Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[N:17]S(C(C)(C)C)=O)[C:6]=2[CH:24]=1.Cl.CCOCC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7](=[NH:17])[C:6]=2[CH:24]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of N-(5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-ylidene)-2-methylpropane-2-sulfinamide (Example 29 Step 1, 2 g, 4.83 mmol) in anhydrous 1,4-dioxane (40 mL) was added 4M HCl in 1,4-dioxane (12.07 mL, 48.27 mmol) and the resulting mixture was stirred under a nitrogen atmosphere at rt overnight. Et2O (30 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM (40 mL) and sat. aq. NaHCO3 (40 mL). The phases were separated and the organic layer concentrated, yielding 1.37 g of the crude title compound which was used immediately in the next step: MS (EI) m/z 309 M.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>C(#N)C>[C:3]1([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][F:14])=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(CO)c1ccccc1
Reactant: FCCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(COCc1ccc(OCCF)cc1)c1ccccc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Sodium hydride (1.4 g; 60% in oil) was added to 20 ml of dry acetonitrile, and a solution of 4.4 g of 2-phenyl-2-methylpropyl alcohol in 10 ml of acetonitrile was added dropwise at 50° C. The mixture was heated under reflux for 30 minutes, and a solution of 5.4 g of 4-(2-fluoroethoxy)benzyl chloride in 10 ml of acetonitrile was added dropwise over 10 minutes. The mixture was further heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (180 g) column chromatography (developing solvent: a 2:1 mixture of toluene and n-hexane) to give 6.5 g of 4-(2-fluoroethoxy)benzyl 2-phenyl-2-methylpropyl ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9](N)=[O:10].[OH-:13].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9]([OH:13])=[O:10]
Reactant: [OH-]
Reactant: CC1(C)CCC(C)(C)C1C(N)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCC(C)(C)C1C(=O)O
Temperature: 80 °C
Yield: 94 %

Procedure:
3.38 g of (2,2,5,5-tetramethylcyclopentane-1-yl)carboxamide was dissolved in 30 ml of methanol, and 15 ml of an aqueous 3N sodium hydroxide solution was added thereto. Then, the mixture was heated at 80° C. for 5 hours. After cooling, 40 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with 100 ml and 50 ml of ethyl acetate. The organic layers were combined, washed with 100 ml of water and 50 ml of aqueous saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure, whereby 3.20 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid was obtained. Yield 94%. (m.p. 113.6° C.)
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:9]1=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)N(CCCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)N(CCCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Yield: 66.6 %

Procedure:
By using 1-(3-diisopropylaminopropyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(3-diisopropylaminopropyl)isatin 3-semicarbazone having a melting point of 173°-175° C. (yield: 66.6%, recrystallizing solvent: methanol-benzene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2([F:13])[F:12].[C:14]([N:22]=C=O)(=[O:21])C1C=CC=CC=1.CCO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:14]([NH2:22])=[O:21])[CH2:7][CH2:6][C:5]2([F:12])[F:13]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: FC1(F)CCNc2ncc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)N1CCC(F)(F)c2cc(Br)cnc21
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A mixture of 6-bromo-4,4-difluoro-1,2,3,4-tetrahydro-[1,8]naphthyridine (86.2 mg, 0.35 mmol) and benzoyl isocyanate (85.9 mg, 0.51 mmol, 90%) in 5 mL CH2Cl2 is heated at 50° C. for 2 hrs. The mixture is concentrated the dryness. The residue is dissolved into 5 mL of EtOH, K2CO3 (81.2 mg, 0.59 mmol) is added and the mixture is heated at 50° C. for 2 h. The mixture is concentrated to dryness. The residue is dissolved into 20 ml of H2O and neutralized by the addition of AcOH. This is extracted with 60 mL EtOAc, washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The residue is applied to a silica preparative TLC plate and eluted (75% EtOAc/hexanes) to give 89.6 mg of 6-bromo-4,4-difluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][NH:17][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: NCCCBr
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccccc1)NCCCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
A solution of phenylmethanesulfonyl chloride (2.19 g, 10 mmol) was added into a suspension of 3-bromopropan-1-amine hydrobromide (2.19 g, 10 mmol) and Et3N (2.02 g, 20 mmol) in THF (50 mL) at 0° C. The mixture was stirred at 0° C. for 5 min. TLC confirmed the completion of reaction. Solid was filtered out with suction, and the filtrate was concentrated to provide compound N-(3-bromopropyl)(phenyl)methanesulfonamide (2.7 g, quant.) as a pale yellow solid which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 4.48 (m, 1H), 4.27 (s, 2H), 3.41 (t, J=6.6 Hz, 2H), 3.16 (q, 2H), 2.01 (m, 2H). LCMS (ESI), m/z, 314 and 316 [M+Na]+, Br pattern found.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[NH2:77])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[NH:77][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:30])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA (110 uL, 0.62 mmol) and 2-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 71 mg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].[C:12]1([C:18]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClCCl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([O:11][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19])=[O:10]
Reactant: O=C(O)CC1CCCCC1=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
To a mixture of (2-oxocyclohex-1-yl)acetic acid (5.6 g), benzoin (7.4 g), 4-dimethylaminopyridine (0.42 g) and dichloromethane (60 ml), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (8.7 g) was added in ice-water bath. After the reaction mixture was raised to room temperature, N,N-dimethylformamide (10 ml) was added to dissolve benzoin and stirred overnight. After usual workup, 1,2-diphenyl-2-oxoethyl (2-oxocyclohex-1-yl)acetate (15.5 g) was obtained as a crude solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[CH2:19]([Si:22](Cl)([CH3:24])[CH3:23])[CH:20]=[CH2:21].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:19]([Si:22]([CH3:24])([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=1)[CH:20]=[CH2:21]
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Reactant: C=CC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC[Si](C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
6.4 mL (10 mmol) of a 1.6 M hexane solution of butyl lithium was added to 60 mL of THF solution containing 2.54 g (10 mmol) of (4-bromo-phenylethynyl)trimethyl silane under an argon atmosphere at a temperature of −78° C. and the resultant mixture was stirred for 30 minutes. Then, 1.5 mL (10 mmol) of allylchlorodimethyl silane was added to the mixture and stirred for 10 minutes, after which the temperature of the mixture was gradually returned to room temperature and additionally stirred for two hours. After an aqueous solution of ammonium chloride was added to the mixture, the resultant solution was subjected to extraction using ether. The organic layer thus created was then washed with saturated brine and dried using magnesium sulfate as a desiccating agent. After the desiccating agent was removed by filtration, the solvent was removed by a rotary evaporator to obtain a crude product, which was then purified by silica gel column chromatography (developing solvent: hexane) to obtain 2.54 g (9.33 mmol) of 1-(allyldimethylsilanyl)-4-trimethylsilanylethynyl benzene. The yield was 93%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[N:27])[N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3([CH2:19][CH2:18][N:17](C(=O)C(F)(F)F)[CH2:16][CH2:15]3)[C:6]=12.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[N:27])[N:5]2[C:6]=1[C:7]1([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=1
Reactant: Cc1cc(C#N)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C#N)n2c1C1(CCNCC1)Oc1ccccc1-2

Procedure:
To a solution of 3′-methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (10 mg, 0.027 mmol) in MeOH (159 μL) was added K2CO3 (7.7 mg, 0.056 mmol) in one portion at 25° C. Water was added (35 mL), and the organics were removed under vacuum and the aqueous layer was extracted with dichloromethane (3×100 ml). The organic phases were combined, dried, filtered, concentrated to a white solid, which was used directly in the next step without further purification (7 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@H:7]([CH2:19][CH3:20])[CH2:6]1.N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:21])[CH2:6][C@H:7]1[CH2:19][CH3:20])=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CC[C@@H]1C[C@H](NC(=O)OC)c2cc(C(F)(F)F)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@@H](NC(=O)OC)C[C@H]1CC
Temperature: -10 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (2R, 4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (5191 g, 17.17 mol), methylene chloride (21 L), and pyridine (4.16 L, 51.4 mol). The reaction vessel was cooled to −10° C. Ethyl chloroformate (4.10 L, 42.9 mol) was slowly added at such a rate that the internal temperature did not exceed −5° C. The reaction solution was brought to 0° C. and held for 20 hours. The reaction was quenched by adding to a mixture of diisopropyl ether (IPE) (36 L), methylene chloride (6.2 L) and 1.5M hydrochloric acid solution (52 L). The resulting phases were separated and the organic layer was extracted with 1 M sodium hydroxide solution (15 L). The resulting phases were separated and the organic layer was washed with saturated aqueous sodium chloride NaCl (15 L). The resulting phases were separated and the organic layer was concentrated by distillation to a volume of 40 L. Crystallization initiated at lower volume. The methylene chloride was displaced with IPE by distilling the mixture and periodically adding IPE to maintain a constant volume at 40L until a temperature of 68° C. was maintained (46 L total IPE used). The mixture was cooled and allowed to granulate with stirring at room temperature for 19 hours. The solids were filtered, rinsed with IPE (8 L), and dried under vacuum at 40° C. to afford 5668 g of the title compound (88%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[CH2:19]([O:26][C:27]1[C:32]([CH2:33]Cl)=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]1[C:32]([CH2:33][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([CH3:1])[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(OC(C)C)ccc2c1C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 50 °C
Yield: 73.9 %

Procedure:
To a 0° C. solution of 8-methyl-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (107a, 30 mg, 0.14 mmol) in tetrahydrofuran (0.46 mL) was added 60% sodium hydride (18 mg, 0.45 mmol). After 30 minutes 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 43 mg, 0.16 mmol) was added and the resulting mixture was heated at 50° C. for 16 hours. The reaction mixture was quenched with water (1 mL) then extracted with ethyl acetate (20 mL), washed with brine (2 mL), dried over sodium sulfate, filtered, then concentrated under vacuum. The residue was purified by column chromatography (EtOAc/heptanes, 0-100), to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (107b, 46 mg, 76%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.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>[CH3:9][S:10][C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C[S-]
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: CN(C)C=O
Product: CSc1cnc(N)cn1
Temperature: 60 °C
Yield: 40.9 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (3.32 g, 2.87 mmol) and 2-amino-5-bromopyrazine (5.00 g, 28.73 mmol) in N,N-dimethylformamide (144 mL) was treated with 95% sodium thiomethoxide (4.24 g, 57.47 mmol). The resulting reaction mixture was heated at 60° C. for 10 h. The reaction mixture was allowed to cool to 25° C. and then was poured into a saturated aqueous sodium bicarbonate solution (500 mL). The product was extracted with ethyl acetate (5×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/7 ethyl acetate/hexanes) afforded 5-methylsulfanyl-pyrazin-2-ylamine (1.66 g, 40.9%) as an orange solid: mp 65–67° C.; EI-HRMS m/e calcd for C5H7N3S (M+) 141.0361, found 141.0357.
Reaction SMILES: CN(C=O)C.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>C(OCC)(=O)C>[Si:22]([O:6][CH2:7][C@@H:8]([OH:9])[C@@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([OH:15])[CH:16]=[O:17])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
DMF (10 mL) was placed in a 50 mL flask and cooled to 0° C. in an ice bath. 5 g of D-glucose was added, followed by 0.9 molar equiv. (6.5 mL) of tert-butylchlorodiphenylsilane. The reaction was left for 21 h at 0° C., after which it was poured into 5 mL of ethyl acetate and washed with saturated NaHCO3, brine, dried, isolated by flash column chromatography and evaporated to a yellow solid of 11 (30%). 1NMR [(300 MHz, CDCl3) 5 (ppm): 7.64 (m, 4 H), 7.32 (m, 6 H), 5.13-2.94 (m, 11 H), 1.0 (s, 9 H)], 13C NMR [(300 MHz, CDCl3) 8 (ppm): 135.5 (s, TBDPS-O), 135.45 (s, TBDPS-O), 133.3 (s, TBDPS-O), 133.2 (s, TBDPS-O), 133.0 (s, TBDPS-O), 132.9 (s, TBDPS-O), 129.6 (s, TBDPS-O), 129.5 (d, TBDPS-O), 127.6 (s, TBDPS-O), 127.55 (s, TBDPS-O), 96.6 (s, C1,β), 92.6 (s, C1,α), 77.8 to 60.7 (C2-C6), 26.7 (s, TBDPS-O, 4° C.), 19.1 (s, TBDPS-O), 19.0 (s, TBDPS-O)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(Cl)Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[N:7]2
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)Nc1cnc2cccc(Br)c2n1
Yield: 99.5 %

Procedure:
A solution of 8-bromo-2-chloroquinoxaline (Example 210e; 1.53 g, 6.28 mmol) and tert-butylamine (Aldrich; 3.30 mL, 31.4 mmol) in DMSO (15 mL) was stirred at 100° C. for 2 h. The mixture was treated with DCM (100 mL), and washed with saturated aq. NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified on a silica gel column (23-32% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinoxalin-2-amine (1.75 g, 97% yield) as a yellow viscous oil which crystallized upon standing. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, s), 7.85 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.8 Hz), 7.19 (1H, t, J=7.9 Hz), 4.89 (1H, br. s.), 1.61 (9H, s). m/z (ESI, +ve) 280/282 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:2]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:4][CH2:5]1>[Pd]>[CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[C:2]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C12CCCC1C1C=CC2C1
Agent: [Pd]
Product: CCOC(=O)C12CCCC1C1CCC2C1
Yield: 93 %

Procedure:
The amount 1.3 g of 5%-Pd/C (with 50% moisture content) was added to 13.1 g of ethyl tricyclo[5.2.1.02,6 ]deca-8-ene-2-carboxylate obtained in the same procedures as in Example 1. The resultant mixture was stirred at 50° C. for 5 hours under hydrogen pressure of 5 kg/cm2. After the catalyst was removed by filtration, the filtrate was distilled to yield 12.3 g of ethyl tricyclo[5.2.1.02,6 ]decane-2-carboxylate. The yield was 93.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.BrC1C=CC=C([N+]([O-])=O)C=1[NH:22][CH2:23][CH2:24][OH:25]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:22][CH2:23][CH2:24][OH:25]
Reactant: O=[N+]([O-])c1cccc(Br)c1NCCO
Reactant: O=[N+]([O-])c1cccc(F)c1F
Product: O=[N+]([O-])c1cccc(F)c1NCCO

Procedure:
2-[(2-Fluoro-6-nitrophenyl)amino]ethanol was prepared starting from 1,2-difluoro-3-nitrobenzene (0.66 g) according to the procedure described for the synthesis of 2-[(2-bromo-6-nitrophenyl)amino]ethanol. Yield 0.78 g (95%). MS (ESI) m/z 201.1 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm: 3.56 (m, 4 H), 4.91 (m, 1H), 6.70 (m, 1H), 7.46 (m, 1H), 7.85 (bs, 1H), 7.89 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:23])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@:9]2([OH:22])[CH3:21])=[CH:4][CH:3]=1.O1CCOCC1>Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:23])[CH2:13][CH2:12][NH:11][CH2:10][C@:9]2([CH3:21])[OH:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]1(O)CNCC[C@]1(O)c1ccc(Cl)cc1
Yield: 201 %

Procedure:
A solution of (3S,4S)-tert-butyl 4-(4-chlorophenyl)-3,4-dihydroxy-3-methylpiperidine-1-carboxylate (2.08 g, 6.08 mmol) in 4 M HCl in dioxane (30.4 mL, 122 mmol) was stirred at room temperature for 45 minutes. The mixture was concentrated in vacuo, then concentrated from methylene chloride (3×) to remove residual HCl, to yield (3S,4S)-4-(4-chlorophenyl)-3-methylpiperidine-3,4-diol hydrochloride (1.7 g, 6.11 mmol, 100% yield) as a powder. 1H NMR (400 MHz, MeOD4) δ 7.55 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.05 (d, J=13.2 Hz, 1H), 2.71 (ddd, J=13.2, 4.8 Hz, 1H), 1.97 (dt, J=14.5, 3.1 Hz, 1H), 1.08 (s, 3H); m/z (ES+)=242.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([CH:13](OC)[O:14]C)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)=O>O>[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1ccn(-c2ncccc2Cl)n1
Solvent: O
Solvent: O=CO
Product: O=Cc1ccn(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 3.35 g of 3-chloro-2-[3-(dimethoxymethyl)-1H-pyrazol-1-yl]pyridine, 24 ml of formic acid and 6 ml of water was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. Ice water was poured into the residue, and a precipitated solid was collected by filtration to obtain 2.38 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-3-carbaldehyde of the formula: