Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Temperature: 145 °C
Yield: 75.8 %

Procedure:
A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl) -pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])C)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>N1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:30][SiH:28]([CH3:31])[CH2:27][CH2:26][O:25][CH2:24][N:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[C:3]1[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[N:6]=[C:5]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:4]=1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: C[SiH](C)CCOCn1c(-c2cc(-n3ccnc3)nn(COCC[Si](C)(C)C)c2=O)nc2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
100 mg of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid (example 55), 35.5 mg of copper(II) acetate and 20 mg of imidazole are dissolved in dry pyridine, and the solution is stirred at 80° C. for 3 hours. For workup, it is diluted with 20 ml of water and extracted several times with ethyl acetate, the organic phases are dried using a silica gel cartridge, and the volatile components are distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][CH2:35][CH:36]([OH:38])[CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][CH2:35][CH:36]([OH:38])[CH3:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(O)CN
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNCC(C)O)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-amino-2-propanol (Eastman Kodak) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2 [(M+H)+] 543.2196, observed 543.2200.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:8](=[O:7])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CN(C)CCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 446 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]([F:27])([F:25])[F:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 83 %

Procedure:
A mixture of 5-benzyloxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid ethyl ester (intermediate 1, step a, 13.6 g, 1.0 eq.) and palladium on activated charcoal (10% by weight, 1.15 g, 0.03 eq.) in ethyl acetate (700 mL), was vigorously stirred for 4 days at room temperature under an atmosphere of hydrogen (1 Atm). The solid was filtered off and washed with ethyl acetate. The filtrate was evaporated to dryness and purified on silica eluting with 1:4 cyclohexane/ethyl acetate to yield 8.6 g (83%) of the desired product as white solid. MS (m/e): 288.5 (MH+, 100%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[OH-].[Na+].COC(OC)OC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[C:33]([CH:38]=O)[CH2:32][CH2:31]3)=[CH:20][CH:19]=1.[BH4-].[Na+].Cl.C(OCC)(=O)C>CO.O1CCCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[C:33]([CH2:38][N:1]2[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]2)[CH2:32][CH2:31]3)=[CH:22][CH:23]=1
Reactant: O=C(O)C1CNC1
Reactant: O=CC1=Cc2ccc(OCCCc3ccc(Cl)cc3)cc2CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CN(CC2=Cc3ccc(OCCCc4ccc(Cl)cc4)cc3CC2)C1
Reaction time: 3.5 h
Yield: 62.7 %

Procedure:
Azetidine-3-carboxylic acid (46 mg) and sodium hydroxide (18 mg) were dissolved in methanol (4 mL). To this solution, trimethoxymethane (0.050 mL) and a tetrahydrofuran (1 mL)-methanol (1 mL) mixed solution of 6-[3-(4-chlorophenyl)propoxy]-3,4-dihydronaphthalene-2-carboaldehyde (100 mg) were successively added under ice cooling. The reaction mixture was stirred for 3.5 hours under ice cooling. To the reaction mixture, sodium borohydride (17 mg) was added under ice cooling. The reaction mixture was stirred under ice cooling for 20 minutes. Thereafter, 4 mol/L hydrogen chloride/ethyl acetate solution was added until it was neutral, and concentrated. The obtained residue was purified by flash silica gel column chromatography (chloroform:methanol:aqueous ammonia=80:10:1 to 80:20:4), to thereby obtain the title compound (79 mg) having the following physical properties.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: OCCOc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1

Procedure:
To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:64][C:65]1[O:69][C:68]([SH:70])=[N:67][N:66]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:70][C:68]1[O:69][C:65]([CH3:64])=[N:66][N:67]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: Cc1nnc(S)o1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.135 ml) in methylene chloride (1.21 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (350 mg) and 4-(N,N-dimethylamino)pyridine (7.9 mg) in methylene chloride (17.5 ml) at -30° C. A solution of trifluoromethanesulfonic anhydride (0.114 ml) in methylene chloride (1.02 ml) was added to the mixture and stirring was continued at the same temperature for 30 minutes. A solution of N,N-diisopropyl-N-ethylamine (0.563 ml) in methylene chloride (5.06 ml) and 5-methyl-1,3,4-oxadiazole-2-thiol (225 mg) were then added thereto, and the reaction mixture was stirred at -30° C. for 30 minutes and allowed to warm to ambient temperature over a period of an hour. After stirring at ambient temperature for 4 hours, the mixture was allowed to stand at 5° C. for 14 hours. After the solvent was removed by evaporation, the residue was dissolved in ethyl acetate (20 ml). The organic solution was washed in turn with water and a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 10% water (7 g), eluting with a mixture of benzene and acetone (20:1 to 10:1) to give 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (290 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:11]([N:14](CC)C(C)C)(C)[CH3:12].BrCC#N>C1COCC1>[Br:10][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:12][C:11]#[N:14])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cc(N)ccc1Br
Agent: N#CCBr
Solvent: C1CCOC1
Product: N#CCNc1ccc(Br)c(C#N)c1
Temperature: 100 °C

Procedure:
Mix 5-amino-2-bromobenzonitrile (0.76 mmol) in anhydrous THF (3 ml), N,N-diisopropylethylamine (0.92 mmol), and bromoacetonitrile (1.0 mmol) at room temperature under inert atmosphere. Heat the mixture to 100° C. for 16 h in a sealed tube. Cool in ice bath, filter the precipitate and evaporate the filtrate to dryness to afford a crude residue. Purify by flash chromatography (Silica gel-CHCl3/Ethanol/NH4OH 9:1:0.1) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Cl:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[S:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a 0.1M solution 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene (89) (774 mg, 2.2 mmol), in EtOAc was added tin(II) chloride dihydrate, obtained from Aldrich, (2.49 g, 11.05 mmol). The resulting mixture was refluxed for 2 hour. The crude reaction mixture was cooled to ambient temperature and excess 2M aqueous NaOH was added and allowed to stir for 15 minutes. Solid tin salts precipitated from the solution, were filtered off through a pad of celite and washed with EtOAc (200 mL). The organic layer was washed twice with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 592 mg (84%) of (90) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:53]=[N+:54]=[N-:55].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:53]=[N+:54]=[N-:55])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Agent: [Na+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CCC3)cc1

Procedure:
In analogy to the procedure described in example 10(b), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] was treated with sodium azide to yield the (3R,4R)-3-[1-(2-azido-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 686 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)C(OS(C(F)(F)F)(=O)=O)=C(C(=O)C([O-])=O)C(C)=C2.C([O:31][CH:32]([C:38]1[C:47]([CH3:48])=[CH:46][C:45]2[C:40](=[CH:41][C:42]([Cl:49])=[CH:43][CH:44]=2)[C:39]=1OS(C(F)(F)F)(=O)=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34])(C)(C)C>>[Cl:49][C:42]1[CH:41]=[C:40]2[C:45]([CH:46]=[C:47]([CH3:48])[C:38]([C:32](=[O:31])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:39]2[C:9]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[CH:44][CH:43]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc2cc(Cl)c(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C(=O)C(=O)[O-]
Product: CCOC(=O)C(=O)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1

Procedure:
Ethyl 2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate was prepared in a similar manner to 2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate of Example 99, except using ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate. 1H-NMR: (400 MHz, CDCl3): δ 8.05 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.74 (s, 1H), 7.58 (dd, J=8.6, 2.0 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 1.40 (t, J=7.0 Hz, 3H). 19F-NMR: (377 MHz, CDCl3): δ−73.2 (s)
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.[K]>CN(C)C=O>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C@H:7]2[CH2:6][N:49]2[C:45](=[O:55])[C:46]3=[CH:54][CH:53]=[CH:52][CH:51]=[C:47]3[C:48]2=[O:50])=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 65.8 %

Procedure:
A solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (4.39 g: 6.93 mmole) and potassium phthalimide (2.57 g: 2 eq.) in dimethylformamide (30 ml) is stirred at 70° C. for 6 hours. The reaction mixture is poured into ice water and the precipitate is filtered off. The precipitate is dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-tritylthiopyrrolidine (3.12 g). Yield: 64.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([OH:7])=[O:6])=[CH:8][C:9]=1[Cl:12]
Reactant: Cc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cc(Cl)c(CBr)c(Cl)c1
Yield: 94 %

Procedure:
99 g (0.48 mole) of the previously prepared 3,5-dichloro-4-methylbenzoic acid and 0.5 g (0.002 mole) of benzoyl peroxide were dissolved in 800 ml of CCl4 and refluxed for 2 hours using a Dean Stark apparatus to remove moisture. The heating was continued at gentle reflux and 94 g (0.53 mole) of N-bromosuccinimide were added in 10×9.4 g portions at 10-15 min intervals with stirring. When addition was completed, the reaction mixture was refluxed for 30 minutes longer. At the end of this time analysis by gas chromatography showed 3% of starting material, 94% of the expected product and the rest dibromo derivatives and other impurities. The reaction mixture was cooled down to room temperature and filtered. The resulting organic solution was washed with concentrated sodium thiosulfate (2×250 ml), dried with anhydrous sodium sulfate and concentrated to give 47.2 g of an oily residue, which was mostly the expected compound. The solid was also the expected 4-bromomethyl-3,5-dichlorobenzoic acid contaminated with succinimide. The solid was slurried in 1 liter of water for 1 hour, filtered and then dried. This yielded another 89.0 g of 4-bromomethyl-3,5-dichlorobenzoic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7].Cl>C(Cl)(Cl)Cl>[C:6]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Methanesulfonyl chloride (229 g) was added dropwise to a solution (800 ml) of t-butylamine (420 g) in chloroform under cooling in an ice bath for 90 minutes. After stirring for 3 hours at room temperature, the solution was refluxed under heating for 1 hour. The resulting reaction mixture was cooled with ice, made acidic by adding dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and dried over sodium sulfate. The resulting solution was distilled under reduced pressure to obtain N-t-butylmethanesulfonamide (244 g) as white solid. This product was immediately subjected to the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[Br:18]Br>BrCCBr.[W]>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: BrBr
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Agent: [W]
Solvent: BrCCBr
Product: O=C1c2cc(CBr)ccc2COc2ccccc21
Temperature: 0 °C

Procedure:
To a stirred and irradiated (Tungsten lamp) solution of 2.0 gm of the 9-methyl compound of Step B in 5 ml of 1,2-dibromoethane, add a solution of 1.7 gm of bromine in 5 ml of 1,2-dibromoethane dropwise over a period of 1 hour at 150° C. Cool the reaction mixture, pour into ice water and extract with water and dry over sodium sulfate. Concentrate to dryness and crystallize the residue from isopropyl ether to obtain the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N:43]2[C:39](=[O:49])[C:40]3[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:42]2=[O:44])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Br)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 5 h
Yield: 57 %

Procedure:
To a solution of 1,1-dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwise duisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warmn to RT over 5 h. The reaction was then concentrated in vacuo and product was triturated out of solution using ethyl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3×100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]+: 460.4.