Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH:15]([CH2:16][CH3:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]1[CH:15]([CH2:16][CH3:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: CCOC(=O)C1C(CC)C1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(C=O)C1CC
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of oxalyl chloride (0.21 mL, 2.4 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under nitrogen atmosphere, dimethylsulfoxide (0.36 mL, 5.0 mmol) was added and stirred for 30 minutes. To this mixture, a solution of ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-ethylcyclopropane carboxylate (350 mg, 2.0 mmol) in anhydrous dichloromethane (20 mL) was added and reaction stirred at the same temperature for 45 minutes. Then, triethylamine (1.4 mL, 10.0 mmol) was added and the mixture was allowed to react at room temperature. After 30 minutes, the reaction was quenched with water (30 mL), the layers were separated and the aqueous one was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium anhydride, filtered and evaporated to dryness. The resulting residue was purified by column chromatography using ethyl acetate and hexane 1:4 as eluent to afford 310 mg (90% yield) of ethyl (1SR,2SR,3RS)-2-formyl-3-ethylcyclopropane carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])N=1.[CH:33](N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:32][C:25]1[CH:33]=[C:23]([NH:22][CH2:21][CH2:20][NH:19][C:13]2[CH:12]=[N:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:14]=2)[CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine (12.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH3:22]O>>[CH3:22][O:16][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)c2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 7 h

Procedure:
4,6-Dimethoxy-1-naphthalenecarboxylic acid (98.5 g, 0.425 mole, described in Example 61) was added to an ice-cooled solution of SOCl2 (59.5 g, 0.5 mole) in anhydrous methanol (225 ml). The mixture was heated at reflux for 18 hr. Another portion of SOCl2 (35.5 ml) was added and the reflux was continued for another 7 hr. The mixture was extracted with diethyl ether. The ether extract was washed with water and then aqueous NaHCO3 solution, dried (Na2SO4) and concentrated to dryness. The solid residue was crystallized from methanol (720 ml) to give 64.5 g of 4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester; mp 102°-104° C.; NMR(CDCl3) δ3.9 (s, 6H), 4.0 (s, 3H), 7.7 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1cnc(CCO)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(2-hydroxyethyl)pyrazine-2-carboxylate (1.07 g) in dichloromethane (20 mL) were added 3,4-dihydro-2H-pyrane (1.6 mL) and pyridinium p-toluenesulfonate (295 mg) at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to obtain methyl 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazine-2-carboxylate (1.25 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([CH3:26])([CH3:27])[C:28](=[O:29])[N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N2CCCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 17.9 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), pyrrolidine (0.0083 mL, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at rt. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[C:11]([O:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:21]=[N:20]1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].CN([CH:39]=[O:40])C>CCOC(C)=O>[C:11]([O:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([C:39]([O:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:40])[CH2:33][CH2:34]2)=[O:35])[N:21]=[N:20]1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)OCc3ccc(Cl)cc3Cl)CC2)nn1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
To a stirred solution of commercially available (2,4-dichlorophenyl)methanol (137 mg, 0.774 mmol) in DMF (2 mL) at RT was added CU (125 mg, 0.774 mmol). The reaction mixture was allowed to heat at 50° C. for 20 hrs. (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5)(272 mg, 0.774 mmol) was added and the reaction mixture was stirred at 50° C. for 10 hrs. The reaction mixture was diluted with EtOAc and washed with a saturated solution of sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford the title product;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:40]2[N:41]=[N:42][NH:43][N:44]=2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH3:39][N:35]1[C:36](=[O:38])[C:37]2[C:33](=[C:32]([C:40]3[N:44]=[N:43][NH:42][N:41]=3)[CH:31]=[CH:30][C:29]=2[NH:28][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)[CH2:34]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1Cc2c(-c3nn[nH]n3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4nn[nH]n4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-amino-2-methyl-4-(2H-tetrazol-5-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 181A). MS (ES+): m/z 618.33 (100) [MH+]; HPLC: tR=1.13 min (UPLC, purity).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13].[SH:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>O>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[S:26][CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (5 ml) solution of this amide (96 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 10 g, eluent—hexane:acetone=5:2) to obtain 88 mg (yield 75%) of the desired compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)=[CH:4][CH:3]=1.[I-:15].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:15])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Clc1ccc(CCCCCCBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(CCCCCCI)cc1

Procedure:
6-(4-Chlorophenyl)hexyl iodide [VIa; Ar is 4-ClC6H4, R is H] was prepared from 17 g. of 6-(4-chlorophenyl)hexyl bromide (Preparation C12) and 10.2 g. of sodium iodide in 325 ml. of acetone, to give 21 g. of product as an oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[Cl-].[C:26]([OH:35])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N+:29]([O-:33])[CH:28]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl.C(O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:26]([C:27]2[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=2)=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:26]([C:27]2[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=2)=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCOc1cccc(CN2CCCC2)c1)c1ccc[n+]([O-])c1
Temperature: 0 °C
Yield: 30 %

Procedure:
To a mixture of 0.03 mol of 3-(3-pyrrolidinomethylphenoxy)propylamine and 0.095 mol of pyridine in 100 ml of methylene chloride, stirred at 0° C., 0.047 mol of nicotinic acid 1-oxide chloride hydrochloride is added portionwise, then the resulting mixture is stirred 1 hour at room temperature and the solvent is evaporated off under reduced pressure. The residue is taken up with N hydrochloric acid and the salts obtained are eliminated by filtration, then the solution is extracted 3 times with 100 ml of ethyl acetate and sodium hydroxide is added thereto up to a basic pH. The solution is extracted 4 times with 100 ml of ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated off under reduced pressure. The oil thus obtained is chromatographied on silica, and eluted with methanol, the fractions of the pure product are collected and the solution thus obtained is treated with a solution of oxalic acid in ethanol; the precipitate which forms is crystallized from ethanol to yield 3.5 g of N-[3-(3-pyrrolidinomethylphenoxy)propyl]3-pyridinecarboxamide 1-oxide sesquioxalate CM 57891A; m.p. 115°-116° C. Yield: 30% of the theoretical value.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1(C)C=CC=CC=1>[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:28][CH:27]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Cc2ccc(C)cc2)cc1
Yield: 71 %

Procedure:
2.4 g(5.37 mmol) of (4-methylbenzyl)triphenylphosphonium bromide and 0.98 g(60%, 24.4 mmol) of NaH were refluxed in toluene for 6 hours. After cooled down, 0.586 g(4.88 mmol) of 4-methylbenzaldehyde was introduced gradually to the solution to be refluxed again for 6 hours. The resulted product was treated with water to be extracted with ethyl acetate. The solvent was distilled off and the residue was recrystallized in ethanol. Yield; 71%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CS(C)=O.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Sc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(CSc1cccc(Br)c1)OCC
Temperature: 25 °C
Reaction time: 120 h
Yield: 103.7 %

Procedure:
To a stirred solution of 3-bromothiophenol (5.0 g, 26 mmol) in DMSO (40 mL) was added a solution of KOH pellets (85% by wt, 2.15 g, 32 mmol) in water (4 mL) followed by bromoacetaldehyde diethyl acetal (4.5 mL, 29 mmol). The mixture was stirred at rt for 5 d, diluted with ether (300 mL) and washed with water (3×100 mL). The combined water washes were extracted with ether (100 mL). The combined ether extracts were washed with brine (100 mL), dried over MgSO4 and concentrated to afford (3-bromophenyl)(2,2-diethoxyethyl)sulfane (8.23 g, 100%) as a colorless oil.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Br:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To a 250 ml flask fitted with reflux condenser, thermometer, and nitrogen inlet were added 4-nitrobenzil (10.83 g, 42.49 mmol), 3-bromophenol (7.35 g, 42.49 mmol) and dimethylsulfoxide (150 ml). After stirring at room temperature for 20 minutes under a nitrogen atmosphere, potassium carbonate (11.73 g, 84.98 mmol) was added to the flask and the flask was heated to an internal temperature of 95° C. for 19 h under nitrogen. When cooled to room temperature the solution was very slowly poured into 12N HCL(500 ml) and extracted with methylene chloride (2×100 ml). The organic layer was washed with water (3×500 ml), dried over anhydrous magnesium sulfate, and evaporated to dryness by rotary evaporation. The light orange oil was then dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 211.94 g, 5 cm dia×24 cm H). The purified product was recrystallized twice from methylene chloride:methanol (25 ml:150 ml) to afford light yellow crystals (11.08 g, 69%): mp 75°-76° C.
Reaction SMILES: FC1C(O[C:9](=[O:31])[NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[S:18][C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[C:20]([C:22]#[N:23])[N:21]=3)[CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH2:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][NH:37]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:22]([C:20]1[N:21]=[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:9]([N:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:36]3)=[O:31])[CH2:12]2)[S:18][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[N:23]
Reactant: c1ccc2c(c1)CNC2
Reactant: N#Cc1nc(N2CCC[C@@H](NC(=O)Oc3c(F)c(F)c(F)c(F)c3F)C2)sc1Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1nc(N2CCC[C@@H](NC(=O)N3Cc4ccccc4C3)C2)sc1Nc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of crude {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid pentafluorophenyl ester (˜50 μmol) in tetrahydrofuran (1 mL) was cooled to 0° C. under an atmosphere of argon and isoindoline (12.6 mg, 106 μmol) and diisopropylethylamine (20 μL, 115 μmol) were added. The reaction mixture was stirred at 0° C. for 1 hour then warmed to ambient temperature and stirred for an additional hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL), poured into water (10 mL) and extracted with ethyl acetate (4×5 mL). The combined organic extracts were washed with brine (2×5 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography using a 12 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo to a yellow solid. The yellow solid was taken up in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a yellow viscous oil (11.3 mg, 50%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1
Reactant: Oc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)cn1
Temperature: 60 °C
Yield: 32.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was mixed with 3-5 ml of dry dimethylformamide and 3-fluorophenol (0.244 ml, 2.7 mmol) was added to the stirred suspension. When the gas evolution was ceased the reaction mixture was heated at stirring at 60° C. and 5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reaction mixture in one portion. The reaction-mixture was stirred at 60° C. for about 12 hours. The reaction mixture was then mixed with 50 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting mixture was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 190 mg (33% yield) of desired product.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40])[CH3:38]>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:45]3[CH2:44][CH2:43][N:42]([S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[CH2:47][CH2:46]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 707.4 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:16])=[CH:3][CH:4]=1)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(C=Cc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(C=Cc2ccccc2)cc1

Procedure:
4-Styrylbenzyl bromide was prepared from 35.4 g. of 4-methylstilbene and 35.6 g. of N-bromosuccinimide in carbon tetrachloride according to the procedure of Example 8(a); yield 35.5 g., m.p. 125°-127° C. after recrystallization from benzene-cyclohexane and acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1>C(O)C.O.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate (700 g, 2.27 mol) and iron (1272.7 g, 22.7 mol) in ethanol (5 L) and water (1 L) was stirred at room temperature for 10 h. The mixture was filtered, the filtrate was concentrated in vacuo, and the crude product was crystallized using EtOAc to give tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate.