Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:20])=[C:6]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[C:5]([Cl:20])=[C:6]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:14])([F:15])[F:16])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@](O)(C(=O)Nc1cccc([N+](=O)[O-])c1Cl)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1cccc(N)c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a stirred solution of (R)-N-[3-nitro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 3) (14.3 g) in EtOAc (250 ml) under a hydrogen atmosphere was added 10% palladium on carbon (1.6 g). The reaction mixture was allowed to stir at room temperature overnight; the mixture was filtered through a pad of diatomaceous earth and volatile material was removed by evaporation to give the title compound (13 g) as a brown solid. NMR (CDCl3) 1.75 (s, 3H), 4.00 (s, 1H), 4.10 (brs, 2H), 6.61 (d, 1H), 7.08 (t, 1H), 7.72 (d, 1H), 8.77 (brs, 1H); m/z: 281.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([Cl:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])=[C:11]([Cl:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Clc1cc(OCc2ccccc2)ccc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 60 °C

Procedure:
To a solution of 4-(benzyloxy)-1-bromo-2-chlorobenzene (1 g, 3.36 mmol) in THF (10 ml) was added 2-tert-butoxy-2-oxoethylzinc chloride (13.44 ml, 6.72 mmol). Nitrogen gas bubbled through the mixture for 10 min. then Pd2(dba)3 (0.154 g, 0.180 mmol) and X-PHOS (0.160 g, 0.336 mmol) were added and the resulting mixture heated at 60° C. for 50 min. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1×15 mL), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 50M, using a gradient eluant of EtOAc/Hexane (0-20%) to afford the title compound. LC/MS (m/z): 333 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[F:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[F:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccncc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cnccc1NC1CCNCC1

Procedure:
A solution of 4-(3-fluoro-pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.54 mmol) in dioxane (10 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 196.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.Cl.[CH2:21]([O:23][C:24](=[O:32])[CH:25](N)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:22]>N1C=CC=CC=1>[CH2:21]([O:23][C:24](=[O:32])[CH:25]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:16])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:22]
Reactant: N=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC

Procedure:
A suspension of 9.2 g. of 5-chloro-2-hydroxy-benzophenone imine in 60 ml. of ethanol is treated with 12.6 g. of aminomalonic acid diethyl ester hydrochloride and 5.0 ml. of pyridine and the mixture boiled at reflux for 1 hour while stirring. The mixture is then concentrated to dryness under reduced pressure and the residue partitioned between toluene and water. The organic phase is washed with water, briefly dried over sodium sulfate and evaporated to dryness. The residual oily residue crystallizes upon trituration with hexane. There is obtained [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester, having a melting point of 55°-56° C. Recrystallization from ethanol yields gold-yellowish leaflets having the same melting point.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.C1(C)C=CC=CC=1.O>CO>[CH3:1][O:2][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[Br:4]
Reactant: C[O-]
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A temperature of 59.8 g of a 28% solution of sodium methoxide in methanol was raised to 60° C., a mixture solution of 70.4 g of o-bromobenzyl bromide and 70.4 g of methanol was added dropwise, and this was retained at 60° C. for 2 hours. After the mixture was cooled to room temperature, 211 g of toluene and 211 g of water were added thereto, the mixture was stirred, and layers were separated, and an organic layer was recovered. An aqueous layer was extracted with 211 g of toluene three times, the recovered organic layer and 211 g of water were added, and this was washed, and concentrated to obtain 55.3 g of 1-methoxymethyl-2-bromobenzene.
Reaction SMILES: CC1(C)COB([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=2)OC1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[Cl:32])[NH:28][CH:27]=[C:26]2[CH:33]=[O:34].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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].C(OCC)(=O)C>[Cl:32][C:31]1[CH:30]=[C:29]2[C:25]([C:26]([CH:33]=[O:34])=[CH:27][NH:28]2)=[CH:24][C:23]=1[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([CH3:17])([CH3:18])[CH2:15][OH:16])=[CH:19][CH:20]=1
Reactant: CC1(C)COB(c2ccc(OCC(C)(C)CO)cc2)OC1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(CO)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Temperature: 110 °C
Yield: 79.8 %

Procedure:
To a solution of 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]-2,2-dimethylpropan-1-ol (60 mg, 0.21 mmol) in toluene (6 mL) was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (64 mg, 0.25 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.021 mmol), 2 M aqueous potassium carbonate (0.42 mL, 0.84 mmol) and ethanol (2 mL). The reaction mixture was degassed with nitrogen for 3 min and heated to 110° C. by microwave irradiation for 1 h. The cooled reaction mixture was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (30 mL) and washed with brine (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash chromatography to give 6-chloro-5-[4-(3-hydroxy-2,2-dimethylpropoxy)phenyl]-1H-indole-3-carbaldehyde (60 mg, 82%) as an off-white solid.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH3:11])C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCCCCC>COC(C)(C)C.O1CCCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][C:34](=[CH:9][O:10][CH3:11])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1
Reactant: O=C1CCC(c2ccc(Br)cc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: COC=C1CCC(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
20.4 g of triphenyl-methoxymethyl-phosphonium chloride were suspended in 60 ml of t-butyl methyl ether while gassing with argon in a sulphonation flask having a thermometer, mechanical stirrer, dropping funnel and solid substance addition tube and treated at -10° C. within 10 minutes with 6.6 g of solid potassium t-butylate. After completion of the addition the mixture was stirred at -10° C. to 0° C. for 30 minutes, then the deep orange, heterogeneous reaction mixture was treated dropwise at 0° C. with a solution of 10 g of 4-(4-bromophenyl)cyclohexanone in 50 ml of absolute tetrahydrofuran, subsequently stirred at room temperature for 24 hours, poured into 500 ml of hexane and filtered. Low-pressure chromatography of the concentrated residue (13.9 g) on silica gel with hexane/ethyl acetate (vol. 9:1) gave 10.4 g of 1-bromo-4-[4-(methoxymethylidene)cyclohexyl]benzene as a colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][P:11](=[O:18])(CC2CC2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.[ClH:19]>C(O)C>[ClH:19].[CH:2]1([CH2:1][N:8]2[CH2:9][CH2:10][PH:11](=[O:18])[CH2:12][CH2:13]2)[CH2:7][CH2:6]1
Reactant: O=P1(CC2CC2)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: O=[PH]1CCN(CC2CC2)CC1
Yield: 92 %

Procedure:
The material from Step 5 was dissolved in ethanol (80 mL) and aqueous HCl (40 mL, 1 M) was added. The solution was degassed with a stream of nitrogen and palladium on carbon (10%, 1.0 g) was added. The mixture was hydrogenated on a Parr shaker overnight at 20 psi. The reaction mixture was filtered through Celite and the solvents were removed under reduced pressure. The product was dissolved in methanol, and benzene was added. The solvents were removed by rotary evaporation. The product was recrystallized from ethanol/diethyl ether to yield 3.526 g of 4-(cyclopropylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride (16.83 mmol, 92%) as a white crystalline solid. 1H NMR (400 MHz, DMSO) 9.60-9.30 (d, 2H); 3.42-3.29 (m, 4H); 2.32-2.21 (m, 2H); 2.16-2.03 (m, 2H); 1.91-1.85 (d of d, 2H); 0.95-0.85 (m, 1H); 0.59-0.51 (m, 2H); 0.26-0.20 (m, 2H); ESMS (m/z): (M+1)+found, 174; (M+23)+ found, 196.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[N:20]=[C:19]([N:23]([CH3:25])[CH3:24])[N:18]([CH3:26])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[N:20]=[C:19]([N:23]([CH3:24])[CH3:25])[N:18]([CH3:26])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: CN(C)c1nc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)c1nc(=O)n(-c2cc(O)c(Cl)cc2F)c(=O)n1C
Yield: 89.2 %

Procedure:
A mixture of 4.62 g (11.4 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H)-dione and 460 mg of 10% palladium on charcoal in 50 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 14 hour period. It was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel eluting with a 1:1 v:v mixture of ethyl acetate and hexane to give 3.2 g of the title compound as a pale grey solid, m.p.: 247°-249° C. (dec); 1H-NMR (DMSO-d6) ppm 7.45 (d, 1H), 6.95 (d, 1H), 3.3 (s, 3H), 3.0 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[O:12][C:13]3[C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].O.[NH4+:25]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[O:12][C:13]3[C:19]([C:20]([NH2:25])=[O:22])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN(C)C)c3)oc12
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
Methyl 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (66 mg, 0.18 mmol) and ammonium water (50.4 mg, 1.44 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (12 mg, yield 22%). 1H-NMR (400 MHz, DMSO-d6) δ 2.88 (s, 5H), 4.36 (s, 2H), 7.02 (s, 1H), 7.37-7.41 (t, J=8 Hz, 1H), 7.54-7.61 (m, 2H), 7.84-7.86 (d, J=8 Hz, 1H), 7.97-7.99 (d, J=8 Hz, 1H), 8.28-8.29 (d, J=4 Hz, 1H), 8.50 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[OH-].[Mg+2:6]>>[C:1](=[O:4])([OH:3])[O-:2].[Mg+2:6].[C:1](=[O:4])([OH:3])[O-:2]
Reactant: O=C=O
Reactant: [OH-]
Agent: [Mg+2]
Product: O=C([O-])O

Procedure:
The instant invention is based upon the discovery of a method for recovering extremely high purity magnesium carbonate from a magnesium hydroxide slurry. The magnesium hydroxide slurry can be produced in any conventional way, for example by adding lightly burned dolomite or lime, preferably the former, to sea water or the like to precipitate magnesium hydroxide, and then processing the precipitated hydroxide in a conventional way. The slurry can also be produced by suspending in water burned magnesite, burned dolomite or other natural or processed materials which will form magnesium hydroxide that can be carbonated. Materials which form slurries containing less than about 90 percent of magnesium oxide, on a dry solids basis, are comparatively undesirable because they usually contain substantial amounts of water-soluble impurities which contaminate the final product and, in addition, are expensive because they require large quantities of high purity carbon dioxide. The method of the invention involves carbonating a magnesium hydroxide slurry to produce magnesium bicarbonate, and then continuing the carbonation to convert a part of the magnesium bicarbonate to a crystalline magnesium carbonate so that the slurry contains both dissolved magnesium bicarbonate and a crystalline magnesium carbonate precipitate. Insoluble material is subsequently removed from the carbonated slurry by filtration, and the filtrate is decarbonated, for example by heating, vacuum, or both. Finally, hydrous magnesium carbonate of high purity, which is precipitated as a result of the decarbonation, is recovered, for example by filtration.
Reaction SMILES: Cl.O[CH:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]1[CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21].C([OH:30])(C)C>CO.[Pd]>[OH:30][C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]([CH2:15][CH2:16][NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])[CH2:3][CH2:8]1
Reactant: CC(C)O
Reactant: NC(=O)c1ccccc1NCCN1CCC(c2ccccc2)CC1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1ccccc1NCCN1CCC(O)(c2ccccc2)CC1

Procedure:
2-[-(2-[Hydroxy-4-phenylpiperidyl]ethyl)amino]benzamide hydrochloride (12 g.) in 200 ml methanol was hydrogenated at 60 psi using 1.5 g 5% Pd-C catalyst (1.5 g and 1.0 g portions of fresh catalyst were added during the reduction). The catalyst was filtered off and the filtrate concentrated to dryness on the rotovap. The residue was recrystallized from 60 ml isopropanol and then from 300 ml isopropanol to give 6.1 product, m.108-13°. Analysis showed 13.39% isopropanol in the product.
Reaction SMILES: [C:1]([C:3]1([C:14]2[C:19]3[N:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[O:22][C:18]=3[C:17]([O:26][CH3:27])=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].[Na+].[Cl-].O>CS(C)=O>[C:1]([C:3]1([C:14]2[C:19]3[N:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[O:22][C:18]=3[C:17]([O:26][CH3:27])=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc(C(C)C)nc23)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)c2nc(C(C)C)oc12
Temperature: 140 °C
Reaction time: 8.5 h
Yield: 77.5 %

Procedure:
0.69 g (1.86 mmol) of methyl 5-cyano-5-(2-isopropyl-7-methoxybenzoxazol-4-yl)-2-oxocyclohexanecarboxylate (starting compound A8) is dissolved in 16 ml of DMSO, a solution of 0.73 g of NaCl in 2 ml of dist. water is added and the mixture is stirred at 140° C. for 8.5 h. After cooling the reaction mixture, it is diluted with 80 ml of dist. water and extracted with ethyl acetate, and the organic phase is separated off, dried over magnesium sulfate and concentrated to dryness in vacuo. After chromatography, the title compound (0.45 g) is obtained as a colorless solid. TLC, silica gel (glass plates), petroleum ether/ethyl acetate (7:3), Rf=0.56, m.p. 118° C.
Reaction SMILES: [ClH:1].C1(C[O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([C:17]4[N:21]5[CH:22]=[C:23]([C@@H:26]([N:31]6[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32]6)[C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:20]5=[N:19][N:18]=4)=[N:14]3)=[CH:9][C:8]=2[F:37])CC1>Cl.CC(O)C>[ClH:1].[NH2:36][C@H:33]1[CH2:34][CH2:35][N:31]([C@H:26]([C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:17]([C:13]4[CH:12]=[CH:11][C:10]5[C:15](=[CH:16][C:7]([OH:6])=[C:8]([F:37])[CH:9]=5)[N:14]=4)=[N:18][N:19]=3)[CH:22]=2)[C:27]([F:29])([F:28])[F:30])[CH2:32]1
Reactant: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCC6CC6)cc5n4)n3c2)C(F)(F)F)C1
Agent: Cl
Solvent: CC(C)O
Product: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(O)cc5n4)n3c2)C(F)(F)F)C1
Yield: 80.8 %

Procedure:
(S)-1-((R)-1-(3-(7-(cyclopropylmethoxy)-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride (Example 134; 50 mg, 0.1 mmol) was heated to 60° C. in 6N HCl in IPA for 3 days. After concentration, the residue was dissolve in 1 mL of MeOH then added to 2N HCl in ether. The resulting solid was dried under high vacuum to yield 2-(6-((R)-1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-ol hydrochloride (39 mg, 87% yield) as a solid. LCMS APCI (+) m/z 447 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9]([CH:10]=O)=[C:8]([O:19][CH3:20])[CH:7]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9](/[CH:10]=[CH:24]/[C:23]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)=[O:25])=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1C=O
Product: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 72 %

Procedure:
The title compound was prepared by condensing 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50C) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 72% yield, mp 191–192° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.29–8.32 (m, 3H), 8.09 (d, 1H, J=16.0 Hz), 7.99 (d, 2H, J=8.1 Hz), 7.92 (d, 1H, J=16.0 Hz), 7.70 (d, 1H, J=3.3 Hz), 7.53–7.56 (m, 3H), 7.14 (dd, 1H, J=5.4, 3.3 Hz), 6.87 (s, 1H), 4.61 (t, 2H, J=5.1 Hz), 4.28 (d, 2H, J=5.1 Hz), 4.00 (s, 3H), 3.60–3.67 (m, 4H), 2.11–2.15 (m, 1H). MS (ESI) m/z=504 ([M+H]+, 100%). Anal. Calcd. for C24H25NO7S2.½H2O: C, 56.23; H, 5.11; N, 2.73; S, 12.51. Found: C, 56.32; H, 5.06; N, 2.83; S, 12.55.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[N:20]=2)[CH:16]=[CH:15][C:14]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=3)[N:20]=2)[CH:16]=[CH:15][C:14]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(Cl)c3)n2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridiniumchlorochromate (3.6 g, 0.017 mol) is added to a solution of {4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-phenyl}-methanol (4.0 g, 0.011 mol) in dichloromethane (40 mL). The reaction mixture is stirred at room temperature for 30 minutes, filtered and washed with dichloromethane (40 mL). Filtrate is concentrated under reduced pressure to give crude which is purified by column chromatography (230; 400 mesh: 9.5:0.5 toluene:ethyl acetate) to yield 4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
5.1 g of (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (Liebich's Annalen der Chemie 529 (1937), page 1) are dissolved in 20 ml of pyridine, and 50 ml of tert.-butanol are added thereto. The solution is cooled to a temperature below -5° C., and 3.5 g of phosphorous oxychloride are added dropwise thereto. The mixture is stirred at the same temperature for about 30 minutes and then at room temperature for 3 hours. The reaction mixture is poured into 200 ml of ice-water, and extracted with ethyl acetate. The extract is washed with 1% hydrochloric acid, an aqueous sodium bicarbonate solution and water, successively. Then, the extract is dried and evaporated to remove solvent. The residue obtained is crystallized with a mixture of ether and n-hexane. 5.5 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 89.0%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Si:32]([O:23][CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][C:11]1=[O:26])[CH2:24][CH3:25])([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 44.7 g (114 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 185, Step B) and 19.4 g (285 mmol) of imidazole in DMF (350 mL) was added 39.4 mL (154 mmol) of tert-butyldiphenylsilyl chloride. The colorless solution was stirred at room temperature for 17 h. The reaction was partitioned between water and ethyl ether (3×), and then the combined organic layers were washed with saturated aqueous sodium chloride (1×), dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 60% EtOAc/hexanes, gradient elution) provided the title compound as a white foam.