Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.[C:21]([O-:24])([O-])=O.[K+].[K+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:10]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:24][CH3:21])=[CH:14][CH:15]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-methoxybenzylbromide (442 mg; 0.317 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.137 mg (36.7%); MS m/z: 374.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.70 (s, 6H), 4.54 (s, 4H); 6.71 (d, 1H, 4J=2.2 Hz); 6.78 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 6.84-6.87 (m, 4H); 7.17-7.20 (m, 4H); 7.33 (d, 1H, 3J=8.9 Hz); 7.93 (s, 1H); 12.03 (br s, 1H); HPLC (METHOD [A]): rt 15.56 min (99.5%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[CH2:14]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15]1.NC1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([N:19]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: Nc1ccccc1
Solvent: CCO
Product: Cc1sc2nc(Cl)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Yield: 112.5 %

Procedure:
To 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[CH:22][CH:21]=[CH:20]3)=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1
Reactant: COC1CCC(OC)O1
Reactant: CC1CC(=O)NN=C1c1ccc(N)nc1
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(-n2cccc2)nc1

Procedure:
A mixture of 1.0 g. (5 mmole) 4,5-dihydro-5-methyl-6-(2-amino-5-pyridyl)-3(2H)-pyridazinone, 0.66 g. (5 mmole) 2,5-dimethoxytetrahydrofuran and 15 ml. acetic acid was heated under reflux for 30 minutes. The reaction mixture was evaporated, the residue was taken up in dichloromethane, washes with an aqueous solution of sodium hydrogen carbonate, evaporated and the residue chromatographed on silica gel (elution agent: trichloromethane/methanol 19:1 v/v). There were obained 0.5 g. of the title compound (39% of theory); m.p. 192°-193° C., after recrystallisation from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28].O>ClCCl>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:17])[CH:3]=1)=[O:28]
Reactant: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)CCl)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 40.5 %

Procedure:
4'-Amino-2'-methylbiphenyl-4-carboxylic acid (D115, 2.45 g, 10.8 mmol) and triethylamine (3.8 ml, 27.3 mmol) were stirred in dichloromethane (50 ml) as chloroacetyl chloride (1.05 ml, 13.2 mmol) was added dropwise. This mixture was stirred for 3 h, when water (20 ml) was added. After vigorous stirring for 15 min and basification with potassium carbonate solution, the mixture was separated. The aqueous portion was washed with dichloromethane, and acidified with conc. hydrochloric acid. The precipitated solid was filtered off and dried, giving the title compound (1.33 g, 40%) as a grey powder.
Reaction SMILES: [O:1]=[C:2]([NH:13][C@H:14]([C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[CH3:15])[CH2:3][CH2:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.C(O)C.[OH-].[Na+]>O>[O:1]=[C:2]([NH:13][C@H:14]([C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])[CH2:3][CH2:4][C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@H](NC(=O)CCC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)CCC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 17 h

Procedure:
A mixture of the phenylmethyl ester product from part (a) (1.3 g., 3.0 mmole), methanol (3.5 ml.), ethanol (3.5 ml.), water (3.5 ml.), and 1N aqueous sodium hydroxide solution (3.5 ml., 3.5 mmole) is stirred at 25° for 17 hours, after which it is partially concentrated by rotary evaporation (to remove volatile alcohols). The solution is then diluted with water and washed with ethyl acetate (the ethyl acetate layer is discarded). The aqueous layer is acidified with hydrochloric acid and extracted twice with ethyl acetate. The extracts are combined, dried, and concentrated to give 1.0 g. of the desired product as a pale yellow oil. This oil is dissolved in water (150 ml.), filtered through charcoal, and lyophilized to give 500 mg. of 1-[N-(1,4-dioxo-4-phenylbutyl)-L-alanyl]-L-proline as a fluffy white powder. TLC (Rf 0.4 on silica gel, 1:1 methanol:ethyl acetate). [α]D =-80° (1% chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>>[F:16][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1NCc1cccnc1
Product: Oc1cccc(Nc2ncc(F)c(NCc3cccnc3)n2)c1
Yield: 43 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) reacted to give 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 43%). 1H NMR (CD3OD): δ 4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz, 1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −170.99; LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[OH-].[K+]>CS(C)=O>[ClH:1].[ClH:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(CCCCN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Yield: 125.7 %

Procedure:
The procedure described in Example 1(a) was followed, using 10.0 g of 4-(4-chlorophenyl)butyl piperazine, 47.2 g of 1-bromo-3-chloropropane, 150 ml of dimethyl sulfoxide and 11.2 g of potassium hydroxide, to give 10.0 g (82% of theory) of 1-[4-(4-chlorophenyl)butyl]-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid, M.p. 266°-268° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1O)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=[O:26].[K+].[K+]>CN(C)C=O>[C:1]([CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1([C:12]#[N:13])[O:26][C:18]1([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(C)(C)C1CCCCC1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1(OC2(C#N)C=CC=CC2C#N)CCCCC1
Yield: 49.6 %

Procedure:
1,2-dicyano-3-nitrobenzene (1.73 g) and 2-tert-butyl-cyclohexanol (4.68 g) were allowed to react with each other at 80° C. for 2 hours in dimethylformamide (DMF, 5 ml) with the addition of K2CO3 (5.0 g). After the completion of the reaction, the reaction product was extracted twice with a mixed solvent of water and ethyl acetate (at a volumetric ratio of 1/1), and the layer extracted with ethyl acetate was dried overnight with the use of MgSO4, followedby removal of ethyl acetate by distillation. The residues were isolated and purified by silica gel column chromatography using chloroform to obtain 1.41 g of 1,2-dicyano-2-(tert-butylcyclohexyloxy)benzene in a 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CS(O[CH2:31][CH:32]1[CH2:35][C:34]([F:37])([F:36])[CH2:33]1)(=O)=O>>[F:36][C:34]1([F:37])[CH2:35][CH:32]([CH2:31][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[O:10][C:11]4[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=4[N:25]=3)=[CH:3][C:2]=2[F:1])[CH2:33]1
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC(F)(F)C4)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (3,3-difluorocyclobutyl)methyl methanesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[O-]CC.[Mg+2].[O-]CC.[Cl:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1C(O)=O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:27][C:25]1[N:26]=[C:18]([Cl:17])[CH:19]=[CH:23][C:24]=1[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Monoethyl malonate (6.61 g, 50.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), and after adding magnesium ethoxide (3.15 g, 28.0 mmol) thereto while cooling with ice, it was stirred at room temperature for 3 hours. The reaction solution was then concentrated under a reduced pressure, thereby preparing a magnesium salt of monoethyl malonate. 2,6-dichloronicotinic acid (3.84 g, 20.0 mmol) was then dissolved in anhydrous tetrahydrofuran (80 ml), and after adding 1,1-carbonyldiimidazole (4.87 g. 30.0 mmol) while cooling with ice, it was stirred at room temperature for 1.5 hours. To this solution, a solution, wherein the previously prepared magnesium salt of monoethyl malonate was dissolved in anhydrous tetrahydrofuran (160 ml), was added dropwise over a period of 10 minutes while cooling with ice. After completion of dripping, the temperature was gradually brought back to room temperature and thereafter, stirring was performed for 4 hours. After adding ethyl acetate (200 ml) to the reaction solution, the organic layer was washed with a 10% aqueous citric acid solution (150 ml×2), saturated sodium bicarbonate water (150 ml), and saturated saline solution (150 ml), in that order, and then dried over anhydrous sodium sulfate. After filtering, the residue obtained by concentration under a reduced pressure of the filtrate was applied to a silica gel chromatography, and 4.24 g (81%) of the title compound was obtained in the form of a pale-pink, oily substance from an n-hexane:ethyl acetate=3:1 eluate.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[N+]([C:20]1C(N2CCC(=O)CC2)=NC=CC=1)([O-])=O>>[CH3:20][C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C:2](=[CH2:1])[CH2:3][CH2:4]2)[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: O=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Product: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Yield: 62 %

Procedure:
The title product was synthesized following the procedure reported for Compound 2a but replacing 1-(6-methyl-3-nitro-2-pyridyl)-4-oxopiperidine for 1-(3-nitro-2-pyridyl)-4-oxopiperidine. Yield: 62%.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)/[C:9]1=[O:39])=O)(C)(C)C.[F:40][C:41]1[CH:42]=[CH:43][C:44]([CH3:56])=[C:45]([CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH:46]=1>C1(C)C=CC=CC=1>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[CH:18]2[CH2:50][C:49](=[O:51])[NH:48][CH:47]([C:45]3[CH:46]=[C:41]([F:40])[CH:42]=[CH:43][C:44]=3[CH3:56])[C:10]32[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:8][C:9]3=[O:39])[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 17.7 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-3-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.2 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (14 mmol) in toluene to give the title compound as a white solid (600 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[NH:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([CH:18]=[O:19])=[CH:3]1
Reactant: CN(C)C=O
Reactant: Brc1c[nH]c2ncccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ncccc12
Temperature: -60 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a suspension of 3-bromo-1H-pyrrolo[2,3-b]pyridine (9.85 g, 50.0 mmol) in THF (300 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (42 mL, 105.0 mmol, 2.1 equiv.) at −70° C. The temperature of the reaction mixture was raised to −60° C. during the addition and became a clear solution. The resulting brick red color solution was slowly allowed to warm to −10° C. during a period of 1 h and then stirred for 4 h at this temperature. Again, the mixture was cooled to −70° C. and a solution of dimethylformamide (8.5 mL, 110.0 mmol) in THF (30 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was dissolved in ethyl acetate (˜70 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with ethyl acetate. After drying in air, 6.05 g (83% yield) of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was isolated as an yellow solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480. found 146.0478.
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].FC(F)(F)C(O)=O.[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=3)[C:25]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH:42]4[CH2:46][CH2:45]N[CH2:43]4)=[C:38]([CH3:47])[CH:37]=3)(=[O:35])=[O:34])=[CH:24]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C>[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=3)[C:25]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH:42]4[CH2:46][CH2:45][N:4]([CH3:3])[CH2:43]4)=[C:38]([CH3:47])[CH:37]=3)(=[O:34])=[O:35])=[CH:24]2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCNC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Formaldehyde (37% in water, 0.19 mL, 2.505 mmol) and sodium cyanoborohydride (63 mg, 1.002 mmol) were added to a solution of 1-benzenesulfonyl-5-fluoro-3-(3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl)-1H-indole trifluoroacetate (0.305 mg, 0.5011 mmol) in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 2 hours, then buffered to pH 12 by addition of 1 M aqueous NaOH. The mixture was extracted with DCM, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH(NH4OH) to give 0.209 g (81% yield) of 1-benzenesulfonyl-5-fluoro-3-[3-methyl-4-(1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-1H-indole as a white foam. MS (M+H)=513.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:41]=[CH:40][C:29]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:41]=[CH:40][C:29]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 88.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (780 mg, 2.5 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (1.5 g, 4.3 mmol) to afford the desired product (1.0 g, 90%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:6]1[N:7]=[C:2]2[CH:15]=[C:14]([Si:11]([CH3:13])([CH3:12])[CH3:10])[O:9][C:3]2=[CH:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(O)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2oc([Si](C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a degased solution of 6-iodo-2-picolin-5-ol (855 mg; 3.64 mmol; 1.00 eq.) in triethylamine (20.00 mL) were added (trimethylsilyl)acetylene (1 g; 10.19 mmol; 2.80 eq.), cuprous iodide (90.07 mg; 0.47 mmol; 0.13 eq.) and dichlorobis(triphenyl phosphine)palladium(II) (229.82 mg; 0.33 mmol; 0.09 eq.). The solution was heated under reflux. After 3 h, the reaction was complete, and allowed to cool down to rt. The solution was filtered over celite (washed with AcOEt and MeOH). The solvents were removed. AcOEt and water were added and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the expected compound. The crude was purified by short flash chromatography using cyclohexane then AcOEt/Cyclohexane 20/80 to afford 603 mg of the desired compound as a solid (Intermediate 5.1). Amount: 603 mg; Yield: 81%; Formula: C11H15NOSi; HPLC Purity: 93.14%; HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=2.17 min; 93.14%; 1H NMR (CDCl3) δ 7.65 (d, 1H, J=8.5 Hz), 7.10 (s, 1H), 7.06 (d, 1H, J=8.5 Hz), 2.67 (s, 3H), 0.36 (s, 9H); LC-MS: M/Z ESI: Rt (min) 1.89 min, 206.06 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)/[CH:5]=[CH:6]/[C:7]([O:9]CC)=O.[CH2:15]([NH2:17])[CH3:16].C[O-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]=[CH:6][C:7]([NH:17][CH2:15][CH3:16])=[O:9]
Reactant: CCN
Reactant: CCOC(=O)/C=C/c1cccc(Br)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)C=Cc1cccc(Br)c1
Temperature: 45 °C

Procedure:
Trans ethyl 3-bromocinnamate (8.4 g), ethylamine (6.7 g), methanol (18 ml) and 4A molecular sieves (1 g) were combined and heated at reflux for 1/2 hour. The mixture was cooled to about 45° C and sodium methylate (0.6 g) added. The mixture was then heated at reflux 11/2 hour and then cooled. It was acidified with concentrated hydrochloric acid (12 ml). The sieves were removed by filtration. Ice water was added to the filtrate to precipitate trans 3-bromo-N-ethylcinnamamide, m.p. 89°-90° C (after recrystallization from ethanol/water).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[O:5][N:4]=1.[C:16]1([C@@H:22]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:23]([O:25][C@@H:26]2[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Cl-:1].[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N+:28]34[CH2:29][CH2:30][CH:31]([CH2:32][CH2:33]3)[C@@H:26]([O:25][C:23](=[O:24])[C@@H:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:27]4)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: COc1cccc(-c2nc(CCl)no2)c1
Solvent: CC#N
Product: COc1cccc(-c2nc(C[N+]34CCC(CC3)[C@@H](OC(=O)[C@H](Nc3ccccc3)c3ccccc3)C4)no2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
3-(Chloromethyl)-5-(3-methoxyphenyl)-1,2,4-oxadiazole (33.4 mg, 0.15 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (50.0 mg, 0.15 mmol) in acetonitrile (2 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated, and the resulting solid was triturated with Et2O (2 ml) to obtain (R)-1-((5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane chloride (82.3 mg, 99% yield).