Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17]([CH2:18][CH2:19][C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:54]1([CH3:64])[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:64][C:54]1[CH:59]=[CH:58][C:57]([S:60]([O:43][CH2:42][C@H:14]2[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17]([CH2:18][CH2:19][C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]2[CH2:12][C:11]2[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)(=[O:62])=[O:61])=[CH:56][CH:55]=1
Reactant: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyloxy)-3-((S)-3-(tert-butyldimethylsilyloxy)octyl)cyclopentyl)methanol (0.3 g, 0.45 mmol) in dry CH2Cl2 (3 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (0.12 ml, 0.9 mmol) and trace amount 4-(dimethylamino)pyridine (DMAP), then p-toluenesulfonyl chloride (0.13 g, 0.67 mmol) was added and the reaction was stirred at room temperature. After the reaction was completed, 20 ml saturated NaHCO3 was added and extracted with CH2Cl2, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent. to give the titled compound 0.2 g, yield 54%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH3:13])[C:8]3[C:14]4([CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[OH2:3].[C:29]([N:17]1[CH2:18][CH2:19][C:14]2([C:8]3[N:9]([CH3:13])[C:10]4[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][C:6]=4[C:7]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(c1)c1c(n2C)C2(CCNCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)c1c(n2C)C2(CC1)CCN(C(=O)c1ccccc1)CC2
Product: O
Yield: 125.1 %

Procedure:
To a solution of 1,4-dihydro-7-methoxy-4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine]hydrochloride (0.50 g) and triethylamine (0.33 g) in dichloromethane (50 ml) was added benzoyl chloride (0.23 g) at 0° C., under nitrogen, with stirring. The reaction mixture was stirred for 5 hrs at ambient temperature. Dichloromethane (200 ml) was added and the mixture was washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 5% ethyl acetate/dichloromethane. The appropriate fractions were collected and concentrated to give 0.40 g (66%) of product, mp 197-198° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Clc1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a clear solution of tert-butyl 4-(3-chloropyridin-2-yl)piperazine-1-carboxylate in anhydrous dichloromethane (25 mL) was added TFA (25 mL) dropwise. The yellow solution was stirred at room temperature for 2.5 hour. Reaction was complete as determined by TLC. TFA was azeotropped with dichloroethane to give 1-(3-chloropyridin-2-yl)piperazine in quantitative yield (1.265 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][C:13]([NH2:15])=[O:14]>>[N:1]1([CH2:11][CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)CCBr
Product: NC(=O)CCn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indole (0.500 g, 4.27 mmol) and 3-bromopropanamide (0.650 g, 4.27 mmol) following a procedure similar to General Procedure A. The title compound was purified by preparatory HPLC method 1 and isolated as a white solid (0.339 g, 42%). 1H NMR (400 MHz, MeOD): δ 7.53 (d, J=7.9 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.19 (d, J=2.9 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.03 (t, J=7.4 Hz, 1H), 6.42 (d, J=2.8 Hz, 1H), 4.47 (t, J=6.8 Hz, 2H), 2.70 (t, J=6.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 172.4, 135.9, 129.0, 128.6, 121.4, 120.8, 119.4, 110.2, 101.0, 42.3, 36.2. ESI-LRMS: [M+H]+=189.1 m/z. ESI-HRMS: calc. for C11H12N2O1: [M+H]+=189.1022 m/z, found: [M+H]+=189.1030 m/z.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([CH2:16][C:17]2[CH:18]=[C:19]([O:31][CH3:32])[CH:20]=[C:21]3[C:26]=2[O:25][C:24](=[O:27])[C:23]([C:28](O)=[O:29])=[CH:22]3)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:57]1[C:58]([C:66]2[CH:67]=[C:68]([NH2:72])[CH:69]=[CH:70][CH:71]=2)=[CH:59][N:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=12>CN(C)C=O>[N:57]1[C:58]([C:66]2[CH:67]=[C:68]([NH:72][C:28]([C:23]3[C:24](=[O:27])[O:25][C:26]4[C:21]([CH:22]=3)=[CH:20][C:19]([O:31][CH3:32])=[CH:18][C:17]=4[CH2:16][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:29])[CH:69]=[CH:70][CH:71]=2)=[CH:59][N:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=12
Reactant: COc1cc(CN2CCOCC2)c2oc(=O)c(C(=O)O)cc2c1
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CN2CCOCC2)c2oc(=O)c(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)cc2c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
DIEA (0.030 mL, 0.17 mmol) was added to 8-(4-morpholinylmethyl)-3-carboxy-6-methoxy-coumarin (0.050 g, 0.16 mmol) and HATU (0.065 g, 0.17 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.033 g, 0.16 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.047 g of 1541D in a 59% yield: LCMS (ESI) m/z 511 (MH+).
Reaction SMILES: [Mg:1].[N+:2]([O-:5])([OH:4])=[O:3]>>[N+:2]([O-:5])([O-:4])=[O:3].[Mg+2:1].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: [Mg]
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])[O-]
Product: [Mg+2]

Procedure:
A magnesium nitrate solution was prepared as shown in Example 1. An amount, 0.764 gram mole (18.34 gm) of magnesium powder was weighed and added to 1.53 gram mole of nitric acid (67%) solution. The procedure and the additions are followed as set forth above.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.O>CC(C)=O>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: CCCCCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCc1ccc(-c2cccc(F)c2F)cc1
Temperature: 40 °C

Procedure:
1-Iodo-4-pentylbenzene (82 g, 0.3 mol), potassium carbonate (100 g, 0.72 mol), 2,3-difluorophenyl boronic acid (47 g, 0.3 mol), water (100 ml) and acetone (300 ml) were placed in a round-bottom three necked flask equipped with condenser, thermometer, mechanical stirrer, nitrogen inlet and outlet. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was heated up to the boiling point to degas the reaction system and then cooled down to 40° C. and the catalyst palladium acetate (0.1 g) was added. The temperature has increased by a few degrees and the solution turned brown. The mixture was refluxed for three days, then it was cooled down, poured on cold water and extracted with dichlorometane and the organic phase separated, dried over MgSO4 and dichlorometane was distilled off. The residue was distilled under reduced pressure at 0.2 mmHg collecting the fraction at 133° C. The colorless liquid fraction 41.5 g of was obtained, 53% of theor. yield.
Reaction SMILES: [Mg:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[F:11][C:12]([F:26])([F:25])[O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][CH:20]=[CH:21][C:22]=1[Mg:1][Br:2].[OH:24][C:17]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([O:13][C:12]([F:11])([F:25])[F:26])[CH:15]=2)[NH:19][C:18]1=[O:23]
Reactant: [Mg]
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(=O)Nc2ccc(OC(F)(F)F)cc21
Product: COc1ccccc1[Mg]Br
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of 2-methoxyphenylmagnesium bromide is prepared from 1.9 g of magnesium in 4 ml of ether and from a solution of 14.54 g of 1-bromo-2-methoxybenzene in 21 ml of ether. This solution is added dropwise, under an argon atmosphere, to a mixture of 5 g of 5-trifluoromethoxy-1H-indole-2,3-dione in 26 ml of THF, cooled beforehand in an ice bath, and then heated at the reflux point of the ether for 1 hour 30 minutes and allowed to cool to RT. The reaction mixture is poured slowly into saturated NH4Cl solution and extracted with EtOAc, the organic phase is washed with 5% K2CO3 solution, with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.8 g of the expected product are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:39]=[CH:38][C:19]3[N:20]([CH3:37])[C:21]([C:23]4[N:31]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:39]=[CH:38][C:19]3[N:20]([CH3:37])[C:21]([C:23]4[N:31]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](N)C3)ccc21
Reaction time: 0.75 h
Yield: 85.2 %

Procedure:
To a stirred solution of (R)-tert-butyl(1-(1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (1.9336 g, 3.47 mmol) in dichloromethane (DCM) (5.5 ml) was added TFA (5.05 ml, 66.0 mmol) dropwise. The reaction mixture was stirred for 45 min. The mixture was concentrated in vacuo, dissolved in methanol and purified by SPE on a pre-conditioned sulfonic acid (SCX) 70 g cartridge. The column was washed with methanol (5 CV) and the product was eluted with a 2M Ammonia in methanol solution (4 CV). The appropriate fractions were combined and the solvent was evaporated in vacuo to give a crude product that was purified by preparative HPLC (MDAP Method E). Appropriate fractions were combined and concentrated in vacuo to yield the title compound (1.35 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N+:10]([C:13]1[C:14]([C:18](O)=O)=[N:15][NH:16][CH:17]=1)([O-:12])=[O:11].[OH-].[NH4+]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([C:14]3[C:13]([N+:10]([O-:12])=[O:11])=[CH:17][NH:16][N:15]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-benzene-1,2-diamine (500 mg) in hydrochloric acid (4N) was treated with 4-nitro-pyrazole-3-carboxylic acid (826 mg) then heated at reflux temperature, under nitrogen. The reaction mixture was cooled to room temperature when the pH was adjusted to 8 by addition of ammonium hydroxide and the mixture was extracted with ethyl acetate. The extracts were evaporated to give 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[O-][O-].[K+].[K+].C1OCCOCCOCCOCCOCC[O:36]C1.Cl>O.CCOC(C)=O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[C:14](=[O:36])[C:13]=4[CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Agent: [O-][O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)N(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2,3-Dihydro-5-benzofuranyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 2) (5.25 g, 13.81 mmol), potassium dioxide (3.92 g, 55.24 mmol) and 18-crown-6 (3.65 g, 13.81 mmol) were mixed with DMF (100 mL) in a 200 mL flask. The reaction mixture was maintained at room temperature overnight. The reaction mixture was slowly added into a separate 500 mL flask containing a mixture of EtOAc (172 mL), H2O (172 mL) and 1N aqueous HCl (50 mL). The mixture was observed to produce tiny gas bubbles. The reaction mixture was stirred at 0° C. for 30 min, resulting in the formation of a precipitate at the surface of the two liquid layers. The precipitate was collected by filtration, washed with H2O (20 mL) and then dried in a vacuum oven to yield the product as a off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:32])C=CC=CC=1.C([N:44]([CH2:47]C)CC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:24][C:47](=[O:32])[NH:44][CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:22])[CH3:23])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(CC2NC(=O)OC2c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(isopropyloxy)benzyl]propanoic acid (7.14 g, 21.5 mmol) in tetrahydrofuran (100 ml) were added diphenylphosphoryl azide (6.0 ml, 27.9 mmol) and triethylamine (4.19 ml, 30.1 mmol), and the mixture was stirred at room temperature for 1 hr. The mixture was heated under reflux for 5 hrs. and concentrated under reduced pressure. The saturated aqueous sodium hydrogen carbonate (100 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1-2:1) to give the-objective substance (14.7 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:26]([C:28]1[CH:29]=[C:30]([C:33](O)=[O:34])[NH:31][CH:32]=1)#[N:27].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:33]([C:30]3[NH:31][CH:32]=[C:28]([C:26]#[N:27])[CH:29]=3)=[O:34])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Yield: 49.8 %

Procedure:
A solution of 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in Example 16, step (d), 68.7 mg, 0.200 mmol), 4-cyano-1H-pyrrole-2-carboxylic acid (Canadian J. Chem. 59, 2673 (1981), 40.8 mg, 0.300 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (57.5 mg, 0.300 mmol), hydroxybenzotriazole (HOBt) (40.5 mg, 0.300 mmol) and DIEA (105 μL, 0.600 mmol) in 2.5 mL of DMF was stirred at RT for 2 d under Ar. The resulting mixture was treated with H2O (20 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (10-20% EtOAc/DCM) to afford the title compound (46 mg, 50%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H31N3O4, 462.2 (M+H). found 462.2.
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[CH:19]=1>C(O)C>[NH:5]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[CH:19]=1)[C:2]([NH2:3])=[NH:1]
Reactant: CCOC(=O)c1cc2cc(N)ccc2o1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cc(NC(=N)N)ccc2o1
Temperature: 50 °C
Yield: 90 %

Procedure:
Ethanol (30 ml) and cyanamide (298 mg, 7.09 mmol) were added to hydrochloride (856 mg, 3.54 mmol) of ethyl 5-amino-2-benzofurancarboxylate, and the mixture was stirred with heating at about 50° C. for 24 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-3/1) to give 902 mg of ethyl 5-guanidino-2-benzofurancarboxylate as a colorless solid (90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH:11]([CH3:15])C(O)=O)[C:3]1=2.[C:16]([N:23]1[CH:27]=[CH:26]N=[CH:24]1)(N1C=CN=C1)=[O:17].N1CCC[CH2:29]1.O>ClCCl>[O:17]=[C:16]([N:23]1[CH2:24][CH2:29][CH2:26][CH2:27]1)[CH2:15][CH2:11][C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1
Reactant: CC(C(=O)O)c1c[nH]c2c1C(=O)CCC2
Reactant: C1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C1CCCc2[nH]cc(CCC(=O)N3CCCC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a suspension of 10 g of 3-(4-oxo-4,5,6,7,tetrahydro-1H-indol-3-yl-propionic acid (48 mmol) in 60 mL of dichloromethane was added 9.3 g (57.6 mmol) of carbonyldiimidazole. After stirring at room temperature for 2 hours, 12 mL (144 mmol) of pyrrolidine was added. The dark red reaction mixture was then stirred at room temperature overnight. The reaction was poured into water and the organic layer washed with brine, dried and concentrated to give 3-(3-oxo-3-pyrrolidin-1-yl-propyl)-1,5,6,7-tetrahydro-indol-4-one (12 g, 96% yield). 1H-NMR (300 MHz, dimethylsulfoxide-d6) δ 11.05 (br s, 1H, NH), 6.46 (d, 1H), 3.35 (m, 2H, CH2), 2.24 (m, 2H, CH2), 2.66–2.73 (m, 4H, 2×CH2), 2.44 (m, 2H, CH2), 2.26 (m, 2H, CH2), 1.96 (m, 2H, CH2), 1.82 (m, 2H, CH2), 1.73 (m, 2H, CH2). MS m/z 260 [M+].
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1.[OH:12]OS([O-])=O.[K+].[OH2:18]>>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)(=[O:12])=[O:18]
Reactant: O=S([O-])OO
Reactant: O
Reactant: CSc1nccc(C(=O)O)n1
Agent: [K+]
Product: CS(=O)(=O)c1nccc(C(=O)O)n1
Reaction time: 24 h

Procedure:
To a solution of 2-(methylthio)pyrimidine-4-carboxylic acid (1.88 g (11.1 mmol) in THf (200 mL) was added Oxone (20.4 g, 33.1 mmol) in water (50 mL). The suspension was stirred for 24 h, then evaporated to dryness. The resulting white paste was extracted 5× each 100 mL EtOAc and 5% MeOH in EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to give the sulfone as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc(Nc2ccc(CCO)cc2)nc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Nc3ncc(C#N)c(-c4ccccc4)n3)cc2)cc1

Procedure:
5-Cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine was prepared from 5-cyano-4-phenyl-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine (3.30 g, 10.43 mmol) and 4-toluenesulphonylchloride (2.19 g, 11.47 mmol) as a pale yellow solid (3.91 g) m.p. 134-135°. δH (d6 DMSO) 8.69 (1H, s), 8.05 (2H, dd, J 6.0, 2.0 Hz), 7.72 (2H, d, J 8.3 Hz), 7.61-7.51 (6H, m), 7.29 (2H, d, J 8.1 Hz), 7.14 (2H, d, J 8.5 Hz), 4.21(2H, t, J 7.0 Hz), 2.95 (2H, t, J 7.0 Hz) and 2.41 (3H, s).
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:62])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]#[C:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:62])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]#[C:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[CH:33][CH2:32]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C#Cc2ccccc2)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(C#Cc2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 22 mg (0.05 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl]benzoate (Compound 90) was converted to the title compound (pale yellow solid) using 11 mg (0.5 ml, 0.26 mmol) of LiOH (0.5 M aqueous solution).