Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[C:25]([CH:28]=1)[C:26]#[N:27]>C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][N:31]=4)=[C:25]([CH:28]=3)[C:26]#[N:27])[NH:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)c(C#N)c3)nc2=O)cn1
Yield: 35.5 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.20 mmol, 1 eq) and 5-(2-Amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (80 mg, 0.26 mmol, 1.3 eq) were heated at 130° C. (sealed bottle) in 500 μl of absolute ethanol for 24 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 11 g normal phase silica KP-NH column and DCM/10% MeOH in DCM solvent system (gradient 10-80% of 10% MeOH in DCM in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting oil was triturated with hexane to obtain 5-{2-[5-(2-methyl-pyrimidin-5-ylmethyl)-4-oxo-1,4-dihydro-pyrimidin-2-ylamino]-ethyl}-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (36 mg, yield=32.4%, purity=92%) in form of tain coloured powder. MS: [M+H]+=508.40. 1H NMR (300 MHz; CDCl3) δ/ppm 2.64 (s, 3H), 2.94 (t, J=7.23 Hz, 2H), 3.53 (s, 2H), 3.57-3.66 (m, 2H), 7.14-7.23 (m, 2H), 7.51 (d, J=8.37 Hz, 2H), 7.55-7.64 (m, 2H), 7.96 (d, J=8.60 Hz, 1H), 8.34 (s, 1H), 8.50 (s, 2H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[NH3:10]>C1COCC1>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: N
Reactant: CSCCCS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CSCCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a stirred suspension of sodium 3-(methylthio)propane-1-sulfonate (20 g) in dry DCM (200 mL), is added dropwise oxalyl chloride (80 mL) at 0° C. After stirring at room temperature for 3 h, the reaction mixture is concentrated under reduced pressure and ice (100 g) is added. The product is extracted with DCM (2×200 mL) and the organic phase is washed with brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 12 g of 3-(Methylthio)propane-1-sulfonyl chloride as colorless liquid. A solution of 3-(methylthio)propane-1-sulfonyl chloride (12 g) in dry THF (100 mL) is added dropwise to a solution of ammonia in dry THF (250 mL) at −78° C. After stirring at room temperature for 3 h, the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography using silica gel (60-120 mesh) and CHCl3/MeOH as eluent to afford 9 g (84%) of the title compound as pale a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 6.80 (br s, 2H), 3.02-3.06 (m, 2H), 2.55-2.59 (m, 2H), 2.03 (s, 3H), 1.89-1.92 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:8]([OH:15])=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:15][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[N:9]=1)[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: Oc1nc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl

Procedure:
Methyl 3,5,6-trichloro-2-pyridyl carbonate was prepared by reacting methyl chloroformate with 3,5,6-trichloro-2-pyridinol at 0° C.-5° C. in the presence of an equivalent of pyridine as acid acceptor and using methylene chloride as the reaction solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[I:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[I:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:17]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: O=C(Cl)c1ccccc1I
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2I)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2-iodobenzoyl chloride according to the procedure of Example 19 to yield 5-(2-iodobenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 215°-216.5° C. after purification from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][NH:6][C:7](=[O:14])[C:8]([C:12]#[N:13])=[C:9]([CH3:11])[CH3:10].[CH3:19]OC(OC)N(C)C.O1CCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH:19]=[CH:10][C:9]([CH3:11])=[C:8]([C:12]#[N:13])[C:7]1=[O:14]
Reactant: COC(OC)N(C)C
Reactant: CC(C)=C(C#N)C(=O)NCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccn(Cc2ccc(Cl)c(Cl)c2)c(=O)c1C#N
Reaction time: 1 h

Procedure:
A solution of 42.8 g. (0.15 mole) of N-(3,4-dichlorobenzyl)-2-cyano-3-methylcrotonamide and 18.0 g. (0.15 mole) of N,N-dimethylformamide dimethyl acetal in 250 ml. of tetrahydrofuran is stirred at ambient temperature for 22 hr. followed by 1 hr. at reflux. The solvent is removed and the tacky solid residue is heated until molten. When evolution of dimethylamine subsides the reaction mixture is allowed to cool and the dark glassy residue is recrystallized from ethanol. The solid product is slurried in ether and isolated by filtration to give 15.79 g. (36%) of product as a brown powder: m.p. 177.5°-180.5° C.; ν (ethanol) 2210 (CN) and 1670 cm.-1 (C=O); δ 8.19 (d, 1H, H6), 7.2-7.8 (m, 3H, aromatic protons), 6.46 (d, 1H, H5), 5.16 (s, 2H, benzyl methylene), and 2.4 (s, 3H, methyl).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>O1CCCC1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]1([CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[O:10][C:19](=[S:20])[NH:1][CH2:2]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: S=C1NCC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1

Procedure:
A solution of the amine (A) (1 g, 3.48 mmole) and 1,1'-thiocarbonyldiimidazole (0.62 g, 3.48 mmole) in tetrahydrofuran (20 ml) was stirred at room temperature for one hour. The solvent was then evaporated and the residue was chromatographed on silica (230-400 mesh), eluting with ethyl acetate. One recrystallization from ethanol gave the pure title compound, 0.65 g (57%), as a white solid, m.p. 232°-235° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18](O)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:30]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[C:19](=[O:30])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(CNc2nc(Cl)cc3nccnc23)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (3.35 g, 8.5 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane (4.33 g, 10.2 mmol) at room temperature. The reaction mixture was stirred at that temperature overnight. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was used directly in the next step. MS (m/z): 392 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10]C[N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[N:24][CH:25]=[C:26](B(O)O)[CH:27]=1>>[C:16]([C:4]1[CH:3]=[C:2]([C:26]2[CH:25]=[N:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=2)[C:11]([OH:10])=[C:6]([CH2:7][NH:8][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:5]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2cncc(C(F)(F)F)c2)c1O

Procedure:
The title compound was prepared as a white solid using the procedure described in Example 1 from 8-bromo-3,6-di-tert-butyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 1) and 3-(trifluoromethyl)pyridine-5-boronic acid [Intermediate 2].
Reaction SMILES: [Br-].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N+:23](CC(=O)C4C=CC=CC=4)([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.[Pd]>[C:42]([O:41][C:39]([NH:38][C@@H:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1)[C:18]([O:20][C@@H:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1)=[O:19])=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O[C@H]1CN2CCC1CC2
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of (R)-3-((S)-3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonylamino)-propanoyloxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (720 mg, 1.06 mmol) and 10% Pd/C (100 mg, 0.09 mmol) in MeOH (30 ml) was hydrogenated at 25 psi for 2 hours. The catalyst was removed by filtration, and the solvent was evaporated to dryness. The residue was dissolved in DCM and filtered through a SCX cartridge. The solution was evaporated to obtain (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (260 mg, 62.9% yield).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([F:36])[N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([F:36])[N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccnc(F)n2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccnc(F)n2)cc1F
Yield: 101.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (648 mg, 0.13 mmol) prepared in Example 24c, triethylsilane (0.11 mL), trifluoroacetic acid (0.13 g) and dichloromethane (1.3 mL), to yield the title compound (0.06 g, 78%) as a colorless solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[S:17]([NH2:20])(=[O:19])=[O:18].[Cl:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[NH2:20][S:17]([C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][Cl:21])(=[O:18])=[O:19]
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)CCCCl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
144 mmol of triethylamine are added to a solution containing 96.4 mmol of 2-amino-5-methoxybenzenesulphonamide in 200 ml of tetrahydrofuran (THF), followed dropwise by a solution containing 135 mmol of 4-chlorobutanoic acid chloride in 30 ml of THF. After stirring overnight at room temperature, the THF is removed by evaporation and the residue is taken up in water. After extraction with ethyl acetate, the organic phase is washed and dried. After evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][C@@H:10]([C:14]([O:16]C)=[O:15])[CH2:9]1>C1COCC1.O>[CH3:3][O:4][C:5]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: COC(=O)[C@@H]1CC(=O)N(Cc2ccc(OC)cc2OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C[C@H](C(=O)O)CC2=O)c(OC)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
LiOH (1.36 g, 32.5 mmol) was added to a solution of (R)-methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (3.18 g, 10.9 mmol) in THF/H2O (1:1, 40 mL) at 0° C. and the reaction mixture was stirred for 1 h. THF was removed and the remaining aqueous solution was washed with diethyl ether (50 mL×2). The aqueous phase was adjusted to pH=5 with 3 N aqueous HCl and the resulting mixture was extracted with DCM (40 ml×3). The combined extracts were washed with water (100 mL×3) and brine (100 mL×1), dried over anhydrous sodium sulfate and concentrated to afford compound (R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (2.76 g, 88% yield) as a colorless solid. (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid was prepared using the same method.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:19]=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:5]1([C:11]2[C:19]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=CN(C)C
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Aluminum chloride (298 mg) was added portionwise to a solution of 2-phenylpyrazolo[1,5-a]pyridine (145 mg) and ethyl 3-dimethylaminoacrylate (316 mg) in methylene chloride (2 ml) at 5° to 6° C. After being stirred at room temperature overnight, the reaction mixture was poured onto water (50 ml), neutralized with saturated aqueous sodium bicarbonate solution, and extracted with chloroform (50 ml×2). The extracts were washed with saturated sodium chloride aqueous solution (20 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel with a mixture of chloroform and n-hexane (1:1) as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give ethyl 3-(2-phenylpyrazolo[1,5-a]pyridin -3-yl)acrylate (trans isomer) (189.4 mg).
Reaction SMILES: [C:1]([CH:3]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25]/[C:26](=[N:33]\[O:34][CH3:35])/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6])#[N:2].[OH-].[K+:37]>>[C:1]([CH:3]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25]/[C:26](=[N:33]\[O:34][CH3:35])/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[CH2:4][C:5]([O-:7])=[O:6])#[N:2].[K+:37]
Reactant: CCOC(=O)CC(C#N)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)[O-])cc2)cc1)c1ccccc1
Yield: 78.34 %

Procedure:
Compound 31 was synthesized from ethyl 3-cyano-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (0.5 g, 1.06 mmol) and potassium hydroxide (0.093 g, 1.66 mmol) by following the procedure described in Scheme 12 (0.4 g, yield: 78.34%); Purity: 99.27%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:10]([O:12][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccc(C(Nc2cccc(F)c2)C(=O)O)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2cccc(F)c2)C(=O)O[C@H]2CN3CCC2CC3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-fluorophenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I76) (48 mg, 0.17 mmol), (R)-quinuclidin-3-ol (24.31 mg, 0.19 mmol), HOBT (29.3 mg, 0.19 mmol), and DCC (39.4 mg, 0.19 mmol) was dissolved in THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH:22]1([NH:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:29][CH2:30][O:31][CH3:32])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: COCCNC1CCCCC1
Product: COCCN(c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1)C1CCCCC1
Yield: 82 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and cyclohexyl-(2-methoxy-ethyl)-amine (Intermediate 26), the title compound was obtained as a white solid in 82% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:22][C:23](=[O:53])[C@H:24]([NH:32][C:33]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]([NH:45]C(OC(C)(C)C)=O)[CH:36]=1)=[O:34])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:11](=[O:21])[C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:45][C:37]1[CH:36]=[C:35]([C:33]([NH:32][C@H:24]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:23]([NH:22][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11](=[O:21])[C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])=[O:53])=[O:34])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]
Reactant: CCOC(=O)CNC(=O)C(=O)[C@@H](COCc1ccccc1)NC(=O)[C@@H](CC1CCCCC1)NC(=O)c1ccc(C(=O)OC)c(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(=O)C(COCc1ccccc1)NC(=O)[C@@H](CC1CCCCC1)NC(=O)c1ccc(C(=O)OC)c(N)c1
Reaction time: 0.5 h

Procedure:
Compound 56 was dissolved in CH2Cl2, and TFA was added under 0° C. The solution was stirred for 30 min and then concentrated. Purification by chromatography (silica, 1/1: Hexane/EtOAc, Rf=0.3) afforded compound 21 as a white solid.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([C:22]([O:24][CH3:25])=[O:23])[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1)(=[O:12])=[O:11].O1C2C(C(OC)=O)=CC=CC=2CC1.C1(S(O)(=O)=O)C=CC=CC=1>>[C:4]1([S:10]([C:13]2[CH:14]=[C:15]([C:22]([O:24][CH3:25])=[O:23])[C:16]3[O:20][CH2:19][CH2:18][C:17]=3[CH:21]=2)(=[O:12])=[O:11])[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2c1OCC2
Agent: COC(=O)c1cccc2c1OCC2
Agent: O=S(=O)(O)c1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2c1OCC2

Procedure:
The title compound was prepared according to the procedure of Intermediate 66 starting from methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; Intermediate 65) and benzenesulfonic acid (0.89 g, 5.6 mmol). Yield: 882 mg (49%). MS (ESI+) for C16H14O5S m/z 319 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][OH:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1>CN(C)C=O.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][O:21][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(CO)c3ccccc3)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(1-benzenesulfonyl-1H-indol-5-yl)-2-phenyl-ethanol CCLXVII (1.06 g, 2.707 mmol), tert-butyldimethylchlorosilane (0.45 g, 2.978 mmol) and imidazole (200 mg, 2.978 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 4 hours. The resulting mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 10/90) to give 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole CCLXVIII as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]1[C:20]2[C:19](=[O:21])[NH:18][CH:17]=[CH:16][C:15]=2[NH:14][C:13]([CH3:22])=[C:12]1[N+:23]([O-:25])=[O:24])[C:6]#[N:7].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32].ClCCl>CO>[CH2:31]([O:21][C:19]1[N:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:11]([C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([N+:23]([O-:25])=[O:24])=[C:13]([CH3:22])[NH:14]2)[CH3:32]
Reactant: CC[O+](CC)CC
Reactant: COc1cc(C#N)ccc1C1C([N+](=O)[O-])=C(C)Nc2cc[nH]c(=O)c21
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C([N+](=O)[O-])=C(C)N2

Procedure:
40 mg (0.11 mmol) of 3-methoxy-4-(2-methyl-3-nitro-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)benzonitrile and 43 mg of triethyloxonium tetrafluoroborate (0.23 mmol) are mixed under a dry argon atmosphere. After addition of dichloromethane (5 ml), the suspension is stirred until a solution is obtained, then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 13 mg (29% of theory) of the title compound as a white solid.
Reaction SMILES: [Se:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Na].[CH3:12]I>O>[CH3:12][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Se:1](=[O:10])[CH2:2]1
Reactant: CI
Reactant: O=[Se]1C=Nc2ccccc21
Agent: [Na]
Solvent: O
Product: CN1C[Se](=O)c2ccccc21
Reaction time: 12 h

Procedure:
0.01 mol of benzoselenazolinone is introduced into a ground-necked round-bottomed flask containing 0.35 gram (0.015 gram-atom) of sodium dissolved in 50 l cm3 of absolute alcohol. 3.1 cm3 (0.05 mol) of methyl iodide are added dropwise and with stirring. After 12 hours, the solvent is evaporated off. The solid obtained is taken up with 30 to 40 cm3 of water and then extracted with chloroform. The chloroform phase is dried over calcium chloride and the solvent is then evaporated off under reduced pressure. The product is recrystallized in cyclohexane.