Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18]O)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH2:21]([SH:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18][S:29][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:2])[CH3:3]
Reactant: SCCc1ccccc1
Reactant: Cc1c(CO)oc2cccc(OCCCNC(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNC(C)C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To a solution of [4-(3-isopropylamino-propoxy)-3-methyl-benzofuran-2-yl]-methanol (14 mg, 0.05 mmol) and phenethyl mercaptan (10.3 mg, 0.075 mmol) in anhydrous CH2Cl2 (0.9 ml) was added TFA (0.2 ml). The Mixture was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give desired compound (15 mg, 74%). FAB-MS: m/z 398 (MH+); 1H-NMR (CDCl3): δ 1.11 (6H, d, J=6.2 Hz), 2.05 (2H, m), 2.34 (3H, s), 2.61-2.96 (7H, m), 3.80 (2H, s), 4.11 (2H, m), 6.56 (1H, m), 6.95-7.28 (7H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Cl)=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cnc(Cl)nc2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of 2,5-dichloropyrimidine and 4-formylphenyl boronic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH3:15].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH2:3]([N:4]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH3:15])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH:2]([CH3:16])[CH3:1]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(F)(F)F)cc1NCC(C)C
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C(F)(F)F)ccc2C)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2-methylpropyl)[2-methyl-5-(trifluoromethyl)phenyl]amine (50 mg, 0.216 mmol) in pyridine (5 mL) in air, at room temperature, was added ethyl 3-[4-(chlorosulfonyl)phenyl]-2,2-dimethylpropanoate (65.9 mg, 0.216 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, then stood overnight. The solvent was evaporated in vacuo to give the crude material which was then purified by MDAP (Method F) to give the required product, 20 mg. LCMS (M+1) 500, RT 1.53 mins.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:31](=[O:32])[CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)CN1CCOCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CN3CCOCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and 2-morpholinoacetic acid as a yellow solid (37%). MS 445 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]

Procedure:
A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example AA1) (24 g, 0.119 mol), nitroethane (70 ml, 0.97 mol) and ammonium acetate (2.75 g, 35 mmol) is heated at reflux under argon for 24 hours. The mixture is concentrated to give an oil which is dissolved in chloroform (200 ml) and washed with water (2×200 ml), followed by brine (100 ml). The organic extract is dried (MgSO4), filtered and the solvent removed to give the product as an orange oil. This was used immediately in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K].[S:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([NH:13][S:12]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:7]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Yield: 69.5 %

Procedure:
2.0 g (0.011 mol) of (4,6-dichlorpyrimidin-2-yl)-methylamine and 5.67 g (0.022 mol) N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water, the inorganic phase was saturated with sodium chloride and the residual ethyl acetate dissolved in the aqueous phase was distilled off on a rotary evaporator. The aqueous phase was made acid with 1N HCl, the crystals which separated were filtered off under suction and washed with water. After drying there were obtained 2.72 g (68%) of N-[4-(6-chloro-2-methylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as beige crystals. m.p.: >240° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>O1CCCC1.CCCCCC>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[CH:9]=[CH:8]1
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(C(=O)O)ccc2O1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-2H-benzo[b]pyran (see J. Med. Chem., 33, 3028 [1990]) (5.0 g) in dry tetrahydrofuran (100 ml) at -70° C. under nitrogen was added, dropwise, a 1.6M solution of n-butyllithium in hexane (17 ml). The reaction mixture was stirred at -70° C. for 15 minutes then treated with an excess of finely ground solid CO2. The reaction was further stirred for one hour, the solvent evaporated in vacuo and the residue taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The organic layer was concentrated in vacuo to a solid which was triturated with hexane to provide a white solid, 1.6 g.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21](NC2C=CC(C3(CC(O)=O)CC4C(=CC=CC=4)C3)=CC=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9]C(NC1C=CC=CC=1C)=O.C([O-])=O.[NH4+].[CH2:47]([OH:49])[CH3:48]>[Pd]>[CH2:47]([O:49][C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([OH:2])[CH:4]=1)[CH3:48]
Reactant: COc1cc(CC(=O)Nc2ccc(C3(CC(=O)O)Cc4ccccc4C3)cc2)ccc1NC(=O)Nc1ccccc1C
Reactant: CCO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)Cc1ccc(N)c(O)c1
Temperature: 50 °C

Procedure:
A solution of (3-hydroxy-4-nitro-phenyl)-acetic acid ethyl ester (5.0 g, Reference Example 4) was dissolved in ethanol (approximately 200 mL) was treated with ammonium formate (approximately 20 g). The mixture was warmed to 50° C. and then treated cautiously with palladium on charcoal (approximately 1 g, 5%)—effervescence was observed. After 30 minutes the mixture was filtered hot through a pad of filter-aid and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11](O)[CH2:12][CH3:13]>>[CH:11]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH:2]([CH2:4][CH3:5])[CH3:1])=[O:6])[OH:3])([CH2:12][CH3:13])[CH3:10]
Reactant: CCC(C)O
Reactant: O=C(O)CC(O)C(=O)O
Product: CCC(C)OC(=O)CC(O)C(=O)OC(C)CC
Temperature: 102 °C

Procedure:
Di-sec-butyl-DL-malate was prepared using a procedure similar to Example 3. This compound was isolated as a bottoms product. To the reaction flask, DL-malic acid (80.23 g), 2-butanol (220 mL) and Amberlyst® 15 ion exchange resin (11.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 102° C., one phase started to collect in the Dean-Stark trap. The reaction was maintained at 102° C. for 4 hr. During this time, the water/alcohol azeotrope was removed as fresh alcohol was added. The product was dissolved in diethyl ether, separated from the catalyst via filtration over a bed of silica, washed with saturated sodium bicarbonate a number of times, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Di-sec-butyl-DL-malate was obtained as a low viscosity, clear light yellow liquid with no detectable odor (46 g, 31% yield) after pumping on the sample in vacuo to remove residual 2-butanol.
Reaction SMILES: C[O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=O)[CH:31]=1)=[NH:28].C([O-])(O)=O.[Na+]>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]=1[C:27]([NH:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:5][C:3]([OH:2])=[O:4])[CH:33]=[CH:34][CH:35]=1)=[NH:28]
Reactant: N=C(Nc1cccc(C=O)c1)c1cc(-c2ccccc2)ccc1F
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(Nc1cccc(C=CC(=O)O)c1)c1cc(-c2ccccc2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (176 mg, 0.97 mmol) in THF (1.5 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (58 mg, 1.46 mmol) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then aldehyde (57) (307 mg, 0.97 mmol) in THF (1.50 mL) was added. After 3-hours further sodium hydride (60% in oil) (1.5 eq) was added and the reaction mixture stirred at ambient temperature overnight. Saturated NaHCO3 solution was added and washed with EtOAc. The aqueous layer was acidified to pH 1 using 1.2 M HCl and extracted with EtOAc. The aqueous layer was then neutralised to pH 7 and extracted into EtOAc. The organic layers were combined, dried (MgSO4) and the solvent concentrated in vacuo. The residue was purified by Flash Master Jones Chromatography using a 2 g silica cartridge and a gradient of EtOAc in heptane and MeOH in EtOAc to yield the title compound. Yield: 25 mg, 7%; LC-MS tr 1.77 min; HPLC Purity: 91%; MS (ES+) m/z 361 (M+H); NMR (400 MHz; MeOH): δ 6.6 (d, 7.35-7.80 (m, 11H), 8.05 (m, 1H), 8.15 (d, 1H)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16].O>CC#N>[CH:15]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15 g, 64.7 mmol) in CH3CN (100 mL) was added dropwise a solution of isopropylamine in water (7.6 g, 0.13 mol) at 0° C. The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure and the residue was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 99.6% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1 H), 8.05 (d, J=7.6 Hz, 1 H), 4.31-4.22 (m, 3 H), 2.46 (s, 3 H), 1.27 (t, J=7.2 Hz, 3 H), 1.20 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][C:16]#N>CCOCC>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]12[CH2:16][CH:15]1[C:3]#[N:1]
Reactant: C=[N+]=[N-]
Reactant: N#CC=C1C(=O)Nc2ccc(Br)cc21
Solvent: CCOCC
Product: N#CC1CC12C(=O)Nc1ccc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
An excess of an ethereal diazomethane solution was added portion-wise from a syringe to a suspension of 5-bromo-1,2-dihydro-2-oxo-3H-indol-3-ylidene-acetonitrile (30 mg, 0.1 mmol), prepared as in Example 1, in dry ether (30 mL). The suspension was stirred at 0° C. for 2 hours. Excess diazomethane was quenched with two drops of acetic acid. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in toluene (20 mL) and the resulting solution was heated to reflux for 6 hours. Upon removal of the solvents, the solid residue was chromatographed using hexane and ethyl acetate (v/v 1:1) as eluent, providing the title compound in 50% yield (15 mg). MS: m/z 263.2 [M+1]+. 1H NMR (CCl3D): δ 9.06 (br, 1H), 7.45 (m, 1H), 7.30 (br, 1H), 6.87(m, 1H), 2.50 (m, 1H), 2.16 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[BH4-].[Na+]>>[CH2:23]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: CCCCCC=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 57.7 %

Procedure:
Using a method similar to Example 201, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol), hexanal (75 mg, 0.750 mmol), and NaBH4 (38 mg, 1.00 mmol) gives the title compound (110 mg) as a colorless glass. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.15 (d, 1H), 7.21-7.14 (m, 2H), 6.90 (m, 2H), 6.05 (br. s, 2H), 3.01 (m, 1H), 2.90-2.79 (m, 2H), 2.69-2.55 (m, 3H), 2.50-2.42 (m, 1H), 1.84-1.64 (m, 4H), 1.49 (m, 2H), 1.29 (m, 6H), 0.89 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1B(O)O.Br[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]3[C:48]([Cl:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[Cl:51])=[CH:35][CH:34]=2)[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:18]([CH3:52])[CH:17]=1>>[Cl:49][C:48]1[CH:47]=[C:46]([CH3:50])[CH:45]=[C:44]([Cl:51])[C:43]=1[O:42][CH2:41][CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:17][C:18]=2[CH3:52])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:34][CH:35]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(Br)cc3C)cc2)c(Cl)c1
Reactant: COCCCc1ccccc1B(O)O
Product: COCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using [2-(3-methoxypropyl)phenyl]boronic acid from step 1 and tert-butyl (2-(4-bromo-2-methylphenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from EXAMPLE 2, step 2 as starting materials.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH2:2][CH3:3].BrC[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>>[CH2:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:2][CH3:3]
Reactant: N#CCCCCBr
Reactant: CCCc1c(O)cccc1Cl
Product: CCCc1c(Cl)cccc1OCCCC#N

Procedure:
Five and seven-tenths grams of 2-propyl3-chlorophenol were then reacted with 5.9 ml. of 5bromovaleronitrile following the procedure of Example 2A. The resulting 4-(2-propyl-3-chlorophenoxy)butane nitrile was provided by chromatography. This purified nitrile intermediate (3.3 g.) was dissolved in about 65 ml. of methylene chloride to which 3.0 g. of aluminum chloride and 1.7 ml. of acetyl chloride had been added and the reaction was heated to reflux overnight. The reaction was cooled, additional methylene chloride was added, and the mixture was poured into ice/hydrochloric acid. The layers were separated and the organic layer was washed first with an aqueous sodium bicarbonate solution and then with water. The organic solution was dried over sodium sulfate and evaporated to dryness. Purification by chromatography provided 2.67 g. of the desired 4-(2-propyl-3-chloro4-acetylphenoxy)butane nitrile. NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)#[CH:16].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]3([OH:25])[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A mixture of 4-bromo-4'-hydroxybiphenyl (747 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis(triphenylphosphine)-palladium (II) chloride (105 mg), copper (I) iodide (55 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 4 hours. The reaction mixture was cooled and the dimethylformamide and triethylamine were removed by evaporation. The residue was purified by flash column chromatography on alumina (ICN--Alumina N32-63) using a gradient of 10% methanol in ethyl acetate to 20% methanol in ethyl acetate as eluent to give 3-[(4'-hydroxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (220 mg) as a solid, m.p. 230°-233° C.; microanalysis, found C, 76.7; H, 6.6, N, 4.4%; C21H21NO2.0.5H2O requires C, 76.8; H, 6.7; N, 4.26%; NMR (DMSO-d6): 1.2-1.42(1H, m), 1.5-1.72(1H, m), 1.8-2.0(3H, m), 2.65-2.8(4H, t), 2.8-3.2(2H, d of d), 5.6-5.7(1H, br), 6.8-6.9(2H, d) and 7.48-7.63(6H, m); m/z 320 (M+H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:39])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[CH2:36][O:37][CH3:38])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]2=[O:39])=[C:28]([CH2:36][O:37][CH3:38])[CH:29]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
25 g (48 mmol) of the compound from Example 31A are dissolved in 500 ml of ethyl acetate and 500 ml of ethanol. 18 g (286 mmol) of ammonium formate and 1 g of palladium on carbon are added, and the mixture is heated at reflux for 45 min. The reaction solution is then allowed to cool and filtered through silica gel. The filtrate is concentrated to dryness under reduced pressure. This gives 25 g (100% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[C:3]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2F)OC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cccc(N)c2F)OC1(C)C

Procedure:
A mixture of Intermediate 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg), 10% palladium on carbon (50 mg) and ethyl acetate (20 ml) was stirred under 1 atmosphere of hydrogen for 16 h. The mixture was sparged with nitrogen and filtered. The filtrate was concentrated to provide the title compound, which was used without further purification. MS m/z 237.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH2:12][OH:13])=[C:4]([CH2:8][CH2:9][OH:10])[S:5][C:6]=1[Cl:7].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:4]([CH2:8][CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[S:5][C:6]=1[Cl:7]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1sc(Cl)c(Cl)c1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1sc(Cl)c(Cl)c1CCOS(C)(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of the product from step (e) (1.99 g, 8.25 mmol) in CH2Cl2 (41 ml) was cooled to 0° C. and treated with triethylamine (3.4 ml, 24.7 mmol) followed by dropwise addition of methanesulfonyl chloride (1.4 ml, 18.1 mmol) over 10 min. After 45 minutes, the crude reaction was diluted with CH2Cl2 (100 ml) and washed with ice water (25 ml), 10% citric acid (2×25 ml), sat. NaHCO3 (2×25 ml) and brine (1×25 ml). The organic layer was dried (MgSO4), concentrated to 20 ml and diluted with anhydrous dioxane (76 ml). This mixture was concentrated to remove remaining CH2Cl2 and the resulting dioxane solution was carried forward to the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3=[O:12])=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)C(=O)C(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C1Nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2C1=O

Procedure:
The title compound is prepared from 5-amino-1H-indole-2,3-dion [Helv. Chim-Acta 19, 1327. (1936)] and (4-benzyl-piperidin-1-yl)-oxo-acetic-acid (Example 5b) according to the method described in Example 1c. Melting Point: 234-236° C. (diethylether)