Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][CH:13]=1.[F:27][C:28]1[CH:34]=[C:33]([I:35])[CH:32]=[CH:31][C:29]=1[NH2:30]>C1COCC1.CCOC(C)=O>[F:27][C:28]1[CH:34]=[C:33]([I:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][CH:13]=1
Reactant: O=C(O)c1cc(-c2ccccc2)ncc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)ncc1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.8 ml, 1.0 M in THF, 2.76 mmol) was added to a suspension of 5-fluoro-2-phenylisonicotinic acid (500 mg, 2.30 mmol) in THF (10 ml) at −78° C. The dark colored suspension was stirred for 30 min. In another flask, 2-fluoro-4-iodoaniline (709.30 mg, 2.99 mmol, 1.30 eq) was dissolved in (15 ml) THF and cooled to −78° C. To this solution lithium bis(trimethylsilyl)amide (5 ml, 1.00 M, 5.06 mmol, 2.20 eq) was added and the mixture was stirred for 1 h. The reaction mixture became very viscous. To this, the homogeneous solution of acid-LiHMDS mixture was added via syringe. The mixture was warmed to room temperature and stirred overnight. Diluted with EtOAc (300 ml), washed with dilute HCl (20 ml), water (20 ml), and then dried and concentrated. Purified on Flashmaster using 100 g cartridge to obtain 565 mg of 5-[(2-fluoro-4-iodophenyl)amino]-2-phenylisonicotinic acid. LC/MS: [8.59 min; 435 (M+1)]
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].ClC1[N:12]=[N:11][C:10]([NH:13][C@@H:14]2[C:19]3[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=3[O:17][C:16]([CH2:29][O:30][CH3:31])([CH2:26][O:27][CH3:28])[C@H:15]2[OH:32])=[CH:9]C=1>C(O)(=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18]2[O:17][C:16]([CH2:26][O:27][CH3:28])([CH2:29][O:30][CH3:31])[C@@H:15]([OH:32])[C@H:14]([NH:13][C:10]3[CH:9]=[CH:2][C:1](=[O:4])[NH:12][N:11]=3)[C:19]=2[CH:20]=1)#[N:25]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(Cl)nn2)[C@@H]1O
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reaction time: 5 h
Yield: 70 %

Procedure:
Potassium acetate (380 mg) and acetic acid (6 ml) were added to (-)-(3S,4R)-4-[(6-chloro-3-pyridazinyl)amino]-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1benzopyran-3-ol (750 mg) obtained in Example 5, and the mixture was refluxed with stirring for 5 hours. The reaction mixture was filtered and the residue was washed with acetic acid. The residue obtained by removing the solvent from the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate:ethanol=95:5), whereby (-)-(3S,4R)-4-[(6-acetyloxy-3-pyridazinyl)amino]-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (180 mg, 22.6%) and (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (500 mg, 69.9%) were obtained in the order of elution.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[CH:12]=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:28]([C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[CH:12]=[N:11][CH:10]=2)=[CH:4][CH:3]=1)#[N:29]
Reactant: O=c1ccccn1-c1ccc(Cn2cncc2Oc2ccc(Br)cc2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Oc2cncn2Cc2ccc(-n3ccccc3=O)cc2)cc1

Procedure:
A mixture of 1-{4-[5-(4-bromophenyloxy)imidazol-1-ylmethyl]-phenyl}-1H-pyridin-2-one (145 mg, 0.35 mmol) and zinc cyanide (24 mg, 0.2 mmol) in DMF (3 mL) was purged with argon for 10 min. A solution of tetrakis(triphenylphosphine)palladium(0) (40 mg, 35 μmol) in DMF (1 mL) was added. The resultant mixture was stirred under argon at 80° C. overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the titled compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:20][CH2:21][O:22][C:5]2=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)C.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:20][CH2:21][O:22][C:5]2=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Fc1cccc2ncnc(Nc3c(Cl)ccc4c3OCO4)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1Nc1ncnc3cccc(Oc4ccccc4)c13)OCO2
Temperature: 90 °C
Yield: 34.8 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.213 g), phenol (0.45 g), potassium carbonate (0.828 g) and DMF (3 ml) was stirred and heated to 90° C. for 30 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a 2N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in diethyl ether and a 6M solution of hydrogen chloride in diethyl ether (1 equivalent) was added. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.05 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 6.18 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.35 (d, 1H), 7.42 (m, 1H), 7.52–7.62 (m, 3H), 8.0 (m, 1H), 9.0 (s, 1H); Mass Spectrum: M+H+ 392 and 394.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)=[O:30])=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
A mixture of ethyl (4-aminophenyl)acetate (0.88 g), (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (1.0 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.81 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.02 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give ethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetate as colorless crystals (1.49 g, yield 89%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH2:18])[C:14]1=[O:19].[Cl:20][C:21]1[N:26]=[C:25]2[CH:27]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[S:29][C:24]2=[CH:23][CH:22]=1>>[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][S:30]([C:28]2[S:29][C:24]3[C:25](=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:27]=2)(=[O:31])=[O:32])[C:14]1=[O:19]
Reactant: N#Cc1ccc(N)c(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Agent: Cl
Product: N#Cc1ccc(N)c(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1

Procedure:
The title compound is prepared from 4-amino-3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile dihydrochloride as described in EXAMPLE 17, Part F using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2 cl2 to afford a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>CO>[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCN(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a mixture of 830 mg of potassium carbonate in 50 ml of methanol was added tert-butyl(piperidin-3-ylmethyl)carbamate (643 mg), followed by 1-(bromomethyl)-4-(trifluoromethyl)benzene (717 mg). The mixture was heated to 70° C. and stirred for 0.5 h. The sample was filtered through a small plug of silica gel and concentrated in vacuo to provide tert-butyl({1-[4-(trifluoromethyl)benzyl]piperidin-3-yl}methyl)carbamate (640 mg). To a solution of this protected amine in 10 ml of dichloromethane was added trifluoroacetic acid (5 ml). The mixture was stirred at 70° C. for 1.5 h, and then concentrated in vacuo. The residue was diluted with 30 ml of ethyl acetate and basified by slow and cautious addition of 30 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted once with 30 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (418 mg, 89%). Mass spectrum (ESI) 273.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][C:21](O)=[O:22])([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][NH3+:26].[Cl-].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([C:17](=[O:18])[N:26]([O:25][CH3:24])[C:21](=[O:22])[CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of (1-benzyloxycarbonyl-4-carboxypiperidin-4-yl)acetic acid (3.64 g) in dimethylformamide (30 ml) dicyclohexylcarbodiimide (2.57 g) was added, and this was followed by stirring at room temperature for 30 minutes. o-Methylhydroxylamine hydrochloride (0.95 g) and triethylamine (1.56 ml) were then added, and this was followed by stirring at room temperature for 30 minutes. The resulting precipitates were removed, and the solvent was evaporated under reduced pressure. To the resulting residual oily compound acetic anhydride (20 ml) and anhydrous sodium acetate (0.39 g) were added, and this was followed by stirring at 100° C. for 30 minutes. After the completion of the reaction, the solvent was removed, and the residual oil was dissolved in 50 ml ethyl acetate. The resulting solution was sequentially washed with a saturated aqueous solution of sodium hydrogencarbonate, 1N hydrochloric acid and water, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure; the resulting residual solid was recrystallized from ethyl ether-petroleum ether to obtain 2.1 g of a colorless crystal having a melting point of 98° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][O:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][O:13][N:12]=1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: Clc1nonc1-c1cccnc1
Reactant: CCC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC#CCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hexyn-1-ol (980 mg, 10 mmol) and sodium hydride (240 mg, 10 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro1,2,5-oxadiazol-4-yl)pyridine (450 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
A solution of 6-Bromoindole (1 g, 5 mmol) in DMF (3 ml) was added to a suspension of NaH (134.7 mg, 5.6 mmol) in DMF (98 ml) at 0° C. and stirred for 15 mins. Triisopropylsilyl chloride (1.082 g, 5.6 mmol) was added dropwise, and the reaction mixture stirred for 2 h before being poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, concentrated in vacuo and the crude product passed through a silica gel column, eluting with hexanes, to give the title compound (406.7 mg, 23%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:30]1([C:36]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:22][CH2:23][N:39]3[CH2:38][CH2:37][C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]3)[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccn1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccn3)C2)CC1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[N:20]=[C:16]([Cl:15])[S:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1csc(Cl)n1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2csc(Cl)n2)C1

Procedure:
61.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 2-chloro-thiazole-4-carboxylic acid (prepared according to R. Walsh et al. Chimica Therapeutica, 1973, 8, 199) to give (R)-3-{[(2-chloro-thiazole-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 343.9 ([M−H]−)
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1(C#Cc2ncc(-c3ccsc3)cc2Cc2ccccc2)CN2CCC1CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of 127 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol (Example 22-a), 61.4 mg of 3-thiopheneboronic acid, 55.4 mg of tetrakis (triphenylphosphine)palladium(0), 2 ml of toluene, 0.5 ml of methanol and 1 ml of aqueous 2 mol sodium carbonate solution was stirred at 80° C. for 2 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 83.9 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[OH-].[K+]>O1CCCC1.CO>[F:1][C:2]1[C:3]([NH:40][CH2:41][C:42]2[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide was dissolved in a mixture of tetrahydrofuran and methanol. A solution of aqueous potassium hydroxide (50% w/v) was added to the reaction mixture, and the combined mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (0-100% [10% methanol in ethyl acetate] in hexanes) to afford 3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide. 1H-NMR (250 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.53-8.41 (m, 3H), 8.09 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.60 (dd, J=7.5, 1.5 Hz, 1H), 7.52 (dd, J=14.0, 2.0 Hz, 1H), 7.33-7.21 (m, 3H), 7.17 (d, J=1.6 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.01 (broad s, 1H), 4.42 (d, J=6.6 Hz, 2H), 3.80 (s, 3H), 2.89 (s, 12H), 2.59 (s, 12H); MS: m/z 496.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19]N(C=O)C.[H-].[Na+].CI>[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1c(Br)c(-c2ccccc2)n(C)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 115 %

Procedure:
Ethyl 4-bromo-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3.31 g, 11.4 mmol) was dissolved into anhydrous DMF (50 mL). After stirring at 0° C. for 15 min, to this solution was added NaH (60%, 0.55 g, 13.7 mmol). The mixture was held at 0° C. for 10 min and then MeI (2.13 mL, 34.2 mmol) was added to the mixture. The reaction mixture was gradually warmed to RT and stirred overnight. The mixture was poured into brine (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide the crude intermediate ethyl 4-bromo-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (4.23 g, 13.1 mmol, 115%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:12]1([S:18]([N:21]=[C:8]=[C:7]2[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH2:6]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1=CCC(=C=NS(=O)(=O)c2ccccc2)C=C1
Temperature: 25 °C

Procedure:
An equimolar mixture of 25.0 g (0.17 mol) 4-carboxybenzaldehyde and 26.7 g (0.17 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 45.7 g (94.8%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.59 (m, 2H); 7.78 (d, 1H); 8.02 (m, 2H); 8.12 (d, 2H); 8.18 (d, 2H); 9.30 (s, 1H); 13C-NMR (400 MHz, DMSO-d6): δ [ppm]=127.8; 129.7; 131.4; 134.1; 135.8; 136.0; 137.9; 166.5; 171.2; 192.9.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.Cl.[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]>ClCCl>[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:18]([C:10]2[N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:19])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)N1CCC(N)CC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g 1-tert.-butoxycarbonylmethyl-1H-indole-2-carboxylic acid and 0.91 ml N-ethylmorpholine in 3 ml dichloromethane 0.6 g O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added and the mixture was stirred for 30 min at room temperature. 0.39 g 1-isopropyl-piperidin-4-ylamine hydrochloride were added to the mixture and the reaction mixture was further stirred for 1 hour. After removal of the solvent under reduced pressure the residue was partitioned between 15 ml water and 15 ml dichloromethane. The organic layer was washed with additional water and then dried over sodium sulphate. After filtration the solvent was removed under reduced pressure and a white solid was obtained. The residue was directly subjected to the subsequent reaction without further purification.