Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][NH2:13].[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][NH:13][S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NCCC1COc2ccccc2O1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NCCC1COc2ccccc2O1

Procedure:
The crude 2-(2,3 dihydrobenzo[1,4]dioxin-2-yl)ethylamine in dioxane (100 mL) was combined with sulfamide (3.0 g, 31 mmol) and heated to reflux for 2 h. The solution was cooled and evaporated in vacuo to yield an orange solid, which was purified by column chromatography (DCM:MeOH—10:1) to yield a white solid. The solid was re-crystallized from DCM to yield the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1C(=O)OC
Reaction time: 8 h

Procedure:
The compound 2 (205 g, 1.0 mol) was dissolved in 2 L of MeOH. Catalytic 10% Pd/C was added and the solution was hydrogenated under H2 (45 psi) on a Parr hydrogenation apparatus at room temperature overnight. Filtered through celite and evaporated to give a quantitative yield of 3-amino-phthalic acid dimethyl ester, 3. 1H NMR (300 MHz, DMSO-d6): 7.26 (t, J=7.33 Hz, 1H), 6.94 (d, J=8.34 Hz, 1H), 6.77 (d, J=8.33 Hz, 1H), 6.12 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H). 13C NMR: 51.51, 51.77, 110.50, 115.16, 118.56, 131.26, 133.16, 148.28, 167.12, 168.11.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:7]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cccnc3N)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 82.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(2-aminopyridin-3-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.06 g, 0.09 mmol) prepared in Example 69c, triethylsilane (0.07 mL), trifluoroacetic acid (0.09 mL) and dichloromethane (0.90 mL), to yield the title compound (34.2 mg, 82%) as a colorless solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)O1.Br[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[S:28][C:27]([N:29]([CH3:40])[CH:30]3[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]3)=[N:26][N:25]=2)=[C:18]([F:41])[CH:17]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:41][C:18]1[CH:17]=[C:16]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[C:24]1[S:28][C:27]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:26][N:25]=1
Reactant: COc1cc(Br)cc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cn[nH]c2)cc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Pd(Ph3P)4 (11 mg, 0.009 mmol) was added to a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55 mg, 0.282 mmol) and 5-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (86 mg, 0.188 mmol) in dioxane (1.5 mL), followed by a solution of NaHCO3 (60 mg, 0.564 mmol) in water (0.375 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (10 mL). The organic phase was separated and SiliaMetS-DMT (0.61 mmol/g, 145 mg, 0.09 mmol) was added. The resulting suspension was stirred at room temperature for ˜2 hours then filtered. The filtrate was concentrated in vacuo to afford the crude product as a light brown oil. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified), collecting at 328 nm to afford the title compound as a white solid (26 mg, 32% yield). LC-MS: Rt 0.76 min; MS m/z 445.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br. s., 1H), 8.26 (br. s., 2H), 7.23-7.31 (m, 2H), 4.27-4.37 (m, 1H), 3.93 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[I:22][CH2:23]I>O1CCCC1>[I:22][CH2:23][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCC1
Reactant: ICI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CI)CCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a stirred solution of N,N-diisopropylamine (1.31 mL, 9.36 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (1.58 M in hexane, 5.43 mL, 8.58 mmol) at −10° C. under nitrogen. After being stirred at −10° C. for 1 h, a solution of methyl cyclopentanecarboxylate (1.00 g, 7.80 mmol) in tetrahydrofuran (3 mL) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 2 h. Diiodomethane (0.628 mL, 7.80 mmol) was added to the mixture and the mixture was warmed to room temperature. After being stirred for 16 h, the mixture was quenched with aq. ammonium chloride (50 mL). The mixture was extracted with diethylether (75 mL×2) and washed with brine (75 mL). The organic layer was combined and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 20:1 to 10:1) to give 1.085 g (52%) of the title compound as a colorless oil.
Reaction SMILES: [Na].[CH:2]1[C:12]2[C:11](=[N:13]O)[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[CH2:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24]Cl)[CH3:20]>C(O)C>[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][N:13]=[C:11]1[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[CH2:8][S:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:12]1=2)[CH3:20]
Reactant: ON=C1c2ccccc2CSc2ccccc21
Reactant: CCN(CC)CCCCl
Agent: [Na]
Solvent: CCO
Product: CCN(CC)CCCN=C1c2ccccc2CSc2ccccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1.65 G. of sodium in 60 ml. of absolute ethanol are treated dropwise with 11.4 g. of dibenzo[b,e]thiepin-11(6H)-one-oxime in 60 ml. of absolute ethanol. The mixture is stirred at 50° C. for 3 hours and then cooled to 5°-10° C. The mixture is then treated dropwise with 15.3 g. of 3-diethylamino-propyl chloride, stirred at 50° C. for 16 hours and subsequently evaporated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue is purified by chromatography over aluminum oxide using chloroform for the elution. A by-product is first eluted and there is subsequently eluted the desired N,N-diethyl-N'-{dibenzo[b,e]thiepin-11(6H)-ylidene}-1,3-propanediamine-N'-oxide which is used directly in the process described in the first paragraph of this Example.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:22][N:23]=[C:24]=[S:25]>C(O)C>[CH3:22][NH:23][C:24]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[CH:14]=1)=[O:19])=[S:25]
Reactant: CN=C=S
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Solvent: CCO
Product: CNC(=S)NNC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2c1
Yield: 93.7 %

Procedure:
A mixture of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide (0.60 g, 2.01 mmol), methyl isothiocyanate (97%, 0.21 g, 2.82 mmol) and ethanol (15 mL) was tightly sealed in a vial, and the microwave was irradiated at 100° C. for 30 min. After cooling, the precipitate was collected by filtration, and washed with ethanol to give the title compound (0.70 g, yield 94%) as colorless crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:20]>C(Cl)Cl>[Cl:5][CH2:6][C:7]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[NH:10][C:11](=[O:20])[CH2:12][CH2:13]2)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(C(=O)CCl)ccc2N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a 10 L, 4-neck flask, fitted with a mechanical stirrer and under N2, AlCl3 (408 g, 3.06 mol) and dry CH2Cl2 (2.7 L, 18 vol) was added. Chloroacetylchloride (89 mL, 1.22 mol) was then added from an addition funnel gradually over 15 minutes at room temperature. The resulting mostly clear solution was maintained at that temp for 30 minutes and turned into a muddy mixture. A solution of 3,4-dihydroquinolin-2(1H)-one (150 g, 1.02 mol) and CH2Cl2 (0.3 L, 2 vol) was added, over 1.5 hours, at such a rate as to keep the internal temperature below 30° C. The resulting brown mixture was stirred at that temp for 2 hours, then heated at 40° C. for an additional 2 hours, and then left to stir overnight at room temperature. The reaction mixture was cooled in an ice bath and connected to an HCl gas trap. Ice-cold H2O (total 3 L) was then added, over 1.5 hours, at such a rate as to keep the internal temperature below 30° C. The resulting mixture was stirred at room temperature for 1 hour and then heated at 40-50° C. to remove the CH2Cl2. To this mixture, THF (1 L) was added and the mixture was stirred at room temperature overnight. The solids were collected by filtration. The yellow cake was washed with H2O (500 mL), THF (200 mL) and hexane (1 L×2) and it was dried in a vacuum oven (@50° C., 1 day) to afford 6-(2-chloroacetyl)-3,4-dihydroquinolin-2(1H)-one (221 g, 97%). 1H NMR (270 MHz, d-DMSO) δ 10.48 (s, 1 H), 7.86-7.77 (m, 2 H), 6.96 (d, J=8.2 Hz, 1 H), 5.08 (s, 2 H), 2.96 (t, J=7.6 Hz, 2 H), 2.51 (t, J=7.6 Hz, 2 H)
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(O)CC>[CH:15]1[C:16]2[N:2]=[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]3[CH2:9][S:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc[n+]1CSc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCO
Product: C1=CC2=Nc3ccccc3SCN2C=C1
Yield: 110.5 %

Procedure:
A mixture of 33.2 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride, 27.7 g of anhydrous potassium carbonate, 0.8 g of copper bronze, and 750 ml of n-propanol is heated and stirred, under reflux, for 24 hours, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 600 ml of ether, and the ether solution is washed, dried, decolorized with Darco, and concentrated to give about 23.7 g of a yellow solid. Recrystallization from cyclohexane-benzene gives about 17.4 g of the named compound, mp about 135-137°.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[N:13]=[CH:14][C:15]3[C:16](=[O:30])[N:17]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=[CH:19][C:20]=3[C:21]=2[OH:22])=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:23]([N:17]1[C:16](=[O:30])[C:15]2[CH:14]=[N:13][C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[O:11])=[C:21]([OH:22])[C:20]=2[CH:19]=[CH:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(NC(=O)c2ncc3c(=O)n(Cc4ccccc4)ccc3c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CC1)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A mixture of 1-[(7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester (23 mg, 0.057 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture to pH about 2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 9 mg of the title compound as a yellow solid. MS: (+) m/z 380.27 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]([NH2:15])=O)=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]#[N:15])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(N)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C#N

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide with triphosgen/triethylamine in THF. mp 105–107° C., 1H NMR(CDCl3) d 6.90(s,2H), 6.26(brs,1H), 6.05(s,1H), 4.24(m,1H), 2.28(s,3H), 2.25(s,3H), 2.17(s,6H), 1.72(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [C:1](=[O:39])([O:3][CH:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][N:9]1[C:13](=[O:14])[N:12](/[CH:15]=[CH:16]/[C:17]([F:20])([F:19])[F:18])[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:10]1)[NH2:2]>CO.[Pt]>[C:1](=[O:39])([O:3][CH:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:37])([F:36])[F:38])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][C:17]([F:20])([F:18])[F:19])[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:10]1)[NH2:2]
Reactant: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Agent: [Pt]
Solvent: CO
Product: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O)c1ccccc1C(F)(F)F

Procedure:
A solution of 30 mg (52 μmol) of the compound of Example 61 in 15 ml of methanol was hydrogenated in a continuous-flow hydrogenation apparatus fitted with a 5% Pt/C cartridge (H-Cube, from Thales Nano, Budapest, Model HC-2-SS) at a flow rate of 1 ml/min, a temperature of 60° C. and at standard pressure. After the reaction had ended, the solution was freed from the methanol on a rotary evaporator and the residue was purified by preparative HPLC [Method 23]. This gave 15 mg (50% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[C:7]([CH3:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:22]([C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:26][CH3:27])(=[O:23])=[O:24])=[C:7]([CH3:14])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)NCC2
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COC(=O)c1cc(C)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2

Procedure:
4-Methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester was reacted with 5-chloro-2-methoxybenzenesulfonyl chloride in analogy to example 34, step 2, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester. Pink solid, MS (ISP): m/e 396.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:14]1[O:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)[O:7][CH2:13]1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cc(C2OCCO2)ccc1O

Procedure:
A solution of 4-hydroxy-3-nitrobenzaldehyde (known compound, 20.6 g, 124 mmol), benzene (150 ml), ethylene glycol (10.3 ml, 185 mmol) and p-toluenesulfonic acid hydrate (catalytic amount) was refluxed overnight removing the resulting water by azeotropic distillation with benzene.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:40])[NH:11][CH:12]([C:19]1[CH:24]=[C:23](Br)[CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:40])[NH:11][CH:12]([C:19]1[CH:24]=[C:23]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2
Reactant: O=C(NC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1)O[C@H]1CN2CCC1CC2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC(c1ccccc1)c1cc(OCCCCCCCCC2OCCO2)cc(-c2ccccc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 120 °C
Yield: 69.2 %

Procedure:
To a stirred solution of (R)-quinuclidin-3-yl((3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-bromophenyl)(phenyl)methyl)carbamate (0.2 g, 0.33 mmol) (prepared in Example 28 Step 8) in toluene (4 mL) and water (1 mL), was added phenyl boronic acid (0.04 g, 0.33 mmol), sodium carbonate (0.07 g, 0.66 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.03 mmol). The reaction mixture was heated in the microwave at 120° C. for 30 minutes. The solvent was removed under reduced pressure, diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were dried (sodium sulphate), filtered and solvent removed under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in ethyl acetate to afford the title compound as a colourless oil (0.14 g, 71%).
Reaction SMILES: [O:1]=[CH:2][C:3]([NH-:5])=[O:4].[N+:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-])=O>[Pd].CCO>[O:1]=[CH:2][C:3]([NH-:5])=[O:4].[NH2:6][C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: O=[N+]([O-])c1cc2ccccc2[nH]1
Agent: [Pd]
Agent: [NH-]C(=O)C=O
Solvent: CCO
Product: Nc1cc2ccccc2[nH]1

Procedure:
Reduction of nitro group to amine group used one of the following methods. Method A: Nitro indole 2-oxoacetyl amide and catalytic amount of palladium on carbon (Pd—C) was mixed in EtOH. The mixture was hydrogenated using Parr reactor under hydrogen pressure of 40-50 psi at room temperature for 24 hours. Then, solid was removed via filtration and filtrate was concentrated under vacuum to give crude amino indole 2-oxoacetyl amide which could be used as was or purified by silica gel chromatography. Method B: An excess of Fe (10-50 eq.) was added into the solution of nitro indole 2-oxoacetyl amide in saturated aqueous NH4Cl-EtOH (volume 1:1). The mixture was stirred at room temperature to 115° C. for 24 hours to 3 days. Solid was removed via filtration and solvents were removed under vacuum. Then, the residue was partitioned between water and EtOAc (equal volume to solvents used in reaction). The aqueous phase was extracted with EtOAc (3×e equal volume to solvents used in reaction). The combined organic phase was dried over MgSO4, filtered and concentrated under vacuum to give a crude amino indole 2-oxoacetyl amide which could be used as was or purified by silica gel chromatography.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=O)=[CH:5]1)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:54][C:55]1[O:59][C:58]([CH2:60][NH2:61])=[N:57][N:56]=1>CN(C=O)C>[CH3:54][C:55]1[O:59][C:58]([CH2:60][NH:61][C:22]([C:6]2[C:7](=[O:21])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[C:9]([CH3:10])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:24])=[N:57][N:56]=1
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Reactant: Cc1nnc(CN)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3, 65 mg, 0.192 mmol), TBTU (75 mg, 0.232 mmol), N-methylmorpholine (42 μL, 0.383 mmol) in DMF (1 mL) is stirred for 15 min at room temperature. C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine (24 mg, 0.211 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 6 mg (7% of theory); ESI mass spectrum: [M+H]+=435; Retention time HPLC: 0.86 min (Z018_S04).
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19]SC1C(C2C=NC=CC=2)=NNC=1.CI>>[CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]1[CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1nc[nH]c1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Solvent: CI
Product: CCCCCCSc1nc[nH]c1C1=CCCN(C)C1

Procedure:
3-(5-Hexylsulfanyl-3H-imidazol-4-yl]-pyridine (77) was converted to the title compound (76B) using the methodology described for the conversion of 21A to 22A (see Scheme 3) (the quarternization however was done at room temperature with a slight excess of CH3I). Yield: 70% (oil). LCMS (method A); Rt: 1.21 min, ([M+H]+=280). 1H-NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 6.40-6.29 (m, 1H), 3.45-3.41 (m, 2H), 2.79-2.72 (m, 2H), 2.59 (t, J=6 Hz, 2H), 2.45 (s, 3H), 2.41-2.37 (m, 2H), 1.55-1.49 (m, 2H), 1.38-1.31 (m, 2H), 1.30-1.19 (m, 4H), 0.85 (t, J=7 Hz, 3H).