Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]1[C:13]2[C:8](=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CO>[CH2:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][NH:5]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCc1cccc2c1CCN2C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CCCCCCCCc1cccc2c1CCN2
Yield: 92.6 %

Procedure:
A solution of the product of Step C (0.07 g; 0.21 mmol) and Cs2CO3 (0.07 g; 0.21 mmol) in MeOH (2 ml) was stirred overnight at room temperature under N2. After removing solvent under reduced pressure, the residue was diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.045 g; 93%), as brownish oil, which was used in the next step without further purification. 1H-NMR (CDCl3) 0.86 (m, 3H); 1.28 (m, 10H); 2.47 (m, 2H); 2.95 (m, 2H); 3.52 (m, 2H); 3.7 (broad s, 1H); 6.47-6.54 (m, 2H); 6.89-7.02 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH:15]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[S:22][C:23]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:25])[C:20]=2[CH:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:26]([C:23]2[S:22][C:21]3[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][C:20]=3[C:24]=2[CH3:25])(=[O:28])=[O:27])=[CH:5][C:4]=1[C:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH:11]=1
Reactant: COc1ccc(N)cc1C1=CCN(C)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1C1=CCN(C)CC1

Procedure:
The title compound (E130) was prepared from 4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine (free base of D39) (100 mg, 0.46 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (129 mg, 0.46 mmol) using the method of Example 1 (177 mg, 77%). MH+=463/465.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8](C(OC(C)(C)C)=O)[C@H:7]([C:22]([OH:24])=[O:23])[CH2:6]2.[ClH:25]>CO>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][C@H:7]([C:22]([OH:24])=[O:23])[CH2:6]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)C[C@@H](C(=O)O)NC2
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid (example 3) (60 g, 0.17 mol) in methanol (300 mL) was added 3 N aqueous HCl (240 mL, 0.72 mol). The mixture was heated to 60° C. and stirred at 60° C. for 2 hrs. The clear reaction solution was evaporated under vacuum to 200 mL. The resulting white suspension was then cooled to 0-5° C. and stirred at 0-5° C., filtered, and rinsed with cold water (2×35 mL). The solid was dried under vacuum to give 42 g of (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (yield 90.9%, ee>98%). 1H NMR (DMSO-d6) δ: 3.06 (dd, J=16.7, 10.8 Hz, 1H, CHHCHCOOH), 3.22 (dd, J=16.7, 4.7 Hz, 1H, CHHCHCOOH), 3.72, 3.73 (s, 6 H, OCH3), 4.21 (br s, 2H, CH2N), 4.32 (dd, J=10.8, 4.7 Hz, 1H, CHCOOH), 6.85, 6.87 (s, 2H, PhH), 10.12 (br s, 2H, NHHCl).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[CH:29][CH:28]=2)=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([F:18])([F:19])[F:20])=[CH:32][CH:31]=1
Reactant: CN(C)CCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CN(C)CCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(O)cc2)cc1
Yield: 39.5 %

Procedure:
2.06 g (4.56 mmoles) of 1-(4-benzyloxyphenyl)-1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-3,3,3-trifluoropropene are dissolved in 45 ml of acetic acid and hydrogenated in the presence of 0.5 g of a 10% palladium-on-carbon catalyst. The solution is evaporated and the radius is crystallized from ether. 0.77 g (39.5%) of the aimed compound is obtained; m.p.: 149°-155° C.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:17][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1
Reactant: OCc1ccc(Oc2ccccc2)nc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of commercially available (6-phenoxypyridin-3-yl)methanol (150 mg; 0.74 mmol) in anh. DCM (6 ml) was treated at rt with CBr4 (247 mg; 0.74 mmol), and with PPh3 (195 mg; 0.74 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 15 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 5-(bromomethyl)-2-phenoxypyridine as a pale yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 263.98 g/mol.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1B(O)O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[CH3:44].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd]>[CH3:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1B(O)O
Reactant: Cc1cnccc1Br
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cnccc1-c1ccncc1N
Reaction time: 1 h

Procedure:
[3-(tert-butoxycarbonylamino)-4-pyridyl]boronic acid (100 mg, 0.4201 mmol), palladium; triphenylphosphane (48.55 mg, 0.04201 mmol), 4-bromo-3-methyl-pyridine (113.9 mg, 0.5461 mmol), K3PO4 (630.0 μL of 2 M, 1.260 mmol), in dioxane (4.000 mL) was heated at 130° C. for 30 min in a MW. The reaction mixture was partitioned between water and DCM. Combined organic extract was dried and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and TFA (2 mL) was added. After 1 h, the reaction mixture was concentrated in vacuo. The residue was loaded on a SCX column, washed with MeOH. The product was eluted with a 2M NH3 in MeOH., filtrate was concentrated in vacuo yielding 3′-methyl-[4,4′-bipyridin]-3-amine that was used in next reaction w/o further purification (90 mg). MS (ES+) 172.1.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@H:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[CH2:3][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S*,4R*)-tert-butyl 3-amino-4-(3-hydroxypropyl)pyrrolidine-1-carboxylate (0.55 g, 2.25 mmol) and p-nitrophenylsulfonyl chloride (0.50 g, 2.25 mmol) and Na2CO3 (0.29 g, 2.70 mmol) in 8 mL THF-water, 3:1, was stirred overnight at room temperature. THF was evaporated, the mixture was diluted with H2O, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1→5% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[N:15]=[C:14]([N:16]([CH:20]([CH:24]2[CH2:26][CH2:25]2)[CH:21]2[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH3:19])[CH:13]=[C:12](Cl)[NH:11]1.[CH3:28][S-:29].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[N:15]=[C:14]([N:16]([CH:20]([CH:24]2[CH2:26][CH2:25]2)[CH:21]2[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH3:19])[CH:13]=[C:12]([S:29][CH3:28])[NH:11]1
Reactant: C[S-]
Reactant: CCCN(C1=NN(c2c(Cl)cc(Cl)cc2Cl)NC(Cl)=C1)C(C1CC1)C1CC1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(C1=NN(c2c(Cl)cc(Cl)cc2Cl)NC(SC)=C1)C(C1CC1)C1CC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of 2-(2',4',6'-trichlorophenyl)-4-(N-dicyclopropylmethyl-N-propylamino)-6-chlorotriazine (130 mg, 0.3 mmole) in 2.5 mL of dimethylformamide was treated with sodium thiomethylate (0.04 mg, 0.57 mmole) with stirring at 23° C. for 1 hour, the mixture was then poured into ethyl acetate/water. The organic phase was washed with water, 0.1M aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated. The residue was purified by preparative TLC (5% diethyl ether/hexane) to give 2-(2',4',6'-trichlorophenyl)-4-(N-dicyclopropylmethyl-N-propylamino)-6-methylthiotriazin (110 mg, 80% yield). 1H NMR (CDCl3): 0.2-0.7 (bm, 8H), 0.7-1.2 (bm, 5H), 1.7-1.8 (bm, 2H), 2.3-2.6 (m, 3H), 3.2-3.5 (bm, 3H), 4.8-5.1 (bm, 2H), 7.35 (5, 1H) and 7.38 (s, 1H). Mass (ion spray): 457 (M+H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[NH:17][C:18]([CH2:20][CH3:21])=[N:19][C:11]1=[N:10]2.C(N(CC)CC)C.[CH:29]([NH:31][CH:32](Cl)[C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[N:17]([CH:32]([NH:31][CH:29]=[O:30])[C:33]([Cl:36])([Cl:35])[Cl:34])[C:18]([CH2:20][CH3:21])=[N:19][C:11]1=[N:10]2
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Reactant: O=CNC(Cl)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1nc2nc3cc(Cl)ccc3nc2n1C(NC=O)C(Cl)(Cl)Cl
Reaction time: 1.25 h

Procedure:
To 240 ml of dry dimethylformamide warmed to 50° was added 3.5 parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline and 1.75 parts of triethylamine. The resulting solution was added, with stirring, to a 500 ml round-bottomed flask containing 3.3 parts of 1-formamido-1,2,2,2-tetrachloroethane and 45 parts of dry dimethylformamide at room temperature. After standing for 75 minutes, the clear solution was poured onto a mixture of 1500 parts of ice and water. The resulting solids were collected, washed with water and dried to give 4.6 parts of 6-chloro-2-ethyl-1-(1-formamido-2,2,2-trichloroethyl)-1H-imidazo[ 4,5-b]quinoxaline, decomposing at 109°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:11]([O:10][C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)[N:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)Oc1cc(C#N)cc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)Oc1cc(C#N)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
The nitrile 25H (1.25 g, 6.4 mmol), 4-trifluoromethylphenylboronic acid (1.34 g, 1 mol eq), palladium acetate (29 mg, 0.02 mol eq), cesium carbonate (4.16 g, 2 mol eq), and XPhos (137 mg, 0.04 mol eq) were mixed, placed under a nitrogen atmosphere and dioxane (8 mL) was added. The mixture was heated at 100° C. for 4 h. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×30 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (9.5/0.5 Petroleum ether/EtOAc) to afford 26M as yellow solid (0.65 g, 36% Yield). 1HNMR (DMSO, 200 MHz) δ 1.37 (d, 6H, J=3.9), 5.15 (m, 1H), 6.7 (s, 1H), 7.32 (s, 1H), 7.87 (d, 2H, J=7.8), 8.33 (d, 2H, J=8).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:20][C:21]1[CH:22]=[C:23]([CH:51]=[CH:52][CH:53]=1)[CH2:24][CH:25]([C:32]([C:34]1[O:35][C:36]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1)=O)[CH2:26][C:27]([O:29]CC)=[O:28])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.COCCOC>[Si:3]([O:20][C:21]1[CH:22]=[C:23]([CH:51]=[CH:52][CH:53]=1)[CH2:24][CH:25]1[CH2:26][C:27](=[O:28])[O:29][CH:32]1[C:34]1[O:35][C:36]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(Cc1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)[Si](Oc1cccc(CC2CC(=O)OC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 181.8 %

Procedure:
NaBH4 (119 mg) was added to a stirred solution of ethyl 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-4-(4,5-diphenyl-2-oxazolyl)-4-oxobutyrate (430 mg) in methanol (2.0 ml) and 1,2-dimethoxyethane (0.5 ml) at room temperature and the resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate—1N hydrochloric acid. The organic layer was washed with 1N hydrochloric acid, aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-2-(4,5-diphenyl-2-oxazolyl)-5-oxotetrahydrofuran (366 mg) as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](OCC)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Li].[H-].O>O1CCCC1>[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(COc2cccnc2N)cc1
Agent: [H-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1OCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of 2-amino-3-(4-ethoxycarbonylbenzyloxy)pyridine (1.04 g) in tetrahydrofuran (15 ml) was added dropwise to a suspension of lithium alminum hydride (0.24 g) in tetrahydrofran (24 ml) with ice cooling over a period of 10 minutes. After being stirred for 1.5 hours at room temperature, the excess reagent was decomposed with a small amount of water and the resulting precipitates were filtered off by suction. The filtrate was evaporated in vacuo and the crystalline residue was washed with diethyl ether to give 2-amino-3-(4-hydroxymethylbenzyloxy)pyridine (0.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
2-Chloro-4-nitroaniline (1.73 g (10.0 mmol)) was dissolved in 5.0 ml of pyridine. To this, p-toluenesulfonyl chloride (1.91 g (10.0 mmol)) was added with stirring at room temperature. After stirring for 18 hours at room temperature, water (50 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water and then dissolved in an aqueous solution of sodium hydroxide. The resulting solution was washed with diethyl ether, and the water layer was made acidic again with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.61 g (80%) of 2′-chloro-4′-nitro-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1.[OH:46]C(C)(C)C>>[OH:46][C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1
Reactant: CC(C)(C)O
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(O)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Temperature: 95 °C

Procedure:
To the uncyclized intermediate from example 3 (30 mg) under nitrogen was added K—OtBu (1M, 0.05 mL) and HOtBu (2 mL). The mixture was then heated at 95° C. for 1 h. After cooling to rt, the mixture was subjected to preparative HPLC to give the titled compound (4.5 mg). LC: 3.54′ (Gradient 1); MH+: 634.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[I:7][C:8]1[N:9]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:11][C:12]=1I>C(O)C.O.C(OCC)(=O)C>[I:7][C:8]1[NH:9][C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(I)[nH]1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
Sodium sulfite (10.31 g, 82 mmol) was added to a solution of (S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.0 g, 8.2 mmol) in ethanol (75 mL) and water (75 mL). The suspension was heated with an oil bath at 100° C. for 4 hours and at 90° C. for 16 h. The reaction was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic phases were dried (brine, Na2SO4), filtered and concentrated in vacuo. The residue was purified by a flash chromatography (sample was dry loaded on silica gel and eluted with, 0 to 40% ethyl acetate/CH2Cl2) to afford (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.17 g, 73.1%) as a white solid. LC-MS retention time 0.930 min; calcd. for C12H181 N3O2 363.04. found m/z 364.06 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. 1H NMR (500 MHz, MeOD) δ ppm 7.52-7.64 (m, 1H), 4.95-5.10 (m, 1H), 3.57-3.70 (m, 1H), 3.47-3.57 (m, 1H), 2.37-2.55 (m, 1H), 1.94-2.10 (m, 3H), 1.46 (s, 4H), 1.27 (s, 5H).
Reaction SMILES: ClCCl.[NH2:4][CH2:5][C:6]1([CH2:10][NH2:11])[CH2:9][O:8][CH2:7]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O>[NH2:4][CH2:5][C:6]1([CH2:10][NH:11][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][O:8][CH2:7]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCC1(CN)COC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
A dichloromethane suspension (3.0 ml) of C-(3-aminomethyloxetan-3-yl)methylamine (411 mg, 3.54 mmol) prepared according to the method described in J. Org. Chem., (1985),50(17), 3211; and Japanese Patent Application Kokai Publication No. (JP-A) S61-69784 (unexamined, published Japanese patent application) was cooled to 0° C., and a dichloromethane solution (3.0 ml) of triphenylmethyl chloride (246 mg, 0.88 mmol) was added thereto. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for one hour. A saturated aqueous sodium bicarbonate solution (1.0 ml) and water (15 ml) were added to the solution. The mixture was extracted three times with dichloromethane (20 ml). The organic layers were combined together, and dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield (3-aminomethyloxetan-3-ylmethyl)tritylamine (162 mg) as a white amorphous material.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.O>CN(C=O)C.CCOC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Sc2ccccn2)nc1
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 2-mercaptopyridine (6.39 g, 57.4 mmol) in DMF (100 mL) was added NaH (60% dispersion in oil, 2.29 g, 57.2 mmol) in portions and the mixture was stirred for 15 min. 6-Bromo-3-pyridine carboxaldehyde (9.28 g, 49.9 mmol) was added and the resultant mixture was stirred for 1 h. Water was added followed by the addition of EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by flash column chromatography (eluents: 20% EtOAc in hexanes and 30% EtOAc in hexanes). Evaporation of the appropriate fractions gave a white solid, which was further purified by recrystallization from diethyl ether to give the product as a white solid (9.66 g, 90% yield). 1H NMR (CDCl3) δ 10.00 (s, 1H), 8.89-8.84 (m, 1H), 8.67-8.64 (m, 1H), 8.01 (dd, J=2.2, 8.9 Hz, 1H), 7.76 (dt, J=2.2, 8.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.35-7.29 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>>[Cl:24][C:20]1[CH:19]=[C:18]([N:17]2[C:13]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:14][C:15]([C:25]([N:57]3[CH2:58][CH2:59][S:55][CH2:56]3)=[O:26])=[N:16]2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1
Reactant: C1CSCN1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1)N1CCSC1

Procedure:
200 mg (0.55 mmol) of the compound of Example 35A is reacted analogously to the synthesis of the compound of Example 1 with 0.05 ml (0.60 mmol) of thiazolidine. 193 mg (80% of theory) of the title compound is obtained.