Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[O:12][C:37](=[O:38])[C:36]([S:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:40]([OH:41])[CH:11]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc3c(c2)OCO3)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3',4'-(methylenedioxy)acetophenone (0.871 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.98 (s, 2 H), 6.13 (s, 2 H), 6.61 (s, 1 H), 7.05 (d, 2 H), 7.27 (m, 7 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1ccccn1

Procedure:
2-Bromopyridine and 2-fluorobenzeneboronic acid were coupled using the procedure described in Example 43 to afford 2-(2-fluorophenyl)pyridine as a pale yellow oil which crystallised on standing: δH (400 MHz, CDCl3) 7.13-7.19 (1H, m), 7.24-7.28 (2H, m), 7.35-7.41 (1H, m), 7.73-7.81 (2H, m), 7.97 (1H, ddd, J 8, 8 and 2), 8.72-8.74 (1H, m); m/z (ES+) 174 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][NH2:12]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][NH:12][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C=O)cc1
Solvent: CC(C)O
Product: COc1ccc(CNNCc2ccc(OC)cc2)cc1

Procedure:
Di-(4-methoxybenzyl) azine was first prepared by reacting 2 moles of p-methoxybenzaldehyde with 1 mole hydrazine in isopropyl alcohol at 10° C. Di-(4-methoxybenzyl) hydrazine was obtained by reacting the azine with diborane in tetrahydrofurane under nitrogen atmosphere at or below 10° C. and isolated as an oil. The dihydrochloride salt of bis-(4-methoxybenzyl) hydrazine was obtained as white solid by mixing with hydrogen chloride gas in isopropanol followed by addition of methylene chloride and toluene (81% yield based on azine). 1,2-Di-(4-methoxybenzyl)hydrazine (3.5 g., 0.01 mole) and 1,3-dimorpholine-1,2-nitropropane (2.6 g., 0.01 mole) were suspended in a mixture of 30 ml of methanol and 20 ml of toluene and heated to reflux for 3 hr. The reaction mixture was evaporated to dryness and the residue extracted with toluene and filtered. The toluene filtrate was evaporated to give 3.5 g. brown oil which was purified by column chromatography using 10% diethyl ether - 90% methylene chloride on silica gel. Nuclear Magnetic Resonance and mass spectra confirmed the structure of title compound. The oil solidified after one day standing at room temperature.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][C@@H:27]([OH:32])[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][CH2:26][C@@H:27]([OH:32])[CH2:28][C:29]([OH:31])=[O:30])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC[C@@H](O)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NC[C@@H](O)CC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), (S)-4-amino-3-hydroxybutanoic acid (67 mg, 0.56 mmol, Sigma-Aldrich) and sodium methoxide (28 mg, 0.53 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes with 0.5% formic acid) to give the title compound in 27 mg. MS: (−) m/z 406.00 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][C:3]=1[F:20].[H-].[Na+].I[CH3:24].O>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH3:17])[C:14](=[O:16])[N:15]([CH3:24])[C:8]=23)=[CH:4][C:3]=1[F:20]
Reactant: CI
Reactant: Cn1c(=O)[nH]c2c(Oc3ccc(N)c(F)c3)ccnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(C)c2c(Oc3ccc(N)c(F)c3)ccnc21
Reaction time: 0.33 h

Procedure:
To a solution of 7-(4-amino-3-fluorophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (100 mg, 0.365 mmol) in THF (4 mL) at 0° C. under argon, NaH (16.77 mg, 0.419 mmol) was added in one portion. The resulting solution was stirred for 20 minutes and iodomethane (0.025 mL, 0.401 mmol) was added. After 1 hour, water was added, and the solution evaporated and extracted with DCM (3×20 mL) to give the title compound.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@:4]1([NH:18]C(=O)OC(C)(C)C)[C:6](=[O:17])[NH:7][S:8]([C:11]1([CH2:14][O:15][CH3:16])[CH2:13][CH2:12]1)(=[O:10])=[O:9])=[CH2:2].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:18][C@:4]1([C:6]([NH:7][S:8]([C:11]2([CH2:14][O:15][CH3:16])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[O:17])[CH2:5][C@H:3]1[CH:1]=[CH2:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(COC)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(COC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of the product of Step 1 (120 mg) in DCM (1 mL) at 0° C. was added TFA (1 mL). The mixture was slowly warmed to room temperature and stirred for 3 hours. The solvent was removed in vacuo and the crude product was used in the next step. 1H NMR (400 MHz, CDCl3): δ (ppm) 5.82 (ddd, 1H), 5.44 (d, 1H), 5.43 (d, 1H), 3.67 (d, 1H), 3.63 (d, 1H), 3.35 (s, 3H), 2.64 (dt, 1H), 1.92 (dd, 1H), 1.83 (dd, 1H), 1.76-1.70 (m, 1H), 1.67-1.60 (m, 1H), 1.14-1.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2ccc(OCCCCCBr)c(C(C)=O)c2c1
Yield: 100.1 %

Procedure:
A mixture of 1.1 g of [[8-acetyl-7-hydroxy-2-naphthalenyl]oxy]acetic acid methyl ester, 9.2 g of 1,5-dibromopentane and 0.83 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and filtrate was concentrated at 60° C./10.15 mm to an oil which was purified by flash column chromatography to yield 1.7 g of [[8-Acetyl-7-(5-bromopentyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[CH:4][N:3]=1.C([Li])CCC.CON(C)[C:18](=[O:33])[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:18](=[O:33])[CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(c1ccccc1)c1ccccc1)c1cc(Cl)ncc1F
Reaction time: 1 h

Procedure:
At −70° C. to a solution of 2-chloro-5-fluoro-4-iodopyridine (873 mg) in THF (20 mL) was added n-butyllithium (2.2 mL, 1.6M in hexane) over a period of 15 min slowly. To that solution N-methoxy-N-methyl-3,3-diphenyl-propionamide (200 mg) in THF (8 mL) was added and stirring was continued at that temperature for 1 h. A saturated solution of NH4Cl was added, the mixture was diluted with EtOAc, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/n-heptane 1:2) to yield the title compound as a white solid, MS (ESI+): m/z=340.09 ([M+H]+, 1Cl).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C1CCCCC1>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Cl:23])=[CH:25][C:26]=3[F:31])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Solvent: C1CCCCC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 20.9 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline hydrochloride (300 mg, 0.89 mmol), (prepared as described for the starting material in Example 3), and 4-chloro-2-fluoroaniline (160 mg, 1.1 mmol) was heated at reflux in cyclohexane (20 ml) for 24 hours. The solvent was removed by evaporation and the residue was triturated with ether. The solid crude product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinoline hydrochloride (83 mg, 21%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[C:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])([C:22]#[N:23])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2([C:22]#[N:23])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[C:25]([F:31])[CH:26]=1
Reactant: COc1ccc(Cl)cc1C1C(C(=O)OC(C)(C)C)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1C1C(C(=O)O)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 97 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 85b (0.3 g, 0.56 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.32 g, 97%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[OH:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1>>[O:35]1[CH2:36][CH2:37][CH:33]([O:32][C:2]2[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=3)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=2)[CH2:34]1
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: OC1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC2CCOC2)cc(F)c1NS(C)(=O)=O
Yield: 39.6 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.11 mmol) and 3-hydroxytetrahydrofuran (18 μl, 0.22 mmol) was reacted as in example 72 to give the title compound (23 mg, 21%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1>C(=S)=S>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:8]2[CH:13]=[CH:12][C:11]([C:11]3[CH:10]=[CH:9][C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:3]4[CH3:2])=[CH:13][CH:12]=3)=[CH:10][CH:9]=2)=[O:30])=[CH:27][CH:26]=1.[ClH:31]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCCC1c1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CN1CCCC1c1ccc(-c2ccc(C(=O)c3ccc(Br)cc3)cc2)cc1
Yield: 30.8 %

Procedure:
350 mg of N-methyl-2-biphenylyl-pyrrolidine hydrochloride are suspended in 10 ml of carbon disulphide and treated with 341 mg of aluminium chloride. A solution of 842 mg of 4-bromo-benzoyl chloride in 3 ml of carbon disulphide is added dropwise to this viscous mass. The mixture is held at reflux for 2 hours and evaporated. The residue is triturated in toluene and then in ethyl acetate, with 90 mg of (±)(4-bromophenyl)-[4′-(1-methylpyrrolidin-2-yl)-biphenyl-4-yl]-methanone•hydrochloride, m.p. 225° C., being obtained.
Reaction SMILES: Br[C:2]1([Br:10])[CH:9]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].[Al]>C1(C)C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Ag+]>[Br:10][C:2]1[CH:3]([CH:12]([OH:13])[C:11]([O:15][CH3:16])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=1
Reactant: COC(=O)CO
Reactant: BrC1(Br)C2CCCCCC21
Agent: [Ag+]
Agent: [Al]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(O)C1CCCCCC=C1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Added to a solution of 8,8-dibromobicyclo[5.1.0]octane (2.5 g i.e. 9.3 mmol) and methyl glycolate (6.35 ml, i.e. 83.9 mmol) dissolved in 5 ml of anhydrous toluene in a dry round-bottomed flask, under Ar and protected from the light by aluminium foil, are 3.85 g of silver perchlorate (i.e. 18.6 mmol). The reaction is stirred for 1 h 30 min at room temperature, then the silver salts are filtered over a frit and washed with AcOEt. The solution is concentrated under vacuum to give a viscous brown oil which is purified by silica gel chromatography (2-15% AcOEt in cyclohexane) to obtain the product in the form of a yellow oil having a mass m=1.6 g, i.e. 65% yield.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][O:9][CH:10]([O:30][CH3:31])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>CO>[CH3:31][O:30][CH:10]([O:9][CH3:8])[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C(OC)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A 2.0 mol/L sodium hydroxide aqueous solution (0.10 L) was added to a THF (0.25 L)-methanol (0.25 L) solution of ethyl 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoate (21 g) as obtained in Example 10-(2), and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off, and then water and acetic acid were added to the residue to adjust it to pH 4. The precipitate was filtered off and dried. Hexane/ethyl acetate (3:1 (v/v)) was added, and the mixture was stirred for a while. The precipitate was filtered off and dried to obtain 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoic acid (white solid) (15 g, 75%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:12]2[CH2:13][C:8]3([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=[O:3].[Cl:16][C:17]1[CH:18]=[N:19][C:20]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[N:21][CH:22]=1>>[Cl:16][C:17]1[CH:18]=[N:19][C:20]([CH:23]2[CH2:27][CH2:26][N:25]([C:2]([O:4][CH:5]3[CH:12]4[CH2:13][C:8]5([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]3[CH2:7]5)[CH2:11]4)=[O:3])[CH2:24]2)=[N:21][CH:22]=1
Reactant: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Reactant: Clc1cnc(C2CCNC2)nc1
Product: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CCC(c2ncc(Cl)cn2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 19 Step 1 using 1-hydroxy-4-adamantyl chloroformate solution and 5-chloro-2-(pyrrolidin-3-yl)pyrimidine. Two isomers were separated by prep HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6](=[O:32])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([O:12]C)=O)[CH3:2].[O-]CC.[Na+].O.Cl>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[CH2:8][CH2:9][C:10](=[O:12])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:33])[C:6]2=[O:32])=[CH:16][CH:17]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)C1=O
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of ethyl[N-(p-(N-benzyloxycarbonylamino)benzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (967 mg) in benzene (15 ml) is added dropwise to a solution of sodium ethoxide (prepared from sodium (60 mg) and ethanol (2 ml)) at room temperature. The mixture is stirred at the same temperature for 30 minutes. The mixture is poured into water. The aqueous solution is neutralized with 10% HCl, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent to give ethyl 1-(p-(N-benzyloxycarbonylamino)-benzyl)-2,4-dioxopiperidine-3-carboxylate (841 mg, 93.5%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:29][CH3:30])[S:25]([CH3:28])(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:29][CH3:30])[S:25]([CH3:28])(=[O:27])=[O:26])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN(CCCCN)S(C)(=O)=O
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)S(C)(=O)=O

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and N-(4-aminobutyl)-N-ethylmethanesulfonamide (Step 3), the title compound was obtained; MS (Found M+1=436).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[O:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1oc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 4.06 mmol) and N-chlorosuccinimide (542 mg, 4.06 mmol) in tetrahydrofuran (20 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (13.5 ml, 81 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (683 mg, 2.55 mmol, 62.8% yield) as a yellow oil: LCMS (ES) m/e 254, 256 (M, M+2)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]C)=[O:24])=[CH:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].Cl>COCCOC>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a solution of methyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) in 1,2-dimethoxyethane (10 ml) was added 6N hydrochloric acid (5 ml), and the mixture was refluxed for 2 days, cooled to room temperature and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with water, 2-propanol and diisopropylether to give colorless crystals of 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (346.1 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[O:11]1CCOC[CH2:12]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:10][C:4]1[S:3][C:2]2[NH:1][C:12](=[O:11])[O:8][C:7](=[O:9])[C:6]=2[CH:5]=1
Reactant: C1COCCO1
Reactant: Cc1cc(C(=O)O)c(N)s1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c(=O)oc(=O)[nH]c2s1
Temperature: 5 °C
Yield: 100 %

Procedure:
step 2—A suspension of 60b (4.0 g, 25.5 mmol) and dioxane (65 mL) was cooled to 5° C. Phosgene (22.5 mL of a 20% solution in toluene, 45.9 mmol) was added dropwise through a septum. The flask was equipped with a condenser and the mixture was refluxed for 4 h. After cooling the solvents were evaporated in vacuo to afford 5.0 g (100%) of 6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (61a) which was used without purification: ms [M−H]=182.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18](=O)[CH2:19]Br>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:19]=[C:18]([C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=2)[N:2]=1
Reactant: N=C(N)NN=Cc1ccccc1
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: CCO
Product: COc1cccc(-c2cn(N=Cc3ccccc3)c(N)n2)c1

Procedure:
A solution of 16.2 g (0.1 mol) of benzaldehyde guanylhydrazone and 11.8 g (0.050 mol) of 3-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98 %, Cat. no. 11,567-3) in 50 ml of ethanol is stirred at 20° C. for 3 hours. The product that has crystallized out is filtered off with suction and dried. In that manner there is obtained the title compound, m.p. 170°-171° C., 1H-NMR (DMSO): δ=8.56 (s, 1H); 8.03 (s, 1H); 7.92 (m, 2H); 7.5 (m, 3H); 7.26 (m, 3H); 6.76 (m, 1H); 6.2 (s, 2H); 3.8 (s, 3H).