Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH2:9])=[O:8].CO.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+]>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([NH2:9])=[O:8])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
To a stirred solution of cis-2-amino-cyclopentanecarboxylic acid amide (1 g, 0.008 mol) in methanol (20 mL, 0.5 mol) and water (10 mL, 0.6 mol) at 0° C. in an ice bath was added 2,4,5-trichloropyrimidine (1.7 g, 0.0094 mol) followed by sodium bicarbonate (1 g, 0.02 mol). The reaction mixture was warmed to room and stirred at room temperature for 24 h. The reaction mixture was diluted with water (25 mL) and washed with ethyl acetate (3×50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid amide as a white solid (1.8 g, 80% yield). No further purification was needed. 1HNMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 6.73 (d, 1H, J=6.8 Hz), 5.56 (broad s, 1H), 5.44 (broad s, 1H), 4.66 (p, 1H, J=7.5 Hz), 2.97 (q, 1H, J=7.5 Hz), 2.05-2.15 (m, 3H), 1.83-1.98 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:33])[N:13]2[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32].[CH:34]1([C:37](=O)[CH3:38])[CH2:36][CH2:35]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([CH:37]([CH:34]3[CH2:36][CH2:35]3)[CH3:38])[CH2:23][CH2:24]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:33])[N:13]2[C:25]1[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(=O)C1CC1
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(OC3CCNCC3)cc2n1-c1c(Cl)cccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C1CC1)N1CCC(Oc2cc(-c3ccccc3Cl)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 8.8 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(piperidin-4-yloxy)quinolin-2(1H)-one in 0.9 mL of MeOH was added 0.1 mL of 1-cyclopropylethanone, then 6.5 mg of sodium cyanoborohydride. The mixture was stirred 4 d at rt. Another 0.5 mL of 1-cyclopropylethanone was added and the mixture was heated to reflux overnight, then concentrated and purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH to yield the title compound. Mass spectrum (ESI) 567 (M+1).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O.O>[CH:1]([CH:4]1[C:9](=[O:10])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)C1Oc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(C(C)C)Oc2ccccc21

Procedure:
To a solution of 2-isopropyl-2H-1,4-benzoxazin-3(4H)-one (19.1 g) in N,N-dimethylformamide (200 ml), sodium hydride (60% in oil, 4.0 g) was added and stirred at room temperature for 30 minutes, to which a solution of methyl bromoacetate (10 ml) in N,N-dimethylformamide (200 ml) was added dropwise with ice-cooling. After stirring with ice-cooling for 1 hour, the reaction mixture was diluted with water and subjected to extraction with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to dryness, to give methyl 3,4-dihydro-2-isopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate as an oil. Yield was 26.0 g (98.9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24](Br)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=3)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1sc(-c2cc(Br)cnc2N)cc1OC(C)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cc(-c3cccc(Cl)c3)cnc2N)cc1OC(C)c1ccccc1Cl
Yield: 42.3 %

Procedure:
5-(2-Amino-5-bromo-pyridin-3-yl)-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (120 mg, 0.26 mmol, 1.0 Eq.), 3-chlorophenyl boronic acid (44 mg, 0.28 mmol, 1.1 Eq.) and Pd(PPh3)4 (30 mg, 0.03 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.5 mL, 1.0 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (40% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (57 mg, 0.11 mmol, 45%); 1H NMR (400 MHz, CDCl3) δ 1.75 (3H, d), 3.94 (3H, s), 5.24 (2H, br s), 5.84 (1H, q), 6.86 (1H, s), 7.01-7.41 (6H, m), 7.48 (1H, s), 7.65 (1H, s), 7.68 (1H, d), 8.24 (1H, d).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>O.O1CCCC1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:12][C:19]([N:18]([CH3:22])[CH3:17])=[S:20])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc(O)ccc21
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=S)Oc1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 4,4-dimethyl-7-hydroxy-1-tetralone (XIV) (3.07 g, 16.16 mmol) in water (10.77 mL) containing potassium hydroxide (904 mg) cooled below 10° C. was added N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) in tetrahydrofuran (4.30 mL); the reaction temperature kept below 12° C. After 10 minutes, reaction mixture is made basic by the addition of a 10% aqueous KOH solution (5.39 mL). Product is extracted with ethyl acetate (2×50 mL), organic phases concentrated in vacuo and the residue chromatographed on silica gel (eluted with 10% ethyl acetate in hexane) to give 3.74 g (Y: 84%) of title product; 1H-NMR (CDCl3): δ7.68 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5, 2.6 Hz, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.73 (t, J=6.8 Hz, 2H), 2.04 (t, J=6.8 Hz, 2H), 1.41 (s, 6H); MS (DCI) m/e: 278 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3ccsc23)CC1
Yield: 102 %

Procedure:
A mixture of tert-butyl 4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.70 g, 1.8 mmol) and 10% palladium on carbon (0.2 g) in methanol (20 mL) was subjected to balloon pressure of H2 at room temperature for 5 h. The reaction mixture was filtered and concentrated and to give the desired product (0.64 g, 100%). LCMS calculated for C17H25N4O2S (M+H)+: m/z=349.2. Found: 349.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.C1CCN2C(=NCCC2)CC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12])=[CH:5]2
Reactant: BrCc1ccccc1
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2[nH]c(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.43 g of 5-methyl-2-indolecarboxylic acid are dissolved in 15 ml of DMF; 2.11 g of DBU are added and the mixture is then left stirring for 1 hour at RT. 2.61 g of benzyl bromide are added dropwise and the mixture is then left stirring for 6 hours at RT. This mixture is concentrated under vacuum and the residue is taken up in EtOAc, washed with water, with saturated Na2CO3 solution, with sulphate buffer and then with saturated aqueous NaCl. It is dried over Na2SO4 and then concentrated. The residue crystallizes from pentane and 3.3 g of the expected compound are obtained: m.p.=150-152° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH:24]1[CH2:28][CH2:27][N:26]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:25]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 3-(tert-butoxycarbonylamino)pyrrolidine to give 3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidine in 41% yield.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:9]([NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][Br:1])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
4.39 g of N-bromosuccinimide and 50 mg of benzoyl peroxide were added to a solution of 6.00 g of N-t-butyl-4'-methylbiphenyl-2-carboxamide [prepared as described in Preparation 38(i)] in 90 ml of carbon tetrachloride, and the mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.04 g of the title compound as crystals, melting at 124°-126° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:50]([OH:51])[CH:41]6[CH:42]([O:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:52]([CH3:54])[CH3:53])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:48]([O:47][C:45]([CH2:44][O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:52]([CH3:54])[CH3:53])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:50]([OH:51])[CH:41]1[O:40]3)[O:36]2)=[O:46])[CH3:49]
Reactant: CCOC(=O)COC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)COC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Yield: 39.1 %

Procedure:
22.4 mg of compound (67) was dissolved in 3 ml of ethyl acetate and stirred together with a catalytic amount of 10% palladium-carbon under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction solution was filtered and concentrated in vacuo. The reaction product was dissolved in 5 ml of methanol and washed with 5 ml of n-hexane twice, and the lower layer was concentrated in vacuo to give 6.8 mg of compound (68) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17]O)=[CH:12]2)=[O:5].C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:25][CH2:17][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23]
Reactant: O=C(Nc1cccc2cc(CO)cnc12)c1c(Cl)cccc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2cc(CBr)cnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethylquinoline (300 mg) in tetrahydrofuran were added carbon tetrabromide (573 mg) and triphenylphosphine (453 mg), and the mixture was stirred for 30 minutes at ambient temperature. Insoluble material was filtered off, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane) to give 3-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline (253.4 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C([O-])(O)=O.[Na+].[CH3:15][CH:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19]>O.C1COCC1>[CH3:15][CH:16]([CH3:21])[CH2:17][C:18]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:19]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(=O)N1CCC[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of (R)-piperidine-3-carboxylic acid (2.0 g, 15.48 mmol) in water (40 mL) and THF (20 mL) were added NaHCO3 (3.30 g, 38.70 mmol) and 3-methylbutanoyl chloride (2.8 mL, 23.2 mmol) at room temperature. The reaction was stirred overnight, concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (1×). The aqueous layer was acidified with 1N HCl, extracted with EtOAc (3×) and the combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.53 g, 76%). MS 214 (MH).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH2:12]1[O:22][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:13]1.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:21]2[O:22][CH2:12][O:13][C:14]=2[CH:15]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 5 ml (60 mmol) of methyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 37.5 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9 g 60 mmol) of 3,4 -methylenedioxybenzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-[3,4-(methylenedioxy) phenyl]-2-butynoate as a brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:12])=[NH:11].[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:11][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:12][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cc2ccccc2[nH]1
Product: NCc1c(N)nc(-c2cc3ccccc3[nH]2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=383.9 (M+H+), was prepared from 1H-indole-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][C:8]([F:11])([F:12])[CH2:7]2)[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)C(CC1CCC(F)(F)C1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(F)(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 49.6 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3,3-difluoro-cyclopentyl)-propionic acid methyl ester (75 mg, 0.22 mmol) and 2-aminothiazole (27 mg, 0.26 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 0.63 mL, 0.44 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3,3-difluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (44.2 mg, 49%) as an off-white solid: mp 154–156° C.; FAB-HRMS m/e calcd for C17H16F2Cl2N2OS (M+H)+ 405.0402, found 405.0404.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CN.C1COCC1.C[CH2:19][N:20](CC)CC.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH3:19])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a stirred solution of 4-fluorobenzoic acid (200 mg, 1.43 mmol) in DCE (3 ml) at RT, was added a solution of methyl amine in THF (2 M, 1.43 mmol) and NEt3 (198 μl, 1.43 mmol) and allowed to stir for ca. 10 mins. HOBt (221 mg, 1.43 mmol) and DCC (295 mg, 1.43 mmol) were added and the reaction mixture heated at 70° C. for 3 h. After cooling to RT, the reaction mixture was washed with sat. NaHCO3 (5 ml) and the aqueous back extracted with DCM. The organics were combined, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH gradient 100:0 to 80:20) provided the title compound as off-white solid (137 mg, 63%).
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].C([O:17][C:18]1[C:19]([CH3:32])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C:23](O)([CH3:30])[CH2:22][CH2:21]2)(=O)C.C(OC1(C)C(C)CC2C(=C(C)C(C)=C(OC(=O)C)C=2C)O1)(=O)C.[OH-].[Na+]>O1CCCC1.C(O)C>[OH:17][C:18]1[C:19]([CH3:32])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C:23]([CH2:7][C:5]([OH:4])=[O:6])([CH3:30])[CH2:22][CH2:21]2
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)C(C)(OC(C)=O)O2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Reaction time: 0.25 h

Procedure:
In a dried flask under N 2, a suspension of 47.2 g (1.10 mol) of 56 percent by weight sodium hydride in mineral oil in 1000 ml of tetrahydrofuran was stirred as 209.4 g (1.15 mol) of trimethyl phosphonoacetate was added over 2.25 hr. The white paste was stirred for 0.25 hr and then a solution of 132.2 g (0.50 mol) of (±)-6-acetoxy-2hydroxy- 2,5,7,8-tetramethylchroman in 1000 ml of tetrahydrofuran was added over 0.50 hr. The pale yellow suspension was stirred at 23° C. for 18 hours and then heated at reflux for 4.0 hours. The cooled solutions from two such reactions were stripped of solvent and worked up and dried by the procedure given in Example 1 to give a cloudy red-brown oil containing (±)-methyl-(6-acetoxy-2,5,7,8 -tetramethylchroman-2-yl) acetate. To a solution of this material in 2000 ml. of ethanol, there was added 2000 ml. of H 2 O and 240 g. (6.0 mol.) of NaOH. The solution was stirred at 23° C. for 4 hours, washed with petroleum ether (b.p. 30° - 60° C.), diluted with 6000 ml. of ice-H2O and acidified by the dropwise addition over 0.50 hour of 600 ml. of concentrated aqueous HCl. The solid was removed by filtration, washed with H 2 O and crystallized from ethanol-H2O to give (±)-(6hydroxy-2,5,7,8-tetramethylchroman-2-yl) acetic acid as a light tan powder: m.p. 168° -171° C.
Reaction SMILES: ClCl.[OH-].[Na+].[CH3:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19](=[O:21])C)=[CH:9][CH:8]=1.[OH:22]S([O-])=O.[Na+].Cl>O>[CH3:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]([OH:21])=[O:22])=[CH:9][CH:8]=1
Reactant: O=S([O-])O
Reactant: COc1ccc2c(C(C)=O)ccc(OC)c2c1
Agent: Cl
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A stream of chlorine gas was passed through a cooled solution of NaOH (17.28 g, 0.432 mole) in water (24 ml) containing 100 g of ice until 12.7 g (0.18 mole) of chlorine was absorbed into the solution. Solid (4,6-dimethoxy-1-naphthalenyl)ethanone [9.2 g, 0.04 mole, described by N. P. Buu-Hoi, J. Org. Chem., 21, 1257 (1956)], was added at 20°-22° C. to the chlorine solution. The mixture was stirred at 65° C. for one hr, cooled in an ice bath and treated with NaHSO3 (5 g) in water (20 ml). The mixture was made neutral by the addition of dilute HCl. The resulting precipitate was collected, washed well with water, dried over P2O5 and recrystallized from methanol to give 4,6-dimethoxy-1-naphthalenecarboxylic acid (7.0 g); mp 227°-229° C.; NMR (DMSO-d6) δ 3.85 (s, 3H), 4.0 (s, 3H), 7.7 (m, 5H); IR (white mineral oil) 2900, 1670 cm-1 ; UVλmax (MeOH) 339 nm (ε4,910), 328 (4500), 304 (8,180), 240 (40,100); Anal Calcd: C, 67.23% H, 5.21%; Found: C, 67.15% H, 5.23%.