Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>C(#N)C>[F:27][C:28]([F:33])([F:32])[C@@H:29]([OH:30])[CH2:31][N:12]1[CH2:13][CH2:14][O:15][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11]1
Reactant: FC(F)(F)c1cccc(C2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O[C@@H](CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
In a 50 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine hydrochloride (515 mg, 1.92 mmol) and DIPEA (249 mg, 336 μl, 1.92 mmol) were combined with acetonitrile (10 ml) to give a white suspension. (S)-2-(trifluoromethyl)oxirane (323 mg, 2.89 mmol) was added. The reaction mixture was stirred at room temperature for 3 days and then was concentrated in vacuo. The reaction mixture was taken up in 100 mL dilute aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford 528 mg (80%) of (2S)-1,1,1-trifluoro-3-(2-(3-(trifluoromethyl)phenyl)morpholino)propan-2-ol, which was used as is in the next step. (M+H)+=344 m/e.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[C:24]([C:27]1[S:28][C:29](B(O)O)=[CH:30][CH:31]=1)([OH:26])=[O:25].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.COCCOC.CCO>[C:11]([O:10][C:9]([N:8]([CH:16]1[CH2:18][CH2:17]1)[C:6]1[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=[C:2]([C:29]2[S:28][C:27]([C:24]([OH:26])=[O:25])=[CH:31][CH:30]=2)[CH:7]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
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: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(c1cc(-c2ccc(C(=O)O)s2)nc2c(C=O)cnn12)C1CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 2.97 mmol) in 30 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-carboxythiophene-5-boronic acid (766 mg, 4.45 mmol), tetrakis(triphenylphosphine)palladium(0) (171 mg, 0.148 mmol), and 2M aqueous solution of Na2CO3 (4.45 mL, 8.91 mmol). The mixture was stirred at 95° C. for 3 hours then cooled to room temperature and partitioned between 2N NaOH and ethyl acetate. The layers were separated and the aqueous layer was acidified to pH<3 with conc. HCl. The aqueous layer was extracted (3×) with methylene chloride. The combined organic layers was washed with brine, dried over MgSO4, filtered, and evaporated to dryness to provide 450 mg of 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid. Some additional material which was in the first ethyl acetate layer was purified by silica gel chromatography (0%-20% MeOH/CH2Cl2) to provide another 550 mg of 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (79%). LCMS (M+1=429)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: BrCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3cccnc3)c2c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 1.00 g, 3.86 mmol) in DMF (50 ml) was added NaH (463 mg, 19.3 mmol) and and 3-(bromomethyl)pyridine (2.62 g, 15.4 mmol). The reaction was stirred at 60° C. for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][NH2:38]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:38][CH3:37])=[O:34])=[CH:35][CH:36]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 40 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:30]4[CH:31]=[CH:32][C:33]5[C:37]([CH:38]=4)=[N:36][N:35]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:34]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:39]([N:35]1[CH:34]=[C:33]2[C:37]([CH:38]=[C:30]([C:22]3[CH:21]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:28]4[C:23]=3[C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)[CH:31]=[CH:32]2)=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(-c3cccc(N4CCNCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1 h
Yield: 30 %

Procedure:
The product from step 5 (55 mg, (0.09 mmol) was dissolved in 1 mL of CH2Cl2 and 1 mL of TFA was added dropwise. The mixture stirred for 1 hour and then concentrated to dryness. The residue was dissolved in acetonitrile and water was added and the pH was adjusted to 9 by the addition of aqueous K3PO4. The mixture was concentrated in vacuo and the solids obtained were extracted with MeOH, and then concentrated in vacuo again. The solid residue obtained was re-extracted with MeOH, filtered and the filtrate purified by preparative HPLC to provide 14 mg (30%) of the title compound. 1H-NMR (DMSO-d6) 8.35 (s, 1H), 7.61 (s, 1H), 7.58 (bs, 2H), 7.39-7.24 (m, 7H), 7.22 (s, 1H), 7.11-7.01, (m, 2H), 6.77 (d, 1H), 6.57 (d, 1H), 6.26 (d, 1H), 5.57 (s, 2H), 3.10 (m, 4H), 2.84 (m, 4H); LC-MS [M+H]+=501.2, RT=2.24 min.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:31](=[O:32])[NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
To a methylene chloride solution (25 mL) of N-tert-butoxycarbonylpiperazine (2.50 g, 13.4 mmol), 4-phenoxyphenyl isocyanate (2.83 mL, 13.4 mmol) was added, followed by stirring at room temperature overnight. Methanol was added to the reaction solution, and the solvent was evaporated to give the target compound (5.71 g, 14.4 mmol).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[I:12].Br/[C:14](=[CH:19]\[CH3:20])/[C:15]([O:17][CH3:18])=[O:16].CN1C(=O)N(C)CCC1>C1COCC1>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:20][CH:19]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([I:12])[CH:6]=1)#[N:9]
Reactant: C/C=C(\Br)C(=O)OC
Reactant: N#Cc1ccc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C=CCOc1ccc(C#N)cc1I
Temperature: 55 °C
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
To a cooled (0° C.) suspension of NaH (1.5 g of 60% suspension in mineral oil, 38 mmol) in THF (80 mL) was added a solution comprised of 4-hydroxy-3-iodo-benzonitrile (8.4 g, 34 mmol) (reference example 12), methyl bromo-crotonate (6.65 mL tech. grade, approx. 51 mmol) and DMPU (10 mL) in THF (20 mL). On complete addition, the cold bath was removed and replaced with an oil bath. The reaction mixture was heated to 55° C. and stirred at this temperature for 4.5 hr, cooled to room temperature and acidified with 2M aqueous HCl. The mixture was then diluted with ethyl acetate, washed sequentially with water and brine, dried over MgSO4 and concentrated. The residue was triturated with hexane several times, leaving 8.6 g of the title compound as a solid. 1H NMR (CDCl3) d 3.78 (s, 3H), 4.80 (dd, J=4, 1 Hz, 1H), 6.35 (dt, J=16, 1 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 7.05 (dt, J=16, 4 Hz, 1H), 7.60 (dd, J=8, 1 Hz, 1H), 8.06 (d, J=1 Hz, 1H). MS (EI) m/z 343 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Cl.[H-].[Na+]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])/[CH:17]=[CH:16]/[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[Cl:25])=[CH:11][N:10]=2)=[C:2]([F:1])[CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(O)cn2)c(F)c1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(OCc3ccccc3Cl)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DMF (40 mL) solution of butyl (E)-3-{3-fluoro-4-[(5-hydroxypyridin-2-yl)oxy]phenyl}prop-2-enoate (3.82 g) and 2-chlorobenzyl chloride (1.6 mL) was added sodium hydride (60% w/w in oil, 0.60 g) at 0° C., and stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of saturated NH4Cl (90 mL), and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=19/1 to 9/1) to afford (E)-3-[4-({5-[(2-Chlorobenzyl)oxy]pyridin-2-yl}oxy)-3-fluorophenyl]prop-2-enoic acid butyl ester (3.53 g).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:21][OH:22]>>[C:1]([N:9]1[CH:14]([O:22][CH3:21])[CH2:13][CH2:12][CH2:11][CH:10]1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC1CCCCN1C(=O)c1ccccc1
Agent: F[B-](F)(F)F
Product: COC1CCCC(C)N1C(=O)c1ccccc1
Yield: 77.6 %

Procedure:
In the same manner as in Example 5, there are electrolyzed 43.8 g of 1-benzoyl-2-methylpiperidine and 60.2 g of methanol in the presence of 0.3 of tertramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-benzoyl-2-methylpiperidine the current is switched off. After work-up of the electrolysis solution, 39.0 g of 1-benzoyl-2-methyl-6-methoxypiperidine (boiling point 78°-81° C./0.1 mm Hg; nD25 = 1.5340) are obtained which corresponds to a product yield of 77.5% and a current efficiency of 62.0%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6]/[N:7]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(OC)c(CCN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: COc1ccc(OC)c(CC/N=C/c2ccccc2)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Under an argon atmosphere, a solution of 2,5-dimethoxyphenethylamine (3.175 g) in benzene (4 mL) was added with stirring to a suspension of benzaldehyde (1.86 g) and magnesium sulfate (3.89 g) in benzene (10 mL). An exothermic reaction took place, followed by further stirring overnight. After the reaction was complete, the reaction liquid was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(2,5-dimethoxyphenyl)-N-[(1E)-phenylmethylene]ethanamine (4.72 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:21]1([CH2:20][CH2:19][C:18]2[O:27][C:14]3[C:15]4[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=4[CH:11]=[CH:12][C:13]=3[N:17]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)CCc3ccccc3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(CCc4ccccc4)oc3c21
Yield: 28.7 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-3-phenylpropanamide (72.5 mg, 0.198 mmol) and pyridinium p-toluenesulfonate (12.4 mg, 0.0493 mmol) were heated under reflux in xylene (5 mL) for 2.5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→60/40) and recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (19.8 mg, yield 29%).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[C:15]([NH2:24])(=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>C1(C)C(C)=CC=CC=1>[OH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:15]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:24]=1
Reactant: NC(=O)c1ccccc1O
Reactant: O=C(O)c1ccccc1O
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: O=c1nc(-c2ccccc2O)oc2ccccc12
Temperature: 37.5 °C
Reaction time: 0.5 h

Procedure:
Xylene (1.5 L) and salicylic acid (1 Kg.) was added to a 5 L 4-neck round bottom flask equipped with a mechanical stirrer and thermocouple. Thionyl chloride (1.29 kg) was added at 10° C. to 15° C. After addition of thionyl chloride reaction mass is stirred at 10° C. to 15° C. for 30 minutes. Reaction mass is heated at 35-40° C. for 1 hr. Salicylamide solution (0.891 kg in 2.0 lit of Xylene) was added in reaction mass at 25° C.-30° C. After addition reaction mass was gradually heated at 80° C.-126° C. and stirred for 2 hrs. After the completion of reaction excess of Xylene was distilled out. Methanol was added in the reaction mass at 70° C.-80° C. and stirred for 1 hr. gradually cooled the reaction mass at 25-30° C. Filtered the solid and washed with Methanol and sucked it dry. Dry the obtained solid at 55-60° C. under vacuum tray drier.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B(O)O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([Pb+3:17])[CH:26]=2)=[CH:21][CH:20]=1
Reactant: [Pb+4]
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Agent: CC(=O)[O-]
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Temperature: 40 °C
Yield: 100 %

Procedure:
To a mixture of lead tetraacetate (2.44 g, 5.50 mmol) and mercuric diacetate (0.16 g, 0.50 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40° C., and 4′-chloro-4-methylbiphenyl-3-ylboronic acid (1.23 g, 5.00 mmol) is added in one portion, and the suspension is heated at this temperature for 5 hours. After cooling to room temperature the mixture is concentrated to a small volume, then triturated with hexanes and filtered to yield crude 4′-chloro-4-methylbiphenyl-3-yllead triacetate (2.93 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]4=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]4[N:25]=[C:24]3[CH3:34])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:34][C:24]1[N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:17][CH:18]=2)[C:27]2=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 4-[4-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-ylmethyl)phenylamino]methylpiperidine-1-carboxylic acid tert-butyl ester (1.53 g, 3.31 mmol) obtained in Step 1 in chloroform (15 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (7.0 mL) followed by stirring at room temperature for 2 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 157 (1.20 g, 3.3 mmol, 99%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH3:22])[C@@H:10]1[CH2:23][O:24]CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:32]>[Pd].C(O)C>[ClH:32].[OH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH3:22])[C@@H:10]1[CH2:23][OH:24]
Reactant: CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1C[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 20 h
Yield: 88 %

Procedure:
A mixture of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-methylpyrrolidine (Compound 3) (38 mg, 0.067 mmol), 10% Pd/C (30 mg), 4 N HCl (0.1 ml) and 99.9% ethanol (5 ml) was reduced in a Parr apparatus at 40 psi for 20 hours. The mixture was filtered and evaporated in vacuo to give (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine, hydrochloride (15 mg, yield 88%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=2.[H+].[B-:18]([F:22])([F:21])([F:20])[F:19].[N:23]([O-])=O.[Na+]>O1CCCC1.O>[F:19][B-:18]([F:22])([F:21])[F:20].[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[N+:1]#[N:23]
Reactant: O=N[O-]
Reactant: COc1cc2ncc(N)c(Cl)c2cc1OC
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2ncc([N+]#N)c(Cl)c2cc1OC
Yield: 89 %

Procedure:
3-amino-4-chloro-6,7-dimethoxyquinoline (3.3 g) was dissolved in tetrahydrofuran (70 ml) with stirring and then cooled in an ice/water bath to below 10° C. 48% aqueous fluoboric acid (7.3 ml) was then added and the mixture stirred for 5 minutes. A solution of sodium nitrite (1.05 g) in water (2 ml) was added keeping the temperature below 10° C. The reaction mixture was then stirred for 30 minutes with cooling. The resulting yellow solid was filtered off, washed with fresh tetrahydrofuran. Carefully vac dried. To give 4-chloro-6,7-dimethoxyquinoline-3-diazonium tetrafluoroborate (4.15 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([OH:28])=O)[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1.Cl.CN.C[CH2:41][N:42]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([NH:42][CH3:41])=[O:28])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1C(=O)CC(c2cc(F)ccc2C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg, 0.13 mmol) prepared in example 146d, Methylamine hydrochloride (11 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (69 mg, 0.533 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-(methylamino-carbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (29 mg as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34]>>[Br:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:2]2[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[C:32]([C:33](=[O:34])[NH:35][CH3:36])[CH:37]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1cc(Br)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 106A. MS (ES+): m/z 646.31 (100) [MH+]; HPLC: tR=1.14 min (UPLC, purity).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[NH:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=O)[N:19]=2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[N:21]=[C:20]([C:28]3[O:1][N:2]=[C:3]([C:5]4[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=4)[N:4]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: N=C(NO)c1ccncc1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2nc(-c3ccncc3)no2)n1

Procedure:
The title compound was prepared from commercially available N-hydroxy-4-pyridinecarboxamidine [CAS-No. 1594-57-6] (0.103 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.088 g, 44%). MS (ISP) 404.1 [(M+H)+]; mp 187.5° C.