Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97.4 %

Procedure:
A rapidly stirred solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CH2Cl2 was cooled to 0° C. under N2 and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 mL saturated NaHCO3 solution and the organic layer was separated. The organic phase was then washed with H2O (3×500 mL) and brine. The organic portion was dried over Na2SO4 and concentrated to give 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I.O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a vigorously stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.07 g, 10.3 mmol) in DMF (25 mL) was added a 60% sodium hydride dispersion in mineral oil (500 mg, 12.5 mmol). After stirring for 20 min, methyl iodide (0.9 mL, 14.5 mmol) was added and the resulting mixture stirred for 48 h before being added to a mixture of water and brine (250 mL, 1:1). Extraction with ethyl acetate (4×50 mL), washing of the combined extracts with brine (100 mL) and drying (MgSO4) gave, after concentration, a residue which was purified via flash chromatography (silica gel, ethyl acetate/hexane, 1:1) to give the title compound as a colourless oil. δH (CDCl3): 1.50 (9H, s), 1.52, 1.88 (4H, 2m) 3.12 (2H, ddd), 3.18 (1H, m), 3.19 (3H, s), 3.77 (2H, m); Rf 0.33 (ethyl acetate/hexane: 1/1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:36])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[O:34][CH3:35])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:36])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[O:34][CH3:35])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Yield: 60 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)-acrylonitrile (1.8 g, 5.6 mmol) prepared in Example 58a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:31])[CH:7](P(OCC)(OCC)=O)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=1)[CH3:4].C(=O)C.[CH2:35]1[CH2:39]O[CH2:37][CH2:36]1>>[CH2:3]([O:5][C:6](=[O:31])[C:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:13][CH:14]=1)=[C:35]([CH2:36][CH3:37])[CH3:39])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)P(=O)(OCC)OCC
Agent: CC=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)=C(C)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (278.8 mg, 60% in mineral oil, 6.97 mmol) in THF (25 mL) at 0° C. was added a solution of 3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-(diethoxyphosphoryl)-propionic acid ethyl ester (2.5 g, 5.81 mmol) in THF (30 mL). The reaction mixture was allowed to stir at 0° C. for 1 h. To the reaction was added acetaldehyde (512 mg, 11.6 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and then stir for 16 h. Acetaldehyde (2.0 g) was added to the reaction vessel and the reaction mixture was allowed to stir at room temperature for an additional 16 h. The reaction was quenched with the slow addition of saturated aqueous ammonium chloride (30 mL). The mixture was extracted with EtOAc, washed with brine and dried to afford the crude product. The crude product was purified by column chromatography (EtOAc/hexane, 1:8) to give ethyl 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-but-2-enoic acid ethyl ester as a mixture of isomers (1.1 g, 60%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2.CN(C)P(=O)(N(C)C)N(C)C.[O:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[OH:38][C:35]1([C:7]2[N:8]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=3)[CH2:36][CH2:37][O:32][CH2:33][CH2:34]1
Reactant: O=C1CCOCC1
Reactant: CSc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSc1ccc2c(c1)cc(C1(O)CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methylthio-1-benzenesulfonylindole (200 mg) in tetrahydrofuran (5 ml), n-butyl lithium (0.49 ml, 1.61 M) was added at −78° C. under nitrogen atmosphere and the mixture was stirred at −78° C. for 30 minutes, followed by addition of hexamethylphosphoric triamide (0.23 ml), and the mixture was stirred for 15 minutes. Subsequently, tetrahydro-4H-pyran-4-one (0.12 ml) was added thereto and the mixture was stirred at −78° C. for 15 minutes and heated to 15 to 30° C. The reaction solution was then poured into a saturated aqueous ammonium chloride solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) and (methanol:chloroform=1:20) to obtain 39 mg of the desired product as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:21])[N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=1)=[O:5])C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[N:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:21])[N:15]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=2)=[O:5])=[N:25][C:26]=1[CH3:31]
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C
Reactant: Cc1nc(N)ccc1F
Product: Cc1ccc(Nc2cc(C3CC3)nn2C)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-fluoro-6-methylpyridine in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow cristalline solid, MS (ISP): m/e=381.4 (M+H+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=[C:11]([CH3:13])[CH:12]=1>>[C:14]([C:9]1[CH:8]=[C:7]([CH3:6])[C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:11]([CH3:13])[CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
85 ml Chlorosulphonic acid (1.3 mole) was added to a mixture of 81 g (0.5 mole) 3,5 -dimethyl-tert.-butylbenzene at 0± 2° C. The reaction mixture was stirred at 0° C. for 1.5 hours, poured on ice and the layers were separated. The organic layer was washed with water, sodium bicarbonate, and water and was then dried with sodium sulphate. The solvent was removed in vacuum giving pale-yellow crystals of the title compound, m.p. 65° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(N(CC)CC)C>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([I:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Cl)cc(I)c1O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Cl)cc(I)c2o1

Procedure:
A mixture of 3-iodo-5-chlorosalicylaldehyde (100 g, 0.354 mole), acetic anhydride (300 mL) and triethylamine (54 mL) was heated at reflux for 18 hours. Upon cooling, the desired coumarin precipitated as a dark brown crystalline material. This was filtered, washed with hexane/ethyl acetate (4:1, 200 mL), and was air dried. Yield: 60 g (55%).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C@@H:12]([F:17])[C:13](OC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:18]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][C@@H:12]([F:17])[CH2:13][OH:14])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H](F)CN(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Yield: 92.4 %

Procedure:
Lithium borohydride (5.3 g, 0.24 mol) was suspended in THF (200 mL) under a nitrogen atmosphere and cooled to −15° C. with stirring. Methyl (2R)-3-(dibenzylamino)-2-fluoropropanoate (56.6 g, 0.19 mol) was suspended in THF (250 mL) and added dropwise to the mixture over 1 h; the internal temperature was maintained below −10° C. during the addition. On completion of addition, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 17 h. The reaction mixture was cooled to 0° C. and cautiously quenched with a saturated aqueous solution of ammonium chloride (300 mL). The reaction mixture was extracted with ethyl acetate (2×200 mL) and the organic phase was concentrated under reduced pressure. The crude residue was dissolved in 2 N hydrochloric acid (200 mL, pH=2 approx.) and the aqueous phase was washed with ether (2×200 mL). The aqueous phase was basified (pH=10 approx.) with 80% ammonium hydroxide in brine, extracted with ethyl acetate (3×200 mL), dried over anhydrous sodium sulfate (10 g), filtered and concentrated under reduced pressure to afford (2R)-3-(dibenzylamino)-2-fluoro-1-propanol (48 g, 93%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ7.15-7.38 (m, 10H), 4.65-4.78 (m, 0.5H), 4.48-4.58 (m, 0.5H), 3.50-3.82 (m, 6H), 2.70-2.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH3:43])[C:21]([N:23]([CH2:33][C:34]1[C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[S:37][CH:38]=1)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH3:43])[C:21]([N:23]([CH2:33][C:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[S:37][CH:38]=2)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 112 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[C:33]([OH:47])(=[O:46])[CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][C:43](O)=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:43]([CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][C:33]([OH:47])=[O:46])=[O:44])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: O=C(O)COCCOCCOCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)COCCOCCOCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one (5), and 21 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 327 mg of 3,6,9-trioxaundecanedioic acid, 57 μl of diisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 638.70 (C34H39F1N2O9); MS (ESI) 639.27 (M+H+)
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][C:7]=1[O:15][CH3:16]>ClCCl>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Cl:3])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(CCO)ccc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCCl)ccc1O
Temperature: 25 °C

Procedure:
Thionyl chloride (0.5 ml) was added, dropwise, to a! stirred solution of 4-hydroxy-3-methoxyphenethyl alcohol (0.83 g--commercially available) in dichloromethane (50 ml). When the addition was complete, the mixture was heated under reflux for 3 hours. On cooling to room temperature, the mixture was concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.36 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(I)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(I)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-iodoacetophenone, 3-(4-chlorophenyl)-1-(4-iodophenyl)prop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:27])=[O:5])C.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>C(O)C>[OH:27][C:7]1[C:8]2[CH:13]=[N:12][C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][C:9]=2[N:32]([CH2:31][CH2:30][O:29][CH3:28])[C:4](=[O:5])[C:6]=1[C:21]([NH:20][CH2:23][CH2:24][O:25][CH3:26])=[O:22]
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O
Solvent: CCO
Product: COCCNC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 1.0 g. (0.0027 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared as in Example 9) was added 0.4 g. (0.0054 mole) of 2-methoxyethylamine in 25 ml. of ethanol and this was heated at reflux for 4 hours. The reaction was then filtered and chilled and the filtrate gave up a solid that was collected on a suction filter and rinsed with petroleum ether. No further purification was necessary--m.p. 150°-154° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:27])[CH:13]([OH:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:27])[CH:13]([O:26][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: COc1cc(C(O)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(2,2-dimethyl-2H-chromen-6-yl)-2-hydroxy-2-(3,4,5-trimethoxy-phenyl)-ethanone (28 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added p-toluenesulfonyl chloride (15.3 mg, 0.080 mmol) and pyridine (6.47 μL, 0.080 mmol). The reaction mixture continues to stir at room temperature. The crude material is purified using silica gel chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][C:9]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1
Reactant: Nc1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1
Temperature: 120 °C

Procedure:
The mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester (0.31 g, 1.0 mmol) (from Example 5a supra) and aniline (3.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel) to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester as a white amorphous solid. (Yield 0.35 g, 82.3%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=O.Cl.[OH:14][NH2:15].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=[N:15][OH:14]
Reactant: NO
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (9.0 g, 52.9 mmol) in THF (120 mL and 60 mL of water) was added hydroxyl amine hydrochloride (3.73 g, 52.9 mmol) and the reaction stirred until clear (10 minutes). Sodium carbonate (2.75 g, 25.9 mmol) was added and the reaction stirred overnight at ambient temperature. The reaction was poured into ethyl acetate (500 mL) and the layers were separated. The organics were washed with water (200 mL), brine (200 mL), dried over magnesium sulfate and concentrated in vacuo to yield (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol, 92.7%).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([OH:19])=[S:18])=[C:11]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([O:19][CH3:1])=[S:18])=[C:11]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
Oxalyl chloride (0.70 mL, 9.6 mmol) was added to a solution of 5-chloro-3-phenylthioindole-2-carboxylic acid (0.97 g, 3.2 mmol) in chloroform (50 mL) under nitrogen. The reaction was refluxed for 3 h, cooled and reduced to dryness in vacuo. The resulting solid was dissolved in chloroform and added to methanol at 0° C. The methanol was removed in vacuo and the crude product chromatographed on silica gel with 20% ethyl acetate in hexane. The title compound was obtained as a solid, mp 193°-196° C. Anal. Calc. for C16H12ClNO2S: C, 60.47; H, 3.81; N, 4.42. Found: C, 60.09; H, 3.50; N, 4.67.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Br-].[CH:14]1([Zn+])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1COCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1N
Reactant: [Zn+]C1CCCCC1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2CCCCC2)ccc1N
Yield: 98 %

Procedure:
A solution of methyl 3-amino-6-bromopicolinate (1.0 equiv.), cyclohexyl zincbromide 0.5 M solution in THF (1.5 equiv.), and tetrakis(triphenylphosphine)-palladium(0) (0.05 equiv.) was stirred at 50° C. for 15 minutes. The reaction was filtered and washed with EtOAc. The organic was washed with H2O (100 mL), NaCl(sat.) (50 mL), dried over MgSO4, and the volatiles were removed in vacuo. The product was purified on silica utilizing the Isco 0-65% gradient of hexane/EtOAc to yield methyl 3-amino-6-cyclohexylpicolinate (98%). LCMS (m/z): 235.2 (MH+); LC Rt=1.89 min.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2(C#N)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=NN=N1.[N+:15]([CH3:18])([O-:17])=[O:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:15]([CH2:18][C:7]1([CH2:6][C:5]#[N:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: N#CC1(Cc2nnn[nH]2)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 70.7 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).