Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])[S:13][N:12]=1)[CH3:2].C([O-])(=O)C.[Na+].[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]([O:41]CC)=[O:40])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:13][N:12]=[C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:33]4[CH2:34][CH2:35][CH:36]([C:39]([OH:41])=[O:40])[CH2:37][CH2:38]4)[CH:7]=[CH:6][CH:5]=3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (100 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (22.9 mg), ethyl 4-piperidinecarboxylate (46.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (85 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.66 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid (E28) (43 mg). δH (DMSO-d6, 400 MHz): 0.87 (6H, d), 1.03 (3H, t), 1.47 (2H, m), 1.71 (2H, m), 1.92 (3H, m), 2.01 (1H, m), 2.70 (4H, m), 2.93 (2H, q), 3.47 (2H, s), 7.24 (1H, t), 7.39 (1H, dd), 7.66 (2H, m), 8.26 (1H, dd), 8.47 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH2:14][C@H:13]2[F:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](F)C2)nc1C
Yield: 81.9 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate obtained in Example (197b) (37.0 mg, 0.099 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (29.6 mg, 0.118 mmol) and sodium carbonate (105 mg, 0.987 mmol), to obtain 36 mg of the title compound (82%) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH2:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:19]([Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([Li])[CH2:33][CH2:34][CH3:35].[Cl-:37].[Cl-].[Cl-].[Cl-].[Zr+4:41]>C(OCC)C>[Cl-:37].[Cl-:37].[C:11]([C:9]1[CH:8]=[C:7]([C:15]2[CH:16]([Zr+2:41][CH:32]3[C:22]4[C:35](=[CH:18][C:19]([Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([Si:24]([CH3:25])([CH3:26])[CH3:27])[CH:21]=4)[CH:34]=[C:33]3[C:7]3[CH:8]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:19]([Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=3)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(C2=Cc3cc([Si](C)(C)C)c([Si](C)(C)C)cc3C2)cc(C(C)(C)C)c1
Reactant: [Li]CCCC
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3cc([Si](C)(C)C)c([Si](C)(C)C)cc3C2[Zr+2]C2C(c3cc(C(C)(C)C)cc(C(C)(C)C)c3)=Cc3cc([Si](C)(C)C)c([Si](C)(C)C)cc32)cc(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-(3,5-Di-t-butylphenyl)-5,6-bis-trimethylsilylindene (1.5 g, 3.35 mmol) was dissolved in diethyl ether (100 mL) and cooled to −78° C. Butyllithium (2.1 mL of a 1.6 M solution in hexanes, 3.35 mmol) was added dropwise, causing a slight color change from yellow to yellow orange. The reaction was warmed to room temperature and allowed to stir for 2 hours. The flask was taken into a drybox where ZrCl4 (389 mg, 1.67 mmol) was added to the reaction in one portion at room temperature. The reaction was stirred overnight at room temperature The yellow suspension, was cooled to 0° C. and filtered through celite. The celite bed was washed with methylene chloride until the washings ran clear. The yellow methylene chloride solution was evaporated under vacuum to give a yellow powder that was roughly 20% unreacted ligand. The sample was used without further purification (1.25 g total, about 1.1 g bis(2-(3,5-di-t-butylphenyl)-5,6-bis(trimethylsilyl)indenyl)zirconium dichloride, 1.04 mmol, 62%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C.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>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cn1ccc2ccc(Br)cc21
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Yield: 56.3 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-methyl-1H-indole (1.12 g , 5.33 mmol) was coupled to 4-(tert-butyl)phenylboronic acid (1.07 g, 6.00 mmol), using tetrakis(triphenylphosphine)palladium (0.655 g, 0.567 mmol), and potassium carbonate (2.94 g, 21.3 mmol) in water (10.6 mL), ethanol (2.2 mL), and toluene (23 mL). Purification by flash chromatography (Biotage apparatus) using 0-1% ethyl acetate in hexane as an eluant then drying at 60° C. yielded 6-[4-(tert-butyl)phenyl]-1-methyl-1H-indole as a yellow solid (0.790 g, 56%), mp: 92-94° C. 1HNMR (200 MHz, DMSO-d6): δ 7.55-7.7 (m, 5H), 7.45 (d, 2H, J=7.5 Hz), 7.3 (d, 2H, J=8.5 Hz), 6.6 (d, 1H, J=3.5 Hz), 3.9 (s, 3H), and 1.3 ppm (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>C1(C)C=CC=CC=1.CO.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>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-bromopyridine (2.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 2M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80° C. for 6 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:7)) to give 3-(3-nitrophenyl)pyridine (3.57 g).
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].Cl.[NH2:9][C:10]1([C:13]#[N:14])[CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:13]([C:10]1([NH:9][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:12][CH2:11]1)#[N:14]
Reactant: CC(C)(C)S(=O)Cl
Reactant: N#CC1(N)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
2-methylpropane-2-sulfinic chloride (1.0 ml, 8.4 mmol) was added to a stirring solution of 1-aminocyclopropanecarbonitrile hydrochloride (1 g, 8 mmol) in dichloromethane (21 ml) and N-ethyl-N-isopropylpropan-2-amine (3.0 ml, 17 mmol) at 0° C. DMAP (10 mg, 0.084 mmol) was added and the reaction was allowed to stir 2 h at rt. The mixture was diluted with dichloromethane and washed with sat NH4Cl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product N-(1-cyanocyclopropyl)-2-methylpropane-2-sulfinamide (1.5 g, 8.1 mmol, 95% yield) as a sticky yellow solid consistent by LCMS. LC-MS retention time: 1.40 min; m/z (MH+): 187. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])[CH2:5]1.[H][H].O>CN(C)C=O>[CH2:7]([C:10]([CH:6]1[CH2:7][CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5]1)([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:9][CH2:4][CH:5]=[CH2:6]
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)C1CCCC(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCC(C(=O)OC)(C(=O)OC)C1CCCC(C)C1

Procedure:
To a slurry of sodium hydride (2.53 g, 0.06 mol) in anhydrous N,N-dimethylformamide (50 mL) was added dropwise dimethyl 2-(3-methylcyclohexyl)-malonate (14.46 g, 0.06 mol). After complete addition, the reaction was stirred until no more hydrogen gas was evolved. To the reaction was then added dropwise 1-bromo-6-hexene (10.33 g, 0.06 mol) followed by stirring. The progress of the reaction was followed by analytical chromatography using silica plates and ethyl acetate:hexanes (40:60). After complete reaction, water (20 mL) was added and most of the solvents removed under high vacuum. The remaining material was partitioned between water and ether and the ether layer washed twice with water. The ether solution was dried with MgSO4 and evaporated to give a thick yellow oil. The product was then distilled at 127-134° C. and 0.4 mm pressure to give clear oil.
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O)([O-:6])=[O:5].[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27](Br)=[N:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I.O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N+:4]([O-:6])=[O:5])=[N:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocnee]dichloropalladium(II), w/DCM (0.077 g, 0.095 mmol) was added to a solution containing (2-nitrophenyl)boronic acid (0.316 g, 1.893 mmol), 5-(benzyloxy)-2-bromopyridine (0.5 g, 1.893 mmol), Copper(I) iodide (0.036 g, 0.189 mmol) and Potassium carbonate (1.420 ml, 2.84 mmol) in DMF (Volume: 6.31 ml). Let the reaction cool to room temperature. Diluted reaction with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated. Purified with Combiflash using 15% ethyl acetate in hexanes to afford 5-(benzyloxy)-2-(2-nitrophenyl)pyridine (0.3 g, 0.979 mmol, 51.7% yield).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21]Br>CC(C)=O>[Br:19][CH2:20][CH2:21][N:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: BrCCBr
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])nn1CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (5.97 g, 34.9 mmol) in acetone (100 mL) was added potassium carbonate (24.1 g, 174 mmol) and 1,2-dibromoethane (19.7 g, 9.02 ml, 105 mmol) and the resulting solution heated to reflux for 2 h and then stirred at room temperature overnight. The resulting mixture was filtered and concentrated and the residue purified by flash chromatography (silica gel, SF65-400 g, 20% to 70% ethyl acetate in hexanes) to give methyl 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (4.86 g, 50%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10].C(N(CC)CC)C.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[C:3]([NH:8][C:9]([C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the crude product of di-tert-butyl (1S)-{1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]pentamethylene}biscarbamate and triethylamine (0.91 g) in chloroform (30 ml) was added triphenylmethyl chloride (2.51 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed successively with 0.10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give di-tert-butyl (1S)-(1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}pentamethylene)biscarbamate (4.23 g) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][NH:28][CH2:29][CH2:30][OH:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:28]([CH2:29][CH2:30][OH:31])[CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN(C)CCO)cc2C)ncn1
Reaction time: 15 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with 2-(methylamino)ethanol (Aldrich, 112.7 mg; 0.42 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:25]1[N:30]=[C:29]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[N:28]=[C:27]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[N:26]=1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:25]1[N:30]=[C:29]([O:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[N:28]=[C:27]([N:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[N:26]=1)[CH:12]=[C:11]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]([OH:5])=[O:21]
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: Clc1nc(OC2CCCC2)nc(N2CCCc3ccccc32)n1
Product: O=C(O)CCC(=O)c1cn(-c2nc(OC3CCCC3)nc(N3CCCc4ccccc43)n2)c2ccc(Cl)cc12

Procedure:
Arylation of 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid 2-trimethylsilanyl-ethyl ester with 1-(4-chloro-6-cyclopentyloxy-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinoline and subsequent hydrolysis as outlined previously yielded the titled compound. Rf 0.30 (5% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.97 (1H, s, ArH), 8.55 (1H, d, J=9 Hz, ArH), 8.18 (1H, d, J=2 Hz, ArH), 7.81 (1H, d, J=8 Hz, ArH), 7.35-7.10 (4H, m, ArH), 5.44 (1H, m, CH), 4.08 (2H, t, J=6 Hz, CH2), 3.22 (2H, t, J=6 Hz, CH2), 2.78 (2H, t, J=6 Hz, CH2), 2.58 (2H, t, J=6 Hz, CH2), 2.01-1.61 (10H, m, CH2); ESI-LCMS e/z calculated for C29H28ClN5O4 545.183, found 546 (M+H)+, 568 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]1[S:11][C:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:15](=O)[NH2:16])[N:14]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[C:15]([C:13]1[N:14]=[C:10]([NH:9][CH3:8])[S:11][C:12]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#[N:16]
Reactant: CNc1nc(C(N)=O)c(-c2ccncc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1nc(C#N)c(-c2ccncc2)s1
Temperature: 0 °C
Reaction time: 6 h
Yield: 25.8 %

Procedure:
Trifluoroacetic acid (2.8 g) was dropwise added to a suspension of 2-methylamino-4-carbamoyl-5-(4-pyridyl)thiazole (2.1 g) and pyridine (2.8 g) in methylene chloride (60 ml) at 5° to 10° C. with stirring, which was continued under the same condition for 6 hours. The reaction mixture was poured into ice-water and the resultant mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% potassium carbonate and extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to afford 4-cyano-2-methylamino-5-(4-pyridyl)thiazole (0.5 g). mp 192°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1 hour with nitrogen bubbling through it. The reaction mixture was then heated at reflux for 1 hour under nitrogen during which a solution formed. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was heated at 50° C. overnight under nitrogen. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate (100 ml of each). The two layer mixture was filtered to remove an insoluble solid and the layers were separated. The aqueous layer was re-extracted once with ethyl acetate and the combined organic layers were washed once with a 5% potassium hydroxide solution (100 ml), dried over sodium sulfate, filtered, and evaporated to a residue weighing 8.9 g. The residue wad dissolved in hot isopropyl alcohol, filtered, cooled to room temperature, and water was added. Solid formed which was collected by filtration to give 4.84 g (76%) of a white solid, after drying under vacuum overnight, mp 104°-105.5° C.
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][CH:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:18]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1C=CC(c2cccnc2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1cncc(C2CCNCC2)c1
Reaction time: 16 h

Procedure:
A solution of 1-benzyloxycarbonyl-4-(3-pyridyl)-1,2,3,4-tetrahydropyridine (0.714 in ethanol (50 mL) was treated with 10% palladium on carbon (0.1 g) and hydrogenated under a hydrogen atmosphere at room temperature and 3.44 bar for 16 hours. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the resulting filtrate was evaporated to afford the piperidine (0.393 g); NMR (CDCl3): 1.7 (m, 4), 2.8 (m, 4), 3.2 (m, 2), 7.3 (m, 1), 7.5 (m, 1), 8.5 (m, 2); MS: m/z=162(M+1).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl>[C:14]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[O:1][C:5]=3[CH2:6]2)=[O:27])=[CH:29][CH:30]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: COC(=O)c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Reaction time: 8 h

Procedure:
To a solution of 72 mg (0.40 mmol) of methyl 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-carboxylate, 0.11 g (0.48 mmol) of 4-benzoylbenzoic acid and 0.11 ml (0.79 mmol) of triethylamine in 30 ml of dichloromethane, 0.07 ml (0.48 mmol) of diethyl cyanophosphonate was added dropwise at room temperature, followed by overnight stirring. After the reaction mixture was evaporated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.