Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([OH:23])=O.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[NH:33][NH2:34].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([NH:34][NH:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
3.1 500 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoic acid, 144 mg of tert-butyl carbazate and 250 mg of DAPECl are dissolved in 1 ml of DMF and stirred at RT for 16 h. The reaction mixture is poured into water, the precipitate formed is filtered off and dried. Purification by column chromatography (ethyl acetate/methanol) gives 120 mg (19%) of tert-butyl N′-{2-[3-(2,6-dichlorophenylamino)-imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=574.2; Rf (polar method): 1.80 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C(O[N:18]1[N:26]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([N:54]2[CH2:59][CH2:58][CH:57]([NH:60][C:61]([C:63]3[NH:64][C:65]([CH3:70])=[C:66]([Cl:69])[C:67]=3[Cl:68])=[O:62])[CH2:56][CH2:55]2)[N:53]=1)[C:48]([OH:50])=O.NN>CN(C=O)C>[Cl:68][C:67]1[C:66]([Cl:69])=[C:65]([CH3:70])[NH:64][C:63]=1[C:61]([NH:60][CH:57]1[CH2:56][CH2:55][N:54]([C:52]2[CH:51]=[C:47]([C:48]([NH:18][NH2:26])=[O:50])[CH:46]=[C:45]([Cl:44])[N:53]=2)[CH2:59][CH2:58]1)=[O:62]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NN)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.1 %

Procedure:
Diisopropylethylamine (0.043 ml, 0.25 mmol), HATU (0.048 g, 0.12 mmol) and HOAT (0.017 g 0.12 mmol) were added to a stirred solution of 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 153; 0.055 g, 0.12 mmol) in DMF (2 ml). The resultant solution was stirred for 5 mins and hydrazine (0.04 ml, 0.12 mmol) was added. The mixture was stirred at room temperature for 14 h, partitioned between water and EtOAc. The layers were separated and the organic layer was washed with water two more times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound (30 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:26]=1)[C:10]([O:12][C@H:13]([CH3:23])[CH2:14][O:15][Si](C(C)(C)C)(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:26]=1)[C:10]([O:12][C@H:13]([CH3:23])[CH2:14][OH:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](CO)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
(1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (16) (4.7 g, 7.2 mmol) was dissolved in anhydrous tetrahydrofuran. Triethylamine trihydrofluoride (9.4 mL, 57.0 mmol) was slowly added. The mixture was stirred at room temperature for 4 hours. Removal of solvent under reduced pressure gave 3.8 g (98% yield) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J=6.4 Hz, 3H), 1.41 (s, 9H), 2.78 (s, 1H, br), 2.96 (m, 2H), 3.51 (m, 1H), 3.68 (m, 1H), 4.36 (dd, J=14.0, 6.4 Hz, 1H), 4.98 (m, 1H), 5.05 (d, 1H, NH), 5.10 (s, 4H), 6.66 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 7.26-7.43 (m, 10H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:15]([CH:35]=1)[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])(=O)C.CC(C)=O>C(Cl)(Cl)Cl.CO>[CH2:37]([O:36][C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:35][C:15]=1[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OC(C)=O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Potassium carbonate (1.6 g) was added to a solution mixture of methyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (3.8 g) in chloroform (5.0 mL), methanol (10 mL), and acetone (10 mL), followed by stirring at room temperature for 1 hour. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure, and 1.0 mol/L hydrochloric acid and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3.4 g of methyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.C[O-].[Na+].O.[C:14](OCC)(=[O:16])C>O1CCCC1.CN(C)C=O.CO>[Cl:1][C:2]1[N:7]=[C:6]([O:16][CH3:14])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1nc(Cl)ncc1I
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-5-iodopyrimidine (500 mg) in tetrahydrofuran (4 mL) and N,N-dimethylformamide (4 mL), a 5.0 mol/L a solution of sodium methoxide in methanol (360 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate to obtain 2-chloro-5-iodo-4-methoxypyrimidine (Q1, 460 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
A mixture of {5-[2-(1-cyano-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 50.2) (300 mg), DCM (5 mL) and TFA (1 mL) is stirred for 4 h at rt, quenched by addition of a saturated solution of NaHCO3, and extracted with DCM. The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→96:4) to afford 181 mg of the title compound as a yellow solid: ESI-MS: 271.1 [M+H]+; tR=2.48 min (System 1); TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:18]([C:19]3[CH:41]=[CH:40][C:22]4[C:23]5[N:24]([CH:28]=[C:29]([C:31]6[N:35]([CH:36]([CH3:38])[CH3:37])[N:34]=[C:33]([CH3:39])[N:32]=6)[N:30]=5)[CH2:25][CH2:26][O:27][C:21]=4[CH:20]=3)=[CH:17][CH:16]=[N:15]2)[CH2:9]1)C1C=CC=CC=1.Cl.O1CCOCC1>CO.[Pd]>[CH:36]([N:35]1[C:31]([C:29]2[N:30]=[C:23]3[C:22]4[CH:40]=[CH:41][C:19]([C:18]5[N:14]([CH:10]6[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]6)[N:15]=[CH:16][CH:17]=5)=[CH:20][C:21]=4[O:27][CH2:26][CH2:25][N:24]3[CH:28]=2)=[N:32][C:33]([CH3:39])=[N:34]1)([CH3:38])[CH3:37]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCN(Cc5ccccc5)C4)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9-(1-(1-benzylpiperidin-3-yl)-1H-pyrazol-5-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (500 mg, 0.0009 mol) was dissolved in Methanol (10 mL). 4.0 M of Hydrogen chloride in 1,4-Dioxane (0.5 mL, 0.002 mol) was added. 10% Palladium on Carbon (0.1:0.9, Palladium: carbon black, 120 mg, 0.00011 mol) was added under a stream of Nitrogen. The reaction mixture was vac/flushed with H2 (balloon) and stirred overnight at room temperature. LCMS show reaction is complete. The reaction mixture was filtered and concentrated to dryness to give 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-(piperidin-3-yl)-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31](=[N:3][OH:2])[NH2:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(C3(C)CC3)[nH]c2c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(C3(C)CC3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a solution of hydroxylammonium chloride (117 mg) in dimethylsulfoxide (1.7 mL) was added sodium hydrogen carbonate (170 mg), and the mixture was stirred at 50° C. for 1 hour. Then, a solution of 6-[6-methoxy-2-(1-methylcyclopropyl)-1H-indol-3-ylmethyl]pyridine-2-carbonitrile (53.6 mg) in dimethylsulfoxide (1.7 mL) was added dropwise thereto, followed by stirring at 80° C. for 2.5 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (62.9 mg). 1H-NMR (CDCl3) δ ppm: 0.68-0.76 (2H, m), 0.84-0.92 (2H, m), 1.34 (3H, s), 3.82 (3H, s), 4.35 (2H, s), 5.68 (2H, br s), 6.69 (1H, dd, J=2.3, 8.8 Hz), 6.82 (1H, d, J=2.3 Hz), 6.98-7.05 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.50 (1H, t, J=7.8 Hz), 7.66-7.73 (1H, m), 7.82 (1H, br s). ESI-MS (m/z): 351 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCBr
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 82.2 %

Procedure:
To 5 ml of a DMF solution containing 100 mg (0.2591 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 331.3 μl (2.591 mmol) of pentyl bromide, there were added 42.9 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 7 g of WAKO-gel C-200, eluent: hexane and toluene/ethyl acetate of 50/1) to obtain 97.2 mg (0.2131 mmol, 82%) of 2-pentyloxy-2'-hydroxy-5,5'-bis (2ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[C:26](Cl)=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:24]=1
Reactant: Nc1c(F)cccc1F
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(F)cccc2F)cc1OC1CCCC1
Yield: 46.5 %

Procedure:
A stirred solution of 2,6-difluoroaniline (1.52 g) and triethylamine (1.19 g) in dichloromethane (50 mL) at room temperature is treated dropwise with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.0 g), that is prepared as described hereinafter in Reference Example 3) in dichloromethane (50 mL). The solution is stirred and heated at reflux for 4 hours, then it is cooled, washed with water and dried over magnesium sulfate. The solution is concentrated and the resulting residue is recrystallized from ethyl acetate, to give N-(2,6-difluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.9 g), m.p. 158°-160° C. [NMR(CDCl3):1.55-1.7(m,3H),1.8-2.05(m,5H), 3.93(s,3H),4.85(m, 1H),6.9(d, 1H),6.95-7.03(m,2H),7.2-7.3(m, 1H),7.35(bs,1H),7.45(q, 1H),7.53(d,1H); Elemental analysis: C,65.1; H,5.6;F, 10.4; N,4.2%; Calculated: C,65.7; H,5.5;F, 10.9; N,4.0%].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[N:11]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH2:22][CH2:23][NH:24][C:25](=[O:26])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:28][C:29]1[N:30]=[CH:31][N:32](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:33]=1[CH3:34].C(=O)(O)[O-].[Na+]>COCCOC.C(O)(=O)C.O>[F:3][C:4]1[C:12]2[N:11]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH2:22][CH2:23][N:24]([CH2:28][C:29]4[N:30]=[CH:31][NH:32][C:33]=4[CH3:34])[C:25](=[O:26])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c1c1cccc(F)c1n2COCc1ccccc1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2COCc2ccccc2)C1=O
Reaction time: 18 h
Yield: 306 %

Procedure:
Sodium hydride (60% dispersion in oil; 28 mg) was added to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-1-one (190 mg) in dry DME (10 ml). The mixture was heated at 50° for 6 h then treated with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl) -1H-imidazole (261 mg) and stirring was continued under nitrogen for 18 h. Water (2 ml) and acetic acid (2 ml) were added and the solution was heated at reflux for 2.5 h. The solution was poured into 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 750 mg) which was purified by FCC eluting with System A (200:10:1) to give the title compound (188 mg), t.l.c (System A, 200:10:1) Rf 0.33.
Reaction SMILES: C(N1CCCCC1)=O.S(Cl)(Cl)=O.[Cl:13][C:14]1[C:15]2[N:16]([CH:24]=[C:25]([C:27]([OH:29])=O)[N:26]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.COC(C1N=C2C([Cl:42])=CC(C(F)(F)F)=CN2C=1)=O>CO.C1(C)C=CC=CC=1>[Cl:13][C:14]1[C:15]2[N:16]([CH:24]=[C:25]([C:27]([Cl:42])=[O:29])[N:26]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: COC(=O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: O=CN1CCCCC1
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Temperature: 90 °C
Reaction time: 1.25 h

Procedure:
To a 3000 mL three-neck round bottom flask equipped with an overhead stirrer, thermo pocket, addition funnel and nitrogen tube was charged toluene (1000 mL), N-formyl piperidine (3.54 g, 0.031 mol) and thionyl chloride (67 g, 0.559 moles) at 23° C. under nitrogen atmosphere. The resultant reaction mass was heated to 82° C. and to this 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (100 g, 0.373 moles) (prepared as in WO 2010/129500) was charged lot wise (5 lots) over a period of 60 min. The walls of the reactor were rinsed with 500 mL toluene. After addition, the resultant reaction mass was stirred at 90° C. for 75 min and the progress of the reaction was monitored by HPLC. For this, 0.5 mL of the reaction mass was diluted with 3 mL of methanol and the formation of acid chloride was analyzed indirectly by detecting its corresponding methyl ester by HPLC). After 2 hours, HPLC analysis indicated about 0.35 a % of unreacted 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid and about 99.0 a % of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester. The resultant reaction mass was further heated to 140° C. (oil bath temperature) and distilled at about 109° C. (mass temperature) and 105-107° C. (vapor temperature) at atmospheric pressure over a period of 2.5 hours to remove toluene (about 600 mL) and excess thionyl chloride present in the reaction mass. After distillation, the reaction mass was gradually cooled to 30° C. over a period of 60 min. The concentration of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid was about 0.07 a % and the concentration of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester about 99.2 a % as measured by HPLC at 230 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30]COCC[Si](C)(C)C)=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)[CH:15]=[CH:16][C:10]=3[C:9](=[O:28])[NH:8][C:7]=2[CH:29]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[OH:30][C:4]1[C:3]([O:2][CH3:1])=[CH:29][C:7]2[NH:8][C:9](=[O:28])[C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)=[CH:13][C:11]=3[NH:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1OCOCC[Si](C)(C)C)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1O)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 476H (429 mg, 0.8 mmol) in methylene chloride (20 mL) and methanol (10 mL) was treated with 4N HCl/dioxane (1 mL, 4.0 mmol) and stirred one hour at room temperature. The mixture was concentrated under vacuum to provide 325 mg (quantitative) of desired product. MS (ESI) m/e 408 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.57 (s, 1H), 8.89 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.26-7.35 (m, 3H), 6.59 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[C:27]([O:26][C:24]([CH2:23][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
Sodium hydride (115 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (600 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. t-Butyl bromoacetate (562 mg) was added thereto and stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized and then extracted with dichloromethane. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-t-butoxycarbonylmethyl-1H-indole-5-carboxylate (944 mg, Y.: quant.).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[C:21](OC)=[O:22])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>O1CCCC1CCO>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH:20]([CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14][CH2:15]2)[CH2:21][OH:22])[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Ca+2]
Product: CC(C)(C)OC(=O)N1CCC(CC(CO)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Under ice cooling, calcium chloride (968 mg; 8.8 mmol) and sodium borohydride (668 mg; 17 mmol) were added to a solution in tetrahydrofuran-ethanol (9 ml-14 ml) of methyl 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl]acetate (1.0 g; 2.1 mmol) synthesized by the process described in Referential Example 3, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resultant concentrated residue was dissolved in chloroform. The solution was washed successively with 3N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 900 mg (yield: 96%) of 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]ethyl alcohol as a colorless oil.