Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].[CH3:27][S-:28].[Na+]>O1CCCC1>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][S:28][CH3:27])(=[O:10])=[O:9]
Reactant: C[S-]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Yield: 99.7 %

Procedure:
A solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (250 mg) and sodium methanethiolate (50 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained crystals were collected by filtration. The crystals were washed with water and diethyl ether, and dried to give the title compound (256 mg, yield 99%) as pale-brown crystals. melting point 213° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C:6]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[C:8](=O)[O:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.N>C1COCC1.CCOCC.C1(C)C=CC=CC=1.O>[NH2:16][CH2:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:25])[CH3:1])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[O:7][CH2:8]2
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OC(=O)c2cc(C#N)ccc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(CN)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
1-(3-Dimethylamino-propyl)-1-(4-fluoro-phenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (5.4 g, 16.2 mmol) was dissolved in dry THF (5 mL) and diluted with dry ether (50 mL). This solution was added dropwise to a refluxing suspension of lithium aluminium hydride (2.5 g, 65 mmol) in dry ether (150 mL) over 10-15 minutes, after which the resulting suspension was heated at reflux for a further 4 h. The solution was allowed to cool to room temperature and was stirred at room temperature overnight. The reaction was quenched with a minimum of water, and the resulting solution/suspension was dried over anhydrous magnesium sulfate. The mixture was filtered, and the solid cake was washed with THF. The combined filtrates were evaporated to give an oil. The oil was dissolved in toluene (200 mL) and was stirred with an aqueous solution of sulfuric acid (10 ml, 70% v/v) for 3 h. The mixture was diluted with water, and the pH was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The toluene was separated, and the aqueous phase was extracted with further toluene. The combined toluene extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a yellow oil (4.4 g, 84%). 1H NMR (CDCl3): δ 1.25-1.40 (m, 1H), 1.40-1.55 (m, 1H), 2.11 (ddd, 1H), 2.13 (t, 3H), 2.15 (ddd, 1H), 2.21 (t, 2H), 3.85 (s, 2H), 5.11 (d, 1H), 5.14 (d, 1H), 6.96 (t, 2H), 7.15 (s, 1H), 7.21 (d, 1H), 7.22 (d, 1H), 7.45 (dd, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]1[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCC1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(C3CCC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=252.4 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromocyclobutane.
Reaction SMILES: [OH:1][CH:2]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].O.[CH3:25][C:26](CC(O)=O)=[O:27].[OH-].[Na+]>C(OC(=O)C)(=O)C>[C:26]([O:1][CH:2]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:27])[CH3:25]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(O)CN1CCCC1
Reactant: CC(=O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCCC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-(2-Hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (5 g) was suspended in acetic anhydride (7.4 ml). The reaction mixture was stirred at ambient temperature for 90 minutes followed by addition of water (2.8 ml) and the reaction mixture was stirred an additional 2 hours in order to hydrolyse the diacetate byproduct. The mixture was cooled with an ice bath, more water (100 ml) was added and a solution of sodium hydroxide (2N) was slowly added to adjust the pH to 9.5. The product was extracted with dichloromethane (3 times) the organic phases were combined, washed with water, brine, dried over magnesium sulphate, filtered and the solvent evaporated to give 7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (4.2 g) as a white solid.
Reaction SMILES: BrC12CC3CC(CC(C3)C1)C2.Br[C:13]12[CH2:22][C:17]3([CH3:23])[CH2:18][CH:19]([CH2:21][C:15]([CH3:24])([CH2:16]3)[CH2:14]1)[CH2:20]2.[Na].[CH3:26][C:27]12[CH2:37][CH:31]3[CH2:32][C:33]([CH3:36])([CH2:35][C:29]([C:38]45[CH2:47][CH:42]6[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]6)[CH2:39]4)[CH2:45]5)([CH2:30]3)[CH2:28]1)[CH2:34]2.BrBr.BrC12CC3CC(CC(C45CC6(C)CC(CC(C)(C6)C4)C5)(C3)C1)C2>C1(C)C=CC=C(C)C=1>[CH3:36][C:33]12[CH2:32][CH:31]3[CH2:37][C:27]([CH3:26])([CH2:28][C:29]([C:38]45[CH2:47][CH:42]6[CH2:41][CH:40]([CH2:46][C:44]([C:19]78[CH2:21][C:15]9([CH3:24])[CH2:14][CH:13]([CH2:22][C:17]([CH3:23])([CH2:16]9)[CH2:18]7)[CH2:20]8)([CH2:43]6)[CH2:45]4)[CH2:39]5)([CH2:30]3)[CH2:35]1)[CH2:34]2
Reactant: CC12CC3CC(C)(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: BrBr
Agent: BrC12CC3CC(CC(C3)C1)C2
Agent: CC12CC3CC(C)(C1)CC(C14CC5CC(CC(Br)(C5)C1)C4)(C3)C2
Solvent: Cc1cccc(C)c1
Product: CC12CC3CC(C)(C1)CC(C14CC5CC(C1)CC(C16CC7CC(C)(CC(C)(C7)C1)C6)(C5)C4)(C3)C2

Procedure:
In the following manner, 1,3-bis-(3-ethynyl-5,7-dimethyl-1-adamantyl)adamantane (Exemplified compound (D-32) is obtained. Described specifically, a coupling reaction between 1-bromoadamantane and 1-bromo-3,5-dimethyladamantane is caused in m-xylene by the addition of metal sodium, whereby 3,5-dimethyl-1,1′-biadamantane (Compound A4) is prepared. Compound A4 is then brominated with bromine into 3′-bromo-3,5-dimethyl-1,1′-biadamantane (Compound A5). Compound (A5) is reacted with 1-bromo-3,5-dimethyladamantane to obtain 1,3-bis-(3,5-dimethyl-1-adamantyl)adamantane (Compound A6). The resulting compound is then treated in a similar manner to that shown in <Synthesis of Exemplified compound (D-2)>, whereby Exemplified compound (D-32) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[C:12]3[CH:19]=[C:18]([C:20]#[C:21][CH2:22][CH:23]([OH:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[C:12]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH:23]([OH:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:32][CH:33]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccccc3)oc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCC(O)c3ccccc3)oc21
Temperature: 25 °C
Yield: 4 %

Procedure:
N-(4-Chlorobenzyl)-2-(4-hydroxy-4-phenylbut-1-ynyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 88, 0.200 g) was dissolved in ethanol (60 mL) with heating and then allowed to cool to room temperature. The mixture was hydrogenated over 10% Pd/C (0.060 g) at 35 psi for 1.5 h. The reaction mixture was filtered through a Celite pad and the pad was washed with CH2Cl2 (60 mL). The filtrate was concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.008 g of the title compound as a yellow solid. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 10.68, 8.51, 7.40-7.30, 6.64, 5.20, 4.584.53, 4.54, 3.90, 2.75-2.72, 1.76-1.64; MS (ESI+) m/z 465 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[F:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[N:42]([CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=1)[C:41](=[O:54])[CH:40]2[C:55]1[C:63]([OH:64])=[CH:62][C:58]2[O:59][CH2:60][O:61][C:57]=2[CH:56]=1>>[F:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[N:42]([CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=1)[C:41](=[O:54])[C:40]2([C:55]1[C:63]([OH:64])=[CH:62][C:58]2[O:59][CH2:60][O:61][C:57]=2[CH:56]=1)[CH2:22][OH:23]
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cccc(F)c2N1Cc1ccc(C(F)(F)F)o1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one, the title compound was obtained (67%): MS (ES+) m/z 488.4 (M+23).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].C(OC([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=O)C1C=CC=CC=1>[OH-].[Na+]>[C:3]([CH2:2][N:22]([CH2:2][C:3]([OH:5])=[O:4])[C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][NH2:16])([OH:5])=[O:4]
Reactant: O=C(O)CBr
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: NCCCC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromacetic acid (28 g, 200 mmole) was dissolved in 100 ml of 2 M sodium hydroxide (NaOH) and cooled to 0° C. A solution of 28 g (100 mmole) of N'-benzyloxycarbonyl-L-lysine in 150 ml of 2 M NaOH was slowly added dropwise into the bromacetic acid solution while stirring in a 0° C. cooling bath. After 2 hours, the cooling bath was removed and the solution was stirred overnight at room temperature. The solution was then heated for two hours at 50° C. and 300 ml of 1 M hydrochloric acid (HCl) was added dropwise. The mixture was then cooled to room temperature allowing the N'-benzyloxycarbonyl-nitrilotriacetic acid (Z-NTA) to precipitate. The Z-NTA was collected by filtration and further purified by dissolving in 1 M NaOH, re-precipitating with the same amount of 1 M HCl and filtering. The dissolving and precipitating cycle was repeated twice.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[C@H:27]([CH:28]=O)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[C@H:27]([CH:28]=[CH2:1])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C[C@@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.07 g, 5.8 mmol) in THF (20 mL) at −78° C. is added KHMDS (11.0 mL, 5.5 mmol) and the mixture is stirred for 1.5 h. A solution of (S)-3-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.94 g, 3.6 mmol) in THF (10 mL) is added and the solution stirred at −78-C for 1.5 h before warming to RT. The reaction is quenched with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extracts are washed with 1N HCl (3×35 mL), brine (2×30 mL) and dried over Na2SO4. Purification by flash chromatography using a gradient of 0-15% EtOAc/hexane affords the title compound.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[N:21]O)[CH:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl-].[NH4+]>CO.[Zn]>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH2:21])[CH:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C=NO)cnc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(CN)cnc32)cc1
Yield: 87.8 %

Procedure:
To a solution of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde oxime (600 mg, 1.9 mmol) in MeOH (10 mL) was added zinc powder (600 mg, 9.5 mmol) and ammonium chloride (1.0 g, 19 mmol). The suspension was refluxed for 18 h and then the solid was filtered. The filtrate was diluted with DCM (200 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated to afford 503 mg (98%) of (1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine as yellow solid which was used in the next step without further purification; MS (ESI) m/z: 302.1 [M+1]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-methylindole (1.0 g, 7.6 mmol) in 8.0 mL of CH2Cl2 was added N,N-dimethylamino pyridine (0.186 g, 1.52 mmol), 2.12 mL (15.24 mmol) of triethylamine and 0.97 mL (1.18 g, 8.39 mmol) of benzoyl chloride. The resulting solution was stirred for 16 hours at room temperature. The solution was diluted with 500 mL of CH2Cl2 and washed with 200 mL of saturated aqueous NaHCO3 and 200 mL of brine. The organic phase was dried over MgSO4, filtered, and concentrated to a yellow oil. The resultant oil was flash chromatographed eluting with 20% ethyl acetate in hexane yielding 1.73 g (96%) of the titled compound as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.030 g, 0.050 mmol) in dichloromethane (2 mL) was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-10% methanol in dichloromethane) to give the title compound as a white solid (0.023 g, 0.047 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1 H), 7.56 (dd, J=4.0, 8.4 Hz, 1 H), 7.38 (d, J=2.4 Hz, 1 H), 7.17-7.10 (m, 2H), 6.84-6.81 (m, 1 H), 6.61 (d, J=9.6 Hz, 1 H), 6.08 (q, J=7.2 Hz, 1 H), 4.87-4.68 (m, 2 H), 4.52-4.14 (m, 1 H), 3.67-3.53 (m, 3 H), 3.50-3.21 (m, 3 H), 3.04-2.91 (m, 1 H), 2.82-2.76 (m, 1 H), 2.62-2.55 (m, 1 H), 2.28-2.20 (m, 1 H), 2.13-2.02 (m, 1 H), 1.99 (d, J=6.8 Hz, 3 H), 1.53 and 1.40 (d, J=6.4 and 6.8 Hz, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2, found 486.4.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][NH:22][C:21]=4[N:20]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)C.[OH-].[Na+].Cl>C1COCC1.O>[C:29]1([CH:6]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][CH2:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[CH2:25][CH2:24][CH2:23][NH:22][C:21]=5[N:20]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:5][C:4]([OH:35])=[O:3])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Temperature: 50 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
A mixture of 3-phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}propionic acid ethyl ester (0.020 g, 0.04 mmol) and sodium hydroxide (0.01 g, 0.25 mmol) in THF/H2O [1/0.3] (1.3 mL) was stirred at 50° C. for 24 h. The reaction mixture was neutralized with 1.0 N HCl to pH 5 and extracted with ethyl acetate. After removal of solvent, the crude product was purified via column chromatography, eluting with methylene chloride/methanol (95/5) to give the title compound (15% yield) as white solid. 1H NMR (CDCl3) δ 10.76 (br, 1H), 8.16 (br, 1H), 7.57 (br, 1H), 7.10–7.45 (m, 8H), 7.03 (m, 1H), 6.95 (m, 2H), 6.18 (m, 1H), 3.38 (m, 2H), 3.21 (m, 2H), 2.61 (m, 2H), 2.43 (m, 2H), 2.03 (m, 2H), 1.82 (m 2H), 1.70 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C28H30N3O2 440.2 (M+H); found 440.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:16])=[C:8]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CCCCCC>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:16])=[C:8]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
1.66 g (6.77 mmol) of N-(5-acetyl-2-fluoro-phenyl)-N-methyl-methanesulfonamide were dissolved in 3.35 ml (3.0 g) (25.18 mmol) of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 2.5 hours. The mixture was cooled at room temperature. To the solid formed was added 20 ml of n-hexane and filtered to yield a solid which was crystallized from ethyl acetate. 1.37 g of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide as a yellowish-white solid were obtained (yield 67.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[Cu][C:33]#[N:34].C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[C:13]([N:11]1[CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:33]#[N:34])[N:9]=[CH:10]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#C[Cu]
Reactant: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-bromo-phenyl)-1-trityl-1H-imidazole (73.0 g, 163.3 mmol) in dimethylformamide (500 ml) was added copper (I) cyanide (17.5 g, 195.9 mmol). The reaction was heated to ˜80° C. under nitrogen for 14 h. After cooling to about 50° C., the reaction was diluted with toluene (ca. 300 ml) and slowly poured onto ammonium hydroxide (3N, 1.5 L) while stirring vigorously. The mixture was stirred for 40 min and then filtered in vacuo over a bed of celite (slow filtration, required ˜2 h). The phases were separated and the organic layer was washed with brine (75 ml×3) and dried (sodium sulfate). Concentration of the solvent afforded a light brown solid. The crude product contains ˜10–15% of trityl alcohol (by HPLC) and was used without further purification in the subsequent step.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[C:16]2[O:15][C:14]([CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[O:19]1[CH2:20][CH2:21][CH:17]([C:14]2[O:15][C:16]3[C:8]([OH:7])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=2)[CH2:18]1
Reactant: COc1cccc2cc(C3CCOC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Product: Oc1cccc2cc(C3CCOC3)oc12
Temperature: 140 °C
Yield: 79.1 %

Procedure:
Sodium hydride (0.19 g, 60% in mineral oil) was added to a stirred solution of ethane thiol (0.34 ml) in N,N-dimethylformramide (6 ml) at room temperature under a dry nitrogen atmosphere. After stirring for 15 minutes 7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran (0.5 g) in N,N-dimethylfornamide (6 ml) was added and the reaction heated to 140° C. for 2 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a brown oil (0.37 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:26]([C:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:15]([CH3:16])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a solution (500 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (29.5 g) synthesized in the above-mentioned (1) in N,N-dimethylformamide were added potassium carbonate (41.4 g) and 2-bromo-1-cyclohexylethanone (25.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a solid. The obtained solid was washed with ethanol-isopropyl ether to give the title object compound (18.0 g, 43%) as a pale-yellow solid.