccc(F)cc1C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)Nc6ccc(F)cc6C(F)(F)F)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (500 mg, 1 mmol) in tetrahydrofuran (30 mL) were added triethylamine (0.29 g, 2.8 mmol) and 4-fluoro-1-isocyanato-2-(trifluoromethyl)benzene (190 mg, 0.95 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Purification by combi-flash using 30-100% EtOAc/hexanes gave 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a powder. LC-MS: 698.1 (M+H)+.
Reaction SMILES: C[Si](I)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26]C)[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11].CO.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][OH:26])[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Reaction time: 24 h
Yield: 65.6 %

Procedure:
Trimethylsilyl iodide (6.06 mL, 42.75 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (2.71 g, 8.55 mmol) in dry acetonitrile (150 mL) and stirred for 24 hours. Methanol (30 mL) was added to quench the reaction and stirred for 10 minutes. 10% w/v Aqueous sodium thiosulfate pentahydrate (20 mL) was added to the mixture and the organic solvents removed in vacuo. The residue was brought to pH5 with 1M hydrochloric acid and ethyl acetate (80 mL) added. A yellow solid (1.4 g) was separated by filtration. The aqueous filtrate was reextracted into ethyl acetate (2×80 mL) and the combined organic layers dried (MgSO4), filtered and the solvents removed in vacuo. This residue was combined with the yellow solid obtained above and purified by column chromatography, eluting with 5% to 10% methanol in DCM, to give the title compound (1.70 g)