Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]2[O:27][N:26]=[C:25]([CH2:28][CH2:29][CH3:30])[N:24]=2)[CH:10]=[CH:11][C:12]=1[O:13][Si](C(C)(C)C)(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:28]([C:25]1[N:24]=[C:23]([CH:22]=[CH:21][C:9]2[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=2)[O:27][N:26]=1)[CH2:29][CH3:30]
Reactant: CCCc1noc(C=Cc2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-vinyl}-3-propyl-[1,2,4]oxadiazole (compound of Example 3, Method B, Step 1; 38 g, 80.03 mmol) was dissolved in THF (300 mL) followed by addition of 1 M solution of TBAF in THF (139 mL, 480.18 mmol) over a period of 10 min. After stirring at room temperature for 3 h, the solvent was evaporated and the reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (100 mL) and stirred for 10 min followed by extraction with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 1.0% methanol in chloroform) to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([CH3:19])([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:20]>ClCCl.C(OCC)C>[ClH:20].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:19])[CH3:18])(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C)(C)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CNCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 4-methanesulfonyl-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (914 mg) in dichloromethane (20 mL) at 0° C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 2 h. The precipitate formed was then collected by filtration and dried to afford 1-methanesulfonyl-2,2-dimethyl-piperazine hydrochloride salt as a white solid (540 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1>>[F:23][C:24]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=4[F:22])[N:12]=[N:13][CH:14]=3)[CH:5]=[CH:6][C:7]=2[F:8])[C:27]([C:28]#[N:29])=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-benzonitrile by the method of Example 12 to give 5,2′-difluoro-5′-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]biphenyl-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 6.99-7.11 (2H, m), 7.27-7.34 (2H, m), 7.47 (1H, t, J 9.4 Hz), 7.87 (1H, dd, J 5.5, 8.6 Hz), 8.30-8.41 (3H, m), 9.66 (1H, s); m/z (ES+) 407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (5.00 g, 29 mmol) in N,N-dimethylformamide (100 ml) were added N-(3-bromopropyl)phthalimide (9.27 g, 35 mmol) and potassium carbonate (4.93 g, 36 mmol), followed by stirring at 60° C. for 6 hours. After allowing to stand overnight, the reaction solution was poured into water, and the insoluble matter was collected by filtration and washed with ethyl acetate and dried under reduced pressure to give N-[3-(4-chloro-3-nitrophenoxy)-propyl]phthalimide (7.78 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.C1([O:34][C:35](=O)[NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)C=CC=CC=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:18]2[CH2:17][CH2:16][N:15]([C:35]([NH:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CCNC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Nc2ccccc2N)cc2c1CCN(C(=O)Nc1cccnc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq). Reaction was stirred at room temperature for overnight. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford N2-(2-aminophenyl)-1-methyl-N5-pyridin-3-yl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxamide.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[NH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1>C1COCC1>[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]1[CH:52]1[CH2:53][CH2:54][S:49][CH2:50][CH2:51]1
Reactant: OC1CCSCC1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 20 h

Procedure:
Diethyl azodicarboxylate (446 mg, 2.56 mmol) was added to a solution of tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (J. Org. Chem., 1995, 60, 1565-1582) (500 mg, 2.13 mmol), triphenylphosphine (672 mg, 2.56 mmol), and tetrahydro-2H-thiopyran-4-ol (Chem. Comm., 2002, 10, 1070-1071) (303 mg, 2.56 mmol) in THF (10 mL). After 20 h, the reaction was concentrated in vacuo and the crude product purified by silica gel column chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 95:5, to give the title compound. MS: m/z=335 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.FC1C=CC(C#N)=CC=1.[Br:21]N1C(=O)CCC1=O>CN(C)C=O>[Br:21][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: N#Cc1ccc(F)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Reaction time: 24 h

Procedure:
To a solution of 300 mg of a compound 1H-5-indazolecarbonitrile (synthesized from 4-fluorobenzonitrile according to the procedures described in literature, Tetrahedron Lett., 33, 7499(1992) and Synthetic. commun., 27, 1199(1997)) in 3 ml dimethylformamide was added 392 mg of N-bromosuccinimide at room temperature, and the mixture was stirred at the same temperature for one day. After removing the solvent by distillation, the residue was added with 25 ml of ethyl acetate. The mixture was sequentially washed with half-saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 440 mg of the title compound as pale red crystals.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][C@@H:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.O=S(Cl)Cl>O1CCOCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C@@H:24]4[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25]4)=[N:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@@H](N)C4)n23)cc1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
To tert-butyl (1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclo-pentylcarbamate (5.03 g, 9.78 mmol) in 1,4-dioxane (103 mL) was added DIEA (7.2 mL, 41 mmol) and SOCl2 (2.3 mL, 31 mmol). The reaction mixture was heated at about 80° C. for about 1 h. The solvent was removed under reduced pressure and the residue was purified using silica gel chromatography (330 g) eluting with a gradient of 0-20% MeOH in DCM to give (1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (2.65 g, 68%): LC/MS (Table 1, Method b) Rt=1.55 min; MS m/z: 397 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C@H:14]2[N:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1.O.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]([CH3:37])=[N:23]1>COCCOC.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>[CH3:18][N:17]([CH3:19])[C@H:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:25]3[C:24]([CH3:37])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)[C@@H]1CCc2ccc(Br)cc21
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)[C@H](N(C)C)CC2
Temperature: 85 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
(Method 1): To a solution of K2CO3 (1.9 mmol) and (R)-(6-bromo-indan-1-yl)-dimethyl-amine (1 mmol) in 1,2-dimethoxyethane (8.8 mL)/water (1.2 mL) was added Pd(PPh3)4 (0.1 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (1.2 mmol). The reaction mixture was degassed and stirred at 85° C. for 6 h. The solvent was evaporated, crude was redissolved in dichloromethane and filtered through a pad of Celite. The filtrate was extracted with 6M HCl (3×0.16 mL). The aqueous layer was basified with 6M NaOH to pH 13 and extracted with dichloromethane. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude was purified by flash chromatography (CH2Cl2-MeOH-NEt3 as eluents) to yield (1R)-dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine as an oil (52% yield). Product was obtained with a final ee of 99.6% (determined by chiral HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)OC)=[CH:6][C:5]([C:13]([F:16])([F:15])[F:14])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[CH3:9][NH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: COC(=O)Nc1cc(C(F)(F)F)cnc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cc(C(F)(F)F)cnc1N
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To a mixture of methyl (2-amino-5-trifluoromethylpyridin-3-yl)-carbamate (100 mg) and THF (15 ml), lithium aluminum hydride (26 mg) was added under ice-cooling. The mixture was stirred for 15 minutes under ice-cooling, heated to 90° C., and stirred with heating for 1.5 hours. Into the reaction mixture cooled to room temperature, aqueous sodium hydroxide solution was poured, and extracted with tert-butyl methyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 77 mg of N3-methyl-5-trifluoromethylpyridin-2,3-diamine.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:33][C:29]1[CH:30]=[N:31][CH:32]=[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:28]=1)=[C:3]([CH3:20])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (44.0 mg, 0.130 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.93 (2H, dd, J=4.3, 2.3 Hz), 7.43 (1H, ddd, J=9.5, 2.5, 1.3 Hz), 7.36 (1H, d, J=14.5 Hz), 6.99 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.64 (1H, t, J=2.2 Hz), 4.16 (2H, br. s.), 3.77-3.89 (4H, m), 3.20-3.30 (4H, m), 2.60 (2H, t, J=7.9 Hz), 2.27 (2H, qd, J=7.5, 7.3 Hz), 2.01 (3H, s). Mass Spectrum (ESI) m/e=440.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][OH:23].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:21][CH2:22][OH:23])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cc(S(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl

Procedure:
40 g of 4-Chloro-3-nitrobenzenesulfinic acid, 27.8 g of potassium carbonate, 24.8 g of 2-bromoethanol and 200 ml of dimethylformamide were mixed together and reacted at 50° C. for a period of 8 hours. The reaction mixture was then poured into of water and extracted with ethyl acetate. The organic layer was recovered and the solvent was removed by distillation under reduced pressure. The oily residue was refined using silica gel short-column chromatography to obtain an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[Li]CCCC.[CH3:14][C:15]([S@:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:21]2([NH:20][S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)N=C1COC1
Reactant: Brc1cncc(I)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)NC1(c2cncc(Br)c2)COC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of 3-bromo-5-iodopyridine (0.14 g, 0.493 mmol) in THF (2 mL) cooled at −78° C. was added nBuLi (462 μl, 0.74 mmol) dropwise over 5 min. The reaction mixture was stirred at −78° C. for 15 min, then (R)-2-methyl-N-(oxetan-3-ylidene)-propane-2-sulfinamide (0.1 g, 0.567 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 10 min then allowed to warm up to RT. The mixture was quenched with water (2 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.096 g, 58%) as a light yellow oil. MS: 333.0 and 335.1 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.[Cl:22]C1C=C2C(=CC=1)NC=C2C(Cl)=O>>[Cl:22][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[C:10]([O:12][CH2:13][C:14]12[CH2:15][CH2:16][N:17]([CH2:20][CH2:21]1)[CH2:18][CH2:19]2)=[O:11]
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: O=C(Cl)c1c[nH]c2ccc(Cl)cc12
Product: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccc(Cl)cc12

Procedure:
Quinuclidin-4-ylmethyl 5-chloro-1H-indole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 5-chloro-1H-indole-3-carbonyl chloride as the electrophile.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:12]#[C:13][Si](C)(C)C)[N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:12]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)#[CH:13]
Reactant: Cc1ccc2c(C#C[Si](C)(C)C)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc2nc(C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 2-methyl-5-trimethylsilanylethynyl-quinoline (140 mg, 0.6 mmol, 1.0 eq) in solution in MeOH (5 mL) was added K2CO3 (324 mg, 2.34 mmol, 4 eq), and the resulting mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure and water was then added. The aqueous layer was extracted twice with cyclohexane, and then the combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration under reduced pressure the crude product was purified by column chromatography on silica gel (Cyclohexane-EtOAc 99:1) to afford 5-ethynyl-2-methyl-quinoline as a yellow oil (99 mg, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=O)[CH2:7]Cl)[CH3:2].[NH2:18][C:19]([NH2:21])=[S:20].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:6]1[N:18]=[C:19]([NH2:21])[S:20][CH:7]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=Cc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
209.2 g of 2-benzylidene-3-oxo-4-chlorobutyric acid ethyl ester (described in J. Amer. Chem. Soc. 66, 1933 (1944)), 63.2 g of thiourea and 104.6 g of sodium acetate were dissolved in a mixture of 1,460 ml of tetrahydrofuran and 630 ml of water. The solution was stirred overnight at room temperature and the tetrahydrofuran was then evaporated off. The aqueous phase was adjusted to pH 8 and extracted three times with ethyl acetate. Drying and evaporation of the organic phase gave a viscous oil, which chiefly consisted of the desired Z-isomer. The product was further processed in the crude form.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:27]([C:29](OCC)=[O:30])[NH2:28]>CCOC(C)=O>[O:30]=[C:29]1[NH:27][N:28]=[C:1]([C:3]2[N:4]=[C:5]([NH:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(C#N)cc2ccccc12
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (S)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)amino)methyl)pyrrolidine-1-carboxylate (0.561 g) was added ethyl hydrazinecarboxylate (0.663 g, 6.36 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with saturated aqueous NH4Cl. The aqueous and organic layers were separated. The organic layer was concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]([C:26]1([CH:32]=[CH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)=[O:25].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:23][C:24]([C:26]1(/[CH:32]=[CH:33]/[C:14]2[CH:13]=[C:12]3[C:17]([CH:18]=[CH:19][C:10]([C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH3:9])=[N:11]3)=[CH:16][CH:15]=2)[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)=[O:25]
Reactant: C=CC1(C(=O)OC)CCCCO1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: COC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1
Yield: 32.8 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (320 mg, 0.9 mmol), 2-vinyl-tetrahydro-pyran-2-carboxylic acid methyl ester (330 mg, 0.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (82 mg, 0.09 mmol), tri(o-tolyl)phosphine (54 mg, 0.18 mmol) and N,N-dicyclohexylmethylamine (526 mg, 0.58 mL, 2.7 mmol) in acetonitrile (4 mL) was heated at 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with ice-cold hydrochloric acid (1 M). The aqueous layer was extracted with ethyl acetate and the organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid methyl ester (130 mg, 21%) as an oil LCMS (m/z) 441.1 [M+H], Tr=2.75 min.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[C:30]([O:34][C:35](=[O:58])[C@H:36]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:37][C:38](=[O:50])[CH2:39][NH:40][CH:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.C(Cl)(Cl)Cl.O>[C:30]([O:34][C:35](=[O:58])[C@H:36]([CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[NH:37][C:38](=[O:50])[CH2:39][N:40]([C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)CNC1Cc2ccccc2C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1Cc2ccccc2C1
Temperature: -15 °C
Yield: 94.5 %

Procedure:
N-Carbobenzoxy-L-alanine (3.5 g) and triethylamine (1.6 g) are dissolved in 50 ml of tetrahydrofuran, followed by dropwise addition of 1.7 g of ethyl chlorocarbonate with stirring at -15° C. After completion of addition, the mixture is stirred for 15 minutes and, a solution of 3.9 g of N-(2-indanyl)glycyl-L-phenylalanine tert-butyl ester in 100 ml of chloroform is added dropwise at -10° C. The mixture is stirred at room temperature for one hour and poured into 50 ml of water. The chloroform layer is separated and distilled. The residue is dissolved in 200 ml of ethyl acetate. The solution is washed twice with 50 ml portions of 1N sodium hydroxide, once with 50 ml of water, twice with 50 ml portions of 10% aqueous solution of phosphoric acid, and once with 50 ml of water in that order. It is then dried over anhydrous magnesium sulfate and distilled to give 5.6 g of N-carbobenzoxy-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine tert-butyl ester as an oil.