Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:24])([CH3:23])[CH2:7]1)=[O:4].[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[C:33]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=2[CH3:46])[N:36]=[C:35]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][C:48]=2[OH:54])[N:34]=1.[OH-].[Na+]>CN(C)C=O>[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[C:33]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=2[CH3:46])[N:36]=[C:35]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH2:2][C:3]([O:5][CH:6]3[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:24])([CH3:23])[CH2:7]3)=[O:4])=[CH:49][C:48]=2[OH:54])[N:34]=1
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)CCl)CC1(C)C
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)COc2ccc(-c3nc(-c4ccc(C)cc4C)nc(-c4ccc(C)cc4C)n3)c(O)c2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A solution of 14.5 g (40.0 mmol) of 1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl chloroacetate in 25 ml of N,N-dimethylformamide is rapidly added to a mixture of 20.0 g (50.2 mmol) of 2,4-bis(2,4-dimethylphenyl)-6-(2,4-dihydroxyphenyl)-1,3,5-triazine (Example 8A), 125 ml of N,N-dimethylformamide, and 4.0 g of 50% sodium hydroxide solution that has been stirred at ambient temperature for 30 minutes. The reaction mixture is then heated at 70° C. for 1 hour and stirred at ambient temperature for 17 hours. The reaction mixture is partitioned between ethyl acetate (300 ml) and a mixture of water (1000 ml) and 1N hydrochloric acid (10 ml). The aqueous layer is extracted with diethyl (2×500 ml) and saturated sodium chloride solution (500 ml), dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (5:1 heptane: ethyl acetate) affords 14.0 g (48% yield) of the title compound, a yellow solid, mp 86°-90° C.
Reaction SMILES: [OH:1][C:2]1([C:14]([F:17])([F:16])[F:15])[C:11]2[C:6](=[C:7]([O:12]C)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.B(Br)(Br)Br>>[OH:1][C:2]1([C:14]([F:16])([F:15])[F:17])[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1
Reactant: COc1cccc2c1C(=O)OC2(O)C(F)(F)F
Agent: BrB(Br)Br
Product: O=C1OC(O)(C(F)(F)F)c2cccc(O)c21

Procedure:
The title compound can be prepared analogously to the above Example (133) from 3-hydroxy-7-methoxy-3-trifluoromethyl-phthalide (see Example 133 ) and boron tribromide; m.p. 128°-129° C.
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][C@H:5]2[C@@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: O=C1CC(=O)C2CCCCC2C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)C[C@@H]2CCCC[C@H]2C1=O
Temperature: 0 °C

Procedure:
A solution of 1.06 gm (6.38 nmole) of decalin-1,3-dione in 3 mL of dry ethanol was cooled in an ice bath and treated with 0.89 mL of (6.4 mmole) triethylamine followed by 1.128 gm (6.50 mmole) of p-toluenesulfonyl azide. The mixture was stirred in the ice bath for 4 hours, then concentrated in vacuo (less than 40° C.). The residue was dissolved in 45 mL of ether and the ether washed with a solution of 0.42 gm KOH in 30 mL of water, dried (Na2SO4), filtered, and concentrated to 1.22 gm of an orange oil. This was chromatographed on 40-micron silica giving 0.45 gm of trans-2-diazodecalin-1,3-dione, mp 81°-3° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([OH:22])=[C:16]2[CH:15]=[N:14]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=4[N:2]([CH3:23])[CH3:1])[N:14]=[CH:15][C:16]=23)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (66 mg, 0.200 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (61 mg, 0.300 mmol) and triphenylphosphine (52 mg, 0.200 mmol) were dissolved in toluene (5 mL) and the mixture stirred at 0° C. for 15 min. Diisopropyl azodicarboxylate (28 μL, 0.200 mmol) was then added and the reaction kept going at rt for 16 h. The solvent was removed under reduced pressure and the crude was purified by HPLC. Compound A100 was obtained as a yellowish solid. Exact mass calculated for C24H32N6O5S 516.22, found 517.3 (MH+, 100%). 1H NMR (400 MHz CDCl3) δ (ppm): 8.50 (s, 1H); 8.22 (s, 1H); 7.42(m, 3H); 5.52 (m, 1H); 3.81 (m, 2H); 3.26 (m, 2H); 3.03 (s, 3H); 2.47 (s, 6H); 2.03 (m, 2H); 1.80 (m, 2H); 1.42 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1.7 g, 7.4 mmol) and Et3N (1.12 g, 11.1 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1 g, 8.87 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was washed with brine. The organic layer was concentrated in vacuo to give crude tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperazine-1-carboxylate (2.1 g, 94%). This was used in the next step without purification. 1H NMR (300 MHz, CDCl3): δ 4.38 (t, 2H, J=5.3 Hz), 3.49-3.44 (m, 4 h), 3.09 (s, 3H), 2.79 (t, 2H, J=5.1 Hz), 2.58 (t, 4 h, J=5.0 Hz), 1.49 (s, 9H). LCMS: No molecular ion observed for desired mass.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=2)[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:2]1[CH2:5][CH:4]([C:6]3[C:7]([N:12]4[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]4)=[N:8][CH:9]=[CH:10][N:11]=3)[CH2:3]1)[CH:30]=[CH:29]2
Reactant: OCC1CCN(c2nccnc2C2CNC2)CC1
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(N3CC(c4nccnc4N4CCC(CO)CC4)C3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of [1-(3-azetidin-3-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (284 mg, 1.0 mmol) and 2-chloro-6-methyl-quinoline (purchased from ALDRICH) (177 mg, 1.0 mmol) in DMF (15 mL) was added Cs2CO3 (650 mg, 2.0 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc:Petrol ether=5:1) on silica gel to give (1-{3-[1-(6-methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-methanol (102 mg, 0.26 mmol 26%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH:47]=[O:48]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)[OH:48])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1ccccn1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccn3)c(F)c2Cl)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42, 2.0 g, 3.9 mmol) in anhydrous THF (10 mL), sec-Butyl lithium (1.4 M in cyclohexane, 2.1 eq) was added and the solution was stirred for ½ h at −78° C. Pyridine-2-carbaldehyde (0.74 mL, 7.8 mmol) in THF (5 mL) was added dropwise and the solution was stirred for additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to obtain product. Yield: 900 mg, (37%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH:21]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:28]([CH3:31])([O-:30])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:21]=[CH:31]/[N+:28]([O-:30])=[O:29])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1-c1ccccc1
Temperature: 50 °C
Yield: 98 %

Procedure:
Nitromethane (1.4 mL) was added to a mixture of aldehyde 6a (0.16g, 0.56 mmol) and ammonium acetate (77 mg, 1.0 mmol) and heated to 50° C. Upon completion (˜15-30 min), the reaction mixture was cooled to RT and purified without work-up by column chromatography (SiO2, 3:1, Hex:EtOAc) to afford nitrostyrene 7a as a yellow oil (182 mg, 0.55 mmol, 98%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=13.6 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 7.50-7.35 (m, 10H), 7.31 (d, J=2.1 Hz, 2H), 7.04 (d, J=2.5 Hz, 1H), 5.15 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 161.8, 146.1, 138.1, 136.4, 136.3, 135.5, 131.8 131.7, 129.9, 129.2, 128.8, 128.0, 121.3, 117.3, 116.3, 116.0, 115.6, 70.7; HRMS (FAB) m/z: [M+Na+] for C21H18NO3, calcd, 332.1281. found, 332.1290.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.Cl>O1CCCC1>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:8]([CH:9]=[O:10])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: O=Cc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=Cc1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 136.3 %

Procedure:
To magnesium turnings (1.23 g, 50.7 mmol) in a dry flask under nitrogen was added anhydrous tetrahydrofuran (THF, 10 mL). The mixture was mechanically stirred while a solution of 1,2-dibromoethane (1.22 g, 6.5 mmol) in THF (10 mL) was added dropwise. Upon completion, a solution of the dimethyl acetal of 2-bromobenzaldehyde (3.00 g, 13.0 mmol) and 1,2-dibromoethane (2.44 g, 13.0 mmol) in THF (10 ml) was added at a rate to maintain gentle reflux. Upon completing, a second solution of 1,2-dibromoethane (1.22 g, 6.5 mmol) in THF (10 mL) was added dropwise. The mixture was then refluxed an additional 20 minutes and decanted into an addition funnel attached to a second reaction flask containing a solution of 4-iodobenzotrifluoride (2.72 g, 10.0 mmol) and iodo(4-trifluoromethyl)bis(triphenylphosphine)palladium (II) (0.21 g, 0.9 mmol) in refluxing THF (20 mL). The Grignard reagent was added dropwise and the mixture refluxed for 11/2 hr. After cooling to room temperature, 3N hydrochloric acid was added (30 mL) and the THF evaporated on the rotary evaporator. The residue was extracted with diethyl ether. The ether extract was washed with 3N hydrochloric acid (20 mL) water (4×25 mL), and saturated sodium chloride solution (10 mL). The ether solution was then dried (MgSO4), treated with charcoal, filtered and evaporated to give a dark yellow oil (3.41 g). This was chromatographed on the Waters Prep 500 HPLC using a 1:1 mixture of methylene chloride and hexane. The product was isolated after evaporation of solvent as a light yellow oil (2.41 g, 96.4%). 'H NMR (CDCl3): 7.6 (m, 7, Ar--H), 8.0 (m, 1, 3-H), 9.9 (s, 1, CHO).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[Na].[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccc(F)cc1
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
36.44 g (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine was added to a solution that consists of 6.6 g of sodium in 450 ml of methanol, and it was refluxed for 16 hours. After another 30 hours of stirring at 60° C., it was cooled, and the crystalline product was suctioned off. 34 g of (5-methoxy-2-nitrophenyl)-(4-fluorophenyl)amine was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH:26]=[CH2:27]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][CH2:27][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5]2[C@@H:16]3[NH:17][C@H:12]([CH2:11][C:6]1=2)[CH2:13][CH2:14][CH2:15]3
Reactant: C=Cc1cc(C)ccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc(C)c(CCn2c3c(c4cc(C)ccc42)[C@H]2CCC[C@@H](C3)N2)c1

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1,4-dimethyl-2-vinylbenzene (129 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.07-1.32 (m, 3H), 1.62 (dd, J=13, 2 Hz, 1H), 1.70-1.95 (m, 3H), 2.00 (s, 3H), 2.15 (s, 3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.94-3.16 (m, 2H), 3.34-3.40 (m, 1H), 4.19 (ddd, J=14, 9, 5 Hz, 1H), 4.28-4.39 (m, 2H), 6.69 (s, 1H), 6.85-6.97 (m, 3H), 7.13 (s, 1H), 7.26 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20](C)[C:19](=[O:34])[CH:18]=2)[CH2:12]1.[ClH:35]>C1COCC1.O1CCOCC1>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[NH:20][C:19](=[O:34])[C:18]=2[Cl:35])[CH2:12]1
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Reactant: Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at rt for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): δ ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 5.09-5.21 (m, 2H), 3.17 (m, 2H), 2.96 (t, J=11.1 Hz, 1H), 2.86 (d, J=10.6 Hz, 1H), 2.65 (m, 1H), 1.90 (d, J=11.6 Hz, 1H), 1.57 (d, J=13.1 Hz, 1H), 1.19-1.31 (m, 1H), 1.03-1.15 (m, 1H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@@H:14]1[O:31][C:18]2=[C:19]3[C:23](=[CH:24][CH:25]=[C:17]2[O:16][CH2:15]1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]3>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C@H:14]2[O:31][C:18]3=[C:19]4[C:23](=[CH:24][CH:25]=[C:17]3[O:16][CH2:15]2)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]4)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc2c3c(ccc2[nH]1)OC[C@H](CO)O3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)OC[C@@H](COS(=O)(=O)c1ccc(C)cc1)O3
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
4-Toluenesulphonyl chloride (2.23 g) was added in one portion to a stirred solution of ethyl (S)-2,3-dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate (2.65 g) in dry dichloromethane (120 ml) at 0° C. 4-Dimethylaminopyridine (1.52 g) was then added and the cooling bath removed. The resulting solution was stirred at ambient temperature for 72 hours, then diluted with dichloromethane (150 ml) and washed successively with water (80 ml), saturated aqueous copper sulphate solution (2×100 ml), and then dried over sodium sulphate. Evaporation of the solvent under reduced pressure gave a purple foam which was purified by flash column chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate, to give ethyl (S)-2,3-dihydro-2-[(4-toluenesulphonyloxy)methyl]-7H-1,4-dioxino[2,3-e]indole-8-carboxylate (3.71 g) as a colourless oil which solidified on standing.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][NH+:6]=[C:5]([CH2:10]Cl)[C:4]=1[CH3:12].[CH3:13][O:14][C:15]1[N:20]=[C:19]2[N:21]=[C:22]([SH:24])[NH:23][C:18]2=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[N:20]=[C:19]2[N:21]=[C:22]([S:24][CH2:10][C:5]3[C:4]([CH3:12])=[C:3]([Cl:2])[C:8]([CH3:9])=[CH:7][N:6]=3)[NH:23][C:18]2=[CH:17][CH:16]=1
Reactant: COc1ccc2[nH]c(S)nc2n1
Reactant: Cc1c[nH+]c(CCl)c(C)c1Cl
Agent: [Cl-]
Product: COc1ccc2[nH]c(SCc3ncc(C)c(Cl)c3C)nc2n1

Procedure:
As a further example, 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride could be reacted with 5-methoxy-1H-imidazo[4,5-b]pyridine-2-thiol according to the procedure described under Example 39 to give 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1H-imidazo[4,5-b]pyridine. Conversion of this product with methanol-d4 following the protocol described under Example 44 would then give rise to formation of 5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-imidazo[4,5-b]pyridine, which, in turn, could be oxidized according to the procedure used in Example 46 to rac-5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC#N>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: COC(=O)CC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)NCc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
To 1-(4-bromophenyl)methanamine hydrochloride (8.56 g, 38.5 mmol), MeCN (50 mL) and NEt3 (5.36 mL, 38.5 mmol) was added methyl 3-chloro-3-oxopropanoate (3.17 mL, 29.6 mmol). The reaction was aged about an hour before NEt3 (10.7 mL, 77 mmol) was added. The reaction was aged about 20 min and was concentrated. The reaction was diluted with EtOAc and washed with brine and aq. 2M Na2CO3 solution followed by aq. 2 M HCl and water. The organic portion was concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-90% EtOAc/hexane to afford the product.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].I[CH:14]([CH3:16])[CH3:15]>CN(C=O)C>[CH:14]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:16])[CH3:15]
Reactant: CC(C)I
Reactant: O=C(O)c1cccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ncccc1C(=O)O
Reaction time: 0.5 h

Procedure:
2-Mercapto-nicotinic acid (5.0 g, 32.22 mmol) was dissolved in DMF (40 mL), and the solution was cooled to 0˜5° C. NaH (6.4 g, 161.1 mmol) was added thereto slowly, and the mixture was stirred at 0˜5° C. for 30 minutes. 2-Iodo-propane (9.65 mL, 96.66 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and water was added to dilute the residue. 3N HCl was added to adjust the pH of the aqueous solution to 2˜3, and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The reaction product was used in the next step without a separate purification process.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)(=[O:7])=[O:6].[I-].[Na+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C.C(Cl)Cl>[N:25]1([CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)(=[O:7])=[O:6])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCCl)ccc2[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 8 h

Procedure:
Ethyl 5-[(3-chloropropyl)sulfonamido]indole-2-carboxylate (PREPARATION 82, 2.3 g) is dissolved in acetonitrile (10 ml) and piperadine (27 ml). Solid sodium iodide (1.0 g) is added and the reaction is stirred overnight at 20°-25°. The reaction is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with a gradient of 5% methanol/methylene chloride to 10% methanol/methylene chloride, pooling and concentration of the appropriate fractions gives the title compound, NMR (300 MHz, d4 -CD3OD) 7.45, 7.32, 7.12, 7.03, 4.28, 2.96, 2.28, 1.18, 1.42, 1.33 and 1.30.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](=[O:15])([O:12][CH2:13][CH3:14])N>C(O)C>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[C:6]([NH:8][C:10]([O:12][CH2:13][CH3:14])=[O:15])[CH:5]=[CH:4][C:3]=1[CH3:9])=[O:15])[CH3:14]
Reactant: Cc1ccc(N)cc1N
Reactant: CCOC(N)=O
Solvent: CCO
Product: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1

Procedure:
275 g of a polyurea mixture based on 2,4-diamino-toluene having terminal amino tolyl groups (average molecular weight: 1500) were introduced into the apparatus described in Example 1. 513 g of 2,4-diamino-toluene, 933 g ethyl carbamate and 1250 g ethanol (approximately 96%) were subsequently added. The mixture was reacted for 6.0 hours at 200° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography (HPLC). A yield of 1100 g (68% of the theoretical yield) of 2,4-bis-(ethoxy carbonylamino)-toluene was obtained.