Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH2:16])[S:14][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:3]=[C:4]4[C:10]([C:11]5[N:12]=[C:13]([NH2:16])[S:14][CH:15]=5)=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Nc1nc(-c2c[nH]c3ncc(Br)cc23)cs1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5csc(N)n5)c4c3)cc2)CC1
Temperature: 175 °C

Procedure:
In a personal chemistry microwave reaction vial 4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (0.2 g, 0.67 mmol) and 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (0.23 g, 0.74 mmol), bis(triphenylphosphine)-palladium(II) dichloride (0.004 g, 0.006 mmol) in acetonitrile (2 mL), and 1 M Na2CO3 (2 mL) were added. The resulting mixture was de-gassed with N2 for 10 min, after which it was heated at 175° C. for 30 min in a Personal Chemistry Optimizer. The mixture was diluted with DMF (3 mL), and concentrated in vacuo and purified on silica gel column using dichloromethane and methanol to afford 4-{5-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-thiazol-2-ylamine.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].ClC[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=2[CH3:50])[CH2:39][CH2:38]1)=O>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:5])[CH2:34][CH2:35][N:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=3[CH3:50])[CH2:39][CH2:38]2)[N:9]=1
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Reactant: Cc1ccc(N2CCN(C(=O)CCCl)CC2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccc(C)cc5C)CC4)c3C2=O)cc1

Procedure:
A target compound (102.8 mg, 0.211 mmol, 55.7%) was yielded as white solid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (130 mg, 0.379 mmol) with potassium carbonate (57.6 mg, 0.417 mmol) and 3-chloro-1-{4-(2,4-dimethylphenyl)piperazin-1-yl}propan-1-one (111.7 mg, 0.398 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:23])([F:22])[F:21]>>[CH3:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:21])([F:22])[F:23]
Reactant: Cc1cc(B(O)O)ccc1OC(F)(F)F
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)c(C)c2)c1

Procedure:
2.7 g (12.5 mmol) of methyl 5-bromonicotinate and 3.3 g (15.0 mmol) of [3-methyl-4-(trifluoromethoxy)phenyl]boronic acid were reacted according to the General Method 1A. Yield: 3.1 g (80% of theory)
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH3:23])[N:9]=2)C(C)=CC=1.Cl.NO>C(O)C.O.O>[NH2:3][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH3:23])[N:9]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(C)c1OCc1ccccc1

Procedure:
To a stirred solution containing 2.85 g (9.27 mmol) 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-benzyloxy-4,6-dimethylpyrimidine (6) in 30 mL of ethanol-water 1:1 were added 6.44 g (93 mmol) of hydroxylamine hydrochloride. The reaction mixture was stirred at reflux overnight under argon atmosphere. The pH of the solution was then brought to 10 and diluted with 20 mL of water. The mixture was extracted with two portions of 30 mL of dichloromethane. The combined organic solution was dried (MgSO4) and then concentrate under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with acetone-hexanes 1:2 gave the expected product as white solid. Yield: 2.1 g (98%). 1H-NMR (CDCl3) δ 7.39 (m, 5H), 4.80 (br. 2H), 4.74 (s, 2H), 2.29 (s, 6H). 13C-NMR (CDCl3) 160.05, 158.45, 141.50, 137.02, 37.27, 19.22.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]1[CH2:36][O:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:32]4[CH2:31][CH2:30][CH2:36][O:35][CH2:34][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: C1CNCCOC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCCOCC4)c23)ccc1OCc1ccccn1
Yield: 20 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 13) and homomorpholine to give the title compound in 20% yield; NMR Spectrum: 1.74-1.79 (m, 2H), 2.75-2.78 (m, 4H), 2.97 (t, 2H), 3.56-3.58 (m, 2H), 3.61-3.64 (m, 2H), 4.41 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.55-7.58 (m, 2H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([O-:15])[CH:11]=2)[C:6]1=[O:19].[K+].S(OC)(O[CH3:26])(=O)=O>CN(C=O)C>[CH3:26][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N+:16]([O-:18])=[O:17])[C:6](=[O:19])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])[C:13]2=[O:14]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)CN1C(=O)c2cc([O-])c([N+](=O)[O-])cc2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)c2cc(OC)c([N+](=O)[O-])cc2C1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of potassium 2-(2-methoxy-2-oxoethyl)-6-nitro-1,3-dioxoisoindolin-5-olate (0.380 g, 1.194 mmol) in DMF (10 ml), dimethyl sulfate (0.324 ml, 3.34 mmol) was added, and the mixture was heated at 60° C. for 6 hours and then stirred at 40° C. overnight. Additional dimethyl sulfate (0.116 ml, 1.194 mmol) was added, and the reaction mixture was heated at 60° C. for 4 hours. The mixture was partitioned between 1N NaHCO3 (150 ml) and diethyl ether (100 ml). The organic phase was washed with 1N NaHCO3 (100 ml), and the combined aqueous layers were extracted with diethyl ether (2×100 ml). The organic layers were mixed, washed twice with brine (2×100 ml) and dried over sodium sulfate; the solvent was removed under vacuum affording methyl 2-(5-methoxy-6-nitro-1,3-dioxoisoindolin-2-yl)acetate (0.225 g, 0.765 mmol, 64% yield). MS/ESI+ 294.9 [MH]+). This product was used without any further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](O)(=O)[CH3:12]>>[C:1]1([NH:7][C:8]2[S:9][CH:11]=[CH:12][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CC(=O)O
Product: c1ccc(Nc2nccs2)cc1
Temperature: 100 °C

Procedure:
10 g (65.7 mmol) of phenylthiourea 37 were dissolved in 100 ml of acetic acid. 9.9 ml of the acetal 38 were added and the mixture was heated at 100° C. for 2 h. The solvent was removed i.v. and the residue was partitioned between 300 ml of 1N NaOH and 300 ml of ethyl acetate. The aqueous phase was extracted twice with in each case 100 ml of ethyl acetate and the combined organic phases were dried using magnesium sulfate. The solvent was removed and the residue was precipitated from 50 ml of diisopropyl ether. The solid was filtered off with suction and dried at 50° C. i.v. 2.5 g of aniline 39 were obtained. The diisopropyl ether mother liquor was evaporated and the residue was chromatographed on silica gel using heptane/ethyl acetate 2:1. This resulted in a further 3.5 g of 39 being obtained. Yield: 6.0 g (52%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][OH:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 65 °C
Yield: 80.8 %

Procedure:
A 2-necked 2-liter round bottom flask was charged with 2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}ethanol (95.0 g, 0.28 mol) and pyridine (400 mL). The suspension was heated to 65° C. To the resulting homogenous solution was added in one portion tert-butyldimethylsilyl chloride (46.4 g, 0.31 mol, 1.1 eq) and 4-(N,N-dimethylamino)pyridine (3.42 g, 0.028 mol, 0.1 eq). The reaction temperature rose to 87° C., was slowly cooled to 65° C., and was maintained overnight at this temperature. The reaction was determined to be incomplete. Additional tert-butyldimethylsilyl chloride (20 g, 0.13 mol, 0.5 eq) was added in one portion and the reaction temperature was increased to 70° C. for 8 hours. The reaction was still not complete. Additional tert-butyldimethylsilyl chloride (21.5 g, 0.14 mol, 0.5 eq) was added in one portion and the reaction was maintained at 70° C. overnight. The reaction was now complete. The reaction mixture was poured into a 2-liter flask, followed by an ethyl acetate rinse, and set aside over the weekend. A precipitate, determined to be pyridine hydrochloride, formed and was removed by filtration. The reaction mixture was then concentrated under reduced pressure to a brown/yellow solid. The solid was slurried in ethyl acetate and collected by filtration; this was repeated three times. The combined filtrates were washed with water and then concentrated to approximately one-third of the original volume until solid began to precipitate. The mixture was diluted with hexane (700 mL) and stirred for an additional hour. A light brown solid was collected by vacuum filtration and dried overnight to provide 102.6 g of 7-(benzyloxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-nitroquinolin-4-amine, which was used without further purification in the next step.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C)C(=O)C>[CH2:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCn1c2ccccc2c2ccccc21
Temperature: 0 °C

Procedure:
20 g of carbazole was dissolved in 100 mL dry N,N-dimethyl acetamide (DMAc) in a 500 mL round bottomed flask. NaH (60% in mineral oil) was added into the flask slowly in nitrogen to form a mixture. The mixture was stirred for 20 minutes in ice/water bath. 30 g of 1-bromohexane was then added slowly to the flask and stirred for 6 hours in ice/water bath. The resulting solution was poured into 2L deionized water and extracted with ethyl acetate several times. The extract was re-extracted by deionized water. The final extract was concentrated by a rotary evaporator and further purified by column chromatography. A product of the following structure was obtained.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:7]1)C.[OH-].[Li+]>>[Cl:24][C:19]1[CH:18]=[C:17](/[CH:16]=[CH:15]/[C:14]([N:9]2[CH2:10][CH2:11][C:12](=[O:13])[N:6]([CH2:5][C:4]([OH:26])=[O:3])[CH2:7][CH2:8]2)=[O:25])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CCOC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O

Procedure:
In analogy to the procedure described in intermediate 5C, {4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetic acid ethyl ester and 1 M aq. lithium hydroxide solution gave after acidification with aqueous 10% KHSO4, filtration and washing with water the title compound in quantitative yield as white solid. MS: 371.0 (MH+, 2Cl).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)CNCC[C@@H](N)CC(C)C
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H]1CCN(CC(C)C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 24.7 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based. [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 25%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (5 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.66 (m, 5H), 1.76-1.82 (m, 1H), 2.05-2.09 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.55-4.66 (m, 2H), 4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H), 7.31-7.34 (m, 2H), 8.27 (s, 1H), 10.49 (m, 1H), 12.61 (s, 1H); ES+ MS: 499 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:18]O>C(O)(=O)C>[CH:14]1[C:9]([NH:8][C:6]([C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[N+:3]([O-:18])[CH:4]=2)=[O:7])=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: OO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)[n+]([O-])c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (2.06 g, 8.2 mmole) in 30 mL of acetic acid was added 30 mL of aqueous hydrogen peroxide (30%). The mixture was warmed to 70° C. and stirred for 18 hours, and then 20 mL of additional hydrogen peroxide (30%) was added and stirred for 2 hours. The mixture was then cooled, concentrated in vacuo and diluted with water (100 mL). Isolation of the precipitate by vacuum filtration afforded 0.43 g (20%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ7.19 (m 2H), 7.75 (M, 3H), 7.95 (M, 1H), 8.94 (d, 1H, J=2.2 Hz), 10.5 (s, 1H); MS (EI) m/z 267.19 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:45]=[CH:44][C:6]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:11]=[CH:10][C:9]=2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:24][C:23]=2[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)(=[O:21])=[O:20])=[CH:5][CH:4]=1.[CH2:48]([O:50][SiH:51]([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[CH3:49]>[Pt].C1(C)C=CC=CC=1>[F:47][C:2]([F:46])([F:1])[C:3]1[CH:45]=[CH:44][C:6]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][Si:51]([O:55][CH2:56][CH3:57])([O:52][CH2:53][CH3:54])[O:50][CH2:48][CH3:49])[CH:11]=[CH:10][C:9]=2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][Si:51]([O:55][CH2:56][CH3:57])([O:52][CH2:53][CH3:54])[O:50][CH2:48][CH3:49])=[CH:24][C:23]=2[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:39]=2)(=[O:20])=[O:21])=[CH:5][CH:4]=1
Reactant: C=CCCOc1ccc(S(=O)(=O)c2ccc(OCCC=C)cc2Cc2ccc(C(F)(F)F)cc2)c(Cc2ccc(C(F)(F)F)cc2)c1
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCO[Si](CCCCOc1ccc(S(=O)(=O)c2ccc(OCCCC[Si](OCC)(OCC)OCC)cc2Cc2ccc(C(F)(F)F)cc2)c(Cc2ccc(C(F)(F)F)cc2)c1)(OCC)OCC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
After 0.61 g of 4-(trifluoromethyl)benzyl-4-(3-butenyloxy)phenyl sulfone and 20 mg of 10% platinum-active carbon were charged in a reaction vessel, and the inside of the vessel was then filled with nitrogen gas, 2 ml of triethoxysilane was added, and the mixture was then further stirred at 100° C. for 4 hours. After the reaction mixture was cooled to room temperature, 20 ml of toluene was added, and the mixture was filtered through a pad of Celite™. After the filtrate was concentrated, dehydrated ethanol was added to the residue, which was then left still over night. After precipitated crystal was removed by filtration, the filtrate was concentrated, and n-hexane was added to collect precipitated crystal by filtration. The obtained crystal was washed with n-hexane to produce 0.53 g of the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])[CH3:5].[CH3:20]I>CN(C=O)C>[CH3:6][C:4]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]1)=[O:9])([CH3:3])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.0 g, 41 mmol, 2.5 equiv) in DMF (30 mL) at −10° C. was added cis-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic acid (4.0 g, 16 mmol, 1.0 equiv). The reaction mixture was allowed to warm to room temperature and then was stirred for 1 h. The mixture was again cooled to −10° C., and MeI (25 g, 260 mmol, 16 equiv) was added dropwise. The cold bath was removed, and the reaction mixture was stirred for 3 h at room temperature. The mixture was poured onto ice, and then NaOH (1.5 g) was added to hydrolyze any undesired methyl ester that formed. This solution was stirred for another 4 hours. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure to remove the DMF. The resulting residue was diluted with water, and the pH was adjusted to ˜3-4. The desired product precipitated as a white solid which was collected by filtration (2.5 g).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].S(=O)(=O)(O)O.[CH3:17]O>>[C:1]([O:11][CH3:17])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of D-(-)-mandelic acid (20 g) in methanol (100 ml) was added concentrated sulfuric acid (6 g) and the mixture was refluxed for 2.5 hours. After cooling to room temperature it was concentrated to about 50 ml and the residue was dissolved in methylene chloride (about 300 ml). The solution was the washed with water, saturated sodium bicarbonte and water, dried (magnesium sulfate) and evaporated to give a clear oil, which crystallized upon cooling to give 21.7 g of methyl D-(-)-mandelate, a compound of Formula 6, wherein R5 is phenyl.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].B1([O-])O[O:17]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])[C:1]([OH:17])=[O:2])#[N:9]
Reactant: CC[C@@H](C)Oc1ccc(C=O)cc1C#N
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC[C@@H](C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 50 °C
Yield: 93.9 %

Procedure:
To a solution of 5-formyl-2-{[(1R)-1-methylpropyl]oxy}benzonitrile (D37) (310 mg, 1.53 mmol) in acetic acid (30 ml) was added sodium perborate tetrahydrate (471 mg, 3.05 mmol), the reaction mixture was heated at 50° C. over the weekend. The reaction mixture was concentrated in vacuo and water (˜50 ml) added, EtOAc (˜30 ml) was added and the layers partitioned, the aq layer was extracted twice more with EtOAc (˜30 ml) and the combined organics evaporated to dryness under reduced pressure to give the title compound (315 mg) as an off-white solid. δH (d6-DMSO, 400 MHz): 8.07-8.24 (2H, m), 7.38 (1H, d), 4.63-4.77 (1H, m), 1.55-1.83 (2H, m), 1.31 (3H, d), 0.95 (3H, t). MS (ES+): C12H13NO2 requires 219; found 220 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a solution of 4-(2-bromophenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 0.00562 mole), in DMF (10 mL) was added NaH (60% w/w dispersion in oil) (0.9 g, 0.02251 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (3.19 g, 0.0225 mole) was then added and stirring was continued for 30 minutes at ambient temperature. The reaction mixture was quenched with aqueous NH4Cl solution and the product was extracted with ether. The ether layer with washed with aqueous NaHCO3 solution followed by brine solution. The ether layer collected was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with ether and dried to afford 0.893 g (45%) of 4-[(2-bromo-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.6-7.54 (m, 1H), 7.28-7.2 (m, 1H), 7.14-7.08 (m, 1H), 6.96-6.88 (m, 1H), 4.2-4.0 (m, 2H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.7 (s, 3H), 1.7-1.6 (m, 2H), 1.6 (m, 1H), 1.45 (s, 9H). A solution of 4-[(2-bromo-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 0.0024 mole) in dioxane.HCl was stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford 0.704 g (95%) of (2-bromo-phenyl)-methyl-piperidin-4-yl-amine. 1H NMR (DMSO-d6): δ 9.0 (bd, 3H), 7.6 (m, 1H), 7.4 (m, 2H), 7.0 (m, 1H), 3.2 (m, 3H), 2.9 (m, 2H), 2.6 (s, 3H), 1.9 (m, 3H).