Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:15]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]3[C@@H:13]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:12]2)=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[H-].[Na+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][OH:52])=[CH:46][CH:45]=1>C1COCC1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][O:52][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:12]3)=[C:4]([NH:26][CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:3]=2)=[CH:46][CH:45]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: OCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The title compound is prepared by adding N-{(3aR,4S,6R,6aS)-6-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (example 235, step 1) to a premixed solution of sodium hydride (60% in oil) and 2-(4-chloro-phenyl)-ethanol (1 equivalent) in dry THF. The reaction is stirred at 50° C. for 48 hours, before quenching residual sodium hydride with excess aqueous ammonium chloride. The reaction mixture id then partioned between ethyl acetate and water; the organic phase is washed consecutively with water and brine before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure yields the crude product; purification by column chromatography/crystallisation affords the title compound.
Reaction SMILES: [Cl-].[CH3:2][CH:3]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:4]=[CH:5][C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]=1[CH3:14].[CH:34]([CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=O>CO>[CH3:45][C:37](=[CH:36][CH:34]=[C:3]([CH3:2])[CH:4]=[CH:5][C:6]1[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][CH2:8][C:7]=1[CH3:14])[CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CC1=C(C=CC(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Reactant: CCOC(=O)C=CC(C)=CC=O
Agent: [Cl-]
Solvent: CO
Product: CCOC(=O)C=CC(C)=CC=C(C)C=CC1=C(C)CCCC1(C)C

Procedure:
In a manner analogous to that described in Example 1, from 1-methyl-3-(2,6,6-trimethyl-1-cyclohexen-1-yl)allyl-triphenylphosphonium chloride and ethyl 5-formyl-4-methyl-2,4-pentadienoate there is obtained ethyl 4,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoate of melting point 65°-66° C. (from methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11]>>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[S:8])=[O:5])[CH3:2]
Reactant: CC(C)CN
Reactant: CCOC(=O)N=C=S
Product: CCOC(=O)NC(=S)NCC(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 5.3 grams of ethoxycarbonyl isothiocyanate (Preparation 1) in 100 ml of petroleum ether (b.p. 35°-60° C.) was cooled with stirring in an ice-water bath. To the above solution was added dropwise in 20 minutes a solution of 3.9 grams of isobutylamine in 50 ml of petroleum ether. The reaction flask was cooled in the ice-water bath during the addition. After the addition was complete the reaction flask was removed from the ice-water bath and let stand at an ambient temperature overnight. The solution was concentrated by stripping off most of the solvent. The concentrated solution was cooled in an ice-water bath. The crystals were collected by filtering and washing with hexanes. The product weighed 7.5 grams and melted at 50°-52° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[CH:12][C:13]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[C:8]3[C:7]([C:24]3[CH:32]=[C:31]4[C:27]([CH2:28][CH2:29][N:30]4[CH3:33])=[CH:26][C:25]=3[F:34])=[CH:6]2)[CH2:2]1.C=O.[C:37]([BH3-])#N.[Na+]>C(Cl)Cl>[F:34][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:24]=1[C:7]1[C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[NH:14][S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])[N:5]([CH:3]3[CH2:2][N:1]([CH3:37])[CH2:4]3)[CH:6]=1)[N:30]([CH3:33])[CH2:29][CH2:28]2
Reactant: CN1CCc2cc(F)c(-c3cn(C4CNC4)c4nccc(NS(=O)(=O)c5ccccc5)c34)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC(n2cc(-c3cc4c(cc3F)CCN4C)c3c(NS(=O)(=O)c4ccccc4)ccnc32)C1

Procedure:
To a solution of N-(1-(azetidin-3-yl)-3-(5-fluoro-1-methylindolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzenesulfonamide D34 (394 mg, 0.825 mmol) in DCM (5 mL) was added formaldehyde (0.307 mL, 4.13 mmol) and sodium cyanoborohydride (104 mg, 1.650 mmol). The final mixture was stirred at RT for 1 h. The mixture was passed through a SCX cartridge eluting with MeOH and followed by 2M ammonia in MeOH. The desired fractions were concentrated and further purified on normal phase silica eluting with 2M ammonia in MeOH and DCM (0-10%) to give the title compound (153 mg). LCMS (A): m/z (M+H)+ 492, C26H26FN5O2S requires 491 (acidic).
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.OO.S(=O)(=O)(O)[OH:23]>C(O)(C)(C)C>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:23])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of crude 2-acetyl-2-[2-(tert-butoxycarbonyl)-ethyl]cyclohexanone (see Preparations 1 and 2) (42 g, 0.15 mol) in t-butanol (84 ml) was cautiously added a 30% aqueous hydrogen peroxide solution (21 ml, 0.187 mol) and conc. sulphuric acid (0.25 ml, 98% w/w) at room temperature, maintaining the reaction temperature below 50° C. during the addition. The mixture was stirred at room temperature for 18 hours, partitioned between dichloromethane (100 ml) and water (100 ml), and the layers separated. The dichloromethane layer was washed with 5% aqueous sodium sulphite solution (50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a pale yellow solid, (43 g). The solid partially crystallized on standing overnight to provide, after collecting and washing with pentane, the title compound, (15.5 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH2:13][CH:14]3[CH2:23][CH2:22][N:21]4[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:15]3)=[O:11])=[CH:2]2)[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Product: O=C(OCC1CCN2CCCCC2C1)c1cn(CC2CC2)c2ccccc12

Procedure:
eq-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was alkylated with cyclopropylmethyl bromide using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E28) as a colourless oil. This was converted to its hydrochloride salt mp 167°-169° C. (acetone/ether).
Reaction SMILES: [OH-].[Na+].C(O)C.O.[O:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:8]1>C1COCC1.C(O)(=O)C>[O:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN3CCCOCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C#Cc2ccc(CN3CCCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
A 10% aqueous solution (6.6 mL) of sodium hydroxide was added to a solution, in THF (15 mL), ethanol (15 mL) and water (10 mL), of ethyl 4-{[4-(1,4-oxazepan-4-ylmethyl)phenyl]ethynyl}benzoate (1.5 g) as obtained in Example 5-(2). The mixture was stirred for 3 hours at room temperature, and then the reaction mixture was neutralized with acetic acid (5.0 mL). The reaction mixture was concentrated, and water was added. The precipitated solid was filtered off and dried to obtain 4-{[4-(1,4-oxazepan-4-ylmethyl)phenyl]ethynyl}benzoic acid (white solid) (0.92 g, 67%).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:12].C(=O)([O-])[O-].[NH4+].[NH4+]>>[NH2:12][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 30 °C

Procedure:
Cells obtained by centrifugation of the culture solution at the stationary phase were resuspended in 1 L of 4 M ammonia/ammonium carbonate (pH 10.3), and 20 g of cinnamic acid was added thereto. The reaction was conducted with stirring at 30° C. and 800 rpm. A part of the reaction solution was sampled every 1 hour, and an amount of L-phenylalanine formed in the reaction solution was determined by HPLC. While a substrate was successively added to keep a substrate concentration at 2%, the reaction was continued. Then, approximately 3.5% L-phenylalanine was accumulated in the reaction solution for approximately 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=O.[C:12](#[N:15])[CH:13]=C.C(N(C(C)C)C(C)C)C>[Pd](Cl)Cl.C1(=O)CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[CH:13][C:12]#[N:15]
Reactant: C=CC#N
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl[Pd]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C1CCCCC1
Product: COc1cccc(C=CC#N)c1
Yield: 6.3 %

Procedure:
The procedure described in Example 1 is repeated, except that 17.05 g (0.1 mol) of 3-methoxybenzoyl chloride, 6.63 g (0.125 mol) of acrylonitrile, 12.96 g (0.1 mol) of ethyldiisopropylamine, 0.1773 g (0.001 mol) of palladium chloride and 50 ml of cyclohexanone, as the solvent, are used. After a reaction time of 13 hours at 120° C, 1 g (0.0063 mol) of 3-methoxycinnamonitrile are obtained, corresponding to a yield of 6.3% of theory; boiling point 159°-166° C./19×102Pa.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[O:15][C:14]2[C:9](=[C:10]([CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:17](O)=[O:18])[CH:11]=[CH:12][CH:13]=2)[O:8]1.O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH2:7]1[O:15][C:14]2[C:9](=[C:10]([CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)[O:8]1
Reactant: CCCCCC(C(=O)O)c1cccc2c1OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CO)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a suspension of 1.26 g (33 mmol) of lithium aluminum hydride (LiAlH4) in 50 ml of tetrahydrofuran (THF) was dropwise added 5.01 g (20 mmol) of 2-(2, 3-methylenedioxyphenyl)heptanoic acid under water cooling. The reaction mixture was stirred at room temperature for 3 hours, and 1.26 ml of water, 1.26 ml of 15% aqueous sodium hydroxide and 3.78 ml of water were added in this order. After 50 ml of ethyl ether was added, the mixture was stirred, and precipitated white solid was filtered off. The filtrate was concentrated in vacuo to give 4.65 g of 2-(2, 3-methylenedioxyphenyl)heptanol as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:7]=1[Cl:23]>CO.O1CCCC1>[Cl:23][C:7]1[CH:8]=[C:9]([CH:12]([OH:22])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:10]=[CH:11][C:6]=1[C:5]([OH:24])=[O:4]
Reactant: COC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(O)C=Cc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
An aqueous solution of sodium hydroxide (1N, 3 mL, 3 mmol) was added to a solution of 2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid methyl ester (Example 92; 310 mg, 0.97 mmol) in methanol/tetrahydrofuran (1:1; 6 mL). The solution was stirred at room temperature overnight and then evaporated to dryness. Water (4 mL) was added and the solution was acidified with 1N hydrochloric acid solution (3.3 mL). The mixture was stirred at room temperature for 1 h, then the solid was filtered off, washed with water and dried to afford 2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid (243 mg, 82% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(F)(F)F)c4=O)cc3)CC2)cc1
Yield: 42.4 %

Procedure:
A mixture of 17.5 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-3H-1,2,4-triazol-3-one prepared as described in example XVII of U.S. Pat. No. 4,267,179, 19.5 parts of 2,2,2-trifluoroethyl 2-naphthalenesulfonate, 10.0 parts of potassium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 145° C. After cooling, water was added. The crystallized product was filtered off under pressure and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-butanone. The product was filtered off and dried, yielding 9.2 parts (42.4%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(2,2,2-trifluoroethyl)-3H-1,2,4-triazol-3-one; mp. 208.0° C. (int. 37).
Reaction SMILES: OOS([O-])=O.[K+].[C:7]([C:11]1[N:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:7]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]=2)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ncc(C=O)cn1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)cn1
Reaction time: 0.25 h

Procedure:
16.9 g (55 mmol) of oxone [70693-62-8] are added in portions with stirring at 10° C. to a solution of 16.4 g (100 mmol) of 2-tert-butylpyrimidine-5-carboxaldehyde [104461-06-5] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 100 ml of DMF and 3 ml of water, and the mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 2 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate solution in 2000 ml of water, stirred for a further 15 min., the solid formed is filtered off with suction, washed three times with 100 ml of water each time and dried in vacuo. The solid is dissolved in about 50 ml of hot ethyl acetate, and, during cooling, diethyl ether is added until slightly cloudy, the mixture is stirred for a further 12 h, the crystals are filtered off with suction, washed once with 50 ml of diethyl ether and dried in vacuo. Yield: 16.6 g (66 mmol), 66%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].O.ClCCl>ClCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of Example 18 (step 4) (0.8 g, 2.63 mmol) in dichloromethane (7.6 mL) was added triethylamine (0.78 mL, 5.60 mmol) and methyl 3-bromopropionate (0.32 mL, 2.93 mmol). The resulting solution was stirred at 30° C. overnight. The reaction mixture was poured into water/dichloromethane (50 mL/50 mL). The crude residue was extracted into dichloromethane. The organic portion was washed with water (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.79 g, 77%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2cccc(Cl)c2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2cccc(Cl)c2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.74 g) and 2-methylthio-5-(3-chlorobenzyl)pyrimid-4-one (0.8 g) were heated together under reflux in pyridine (2.5 ml) for 26 hr. After stripping, the residue was recrystallised three times from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino) propylamino]-5-(3-chlorobenzyl)pyrimid-4-one 1H2O, 0.7 g (58%) mp 105°-7° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([O:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]4)[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([O:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:31][CH2:30][N+:29]([O-:9])([CH2:34][CH2:33]3)[CH2:28]4)[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc(OC2CCCC2)n1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc(OC4CCCC4)ncn3)O1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
mCPBA (0.114 g, 0.510 mmol) was added to a solution of (R)—N-(6-(cyclopentyloxy)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.175 g, 0.510 mmol) in THF (15 ml). The mixture was stirred at room temperature for 18 h and concentrated. The residue was purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (S)-2-(6-(cyclopentyloxy)pyrimidin-4-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide an off-white solid (0.076 g, 0.207 mmol, 41%). 1H NMR (400 MHz, MeOD) δ ppm 8.38 (1H, s), 6.34 (1H, br. s.), 5.18-5.37 (1H, m), 4.01 (1H, d, J=11.08 Hz), 3.85 (1H, d, J=10.83 Hz), 3.58-3.75 (2H, m), 3.34-3.53 (3H, m), 3.20-3.27 (1H, m), 2.32-2.46 (1H, m), 2.23-2.31 (1H, m), 1.98-2.19 (3H, m), 1.93-1.99 (2H, m), 1.68-1.84 (4H, m), 1.55-1.70 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21](=[O:23])[NH2:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccc(Cl)cc2)sc1C(N)=O

Procedure:
To a solution of 1b (1.3 g, 3.7 mmol) in DMF (10 mL) was added 1,1′-carbonyl diimidazole (1.2 g, 7.4 mmol). The resultant solution was stirred for 1 h and mixed with ammonium hydroxide (37%, 5 mL). The mixture was diluted with brine solution (100 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then provided compound 1c as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[O:25])=[CH:22][CH:23]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(=O)Nc1nc(O)c2cc(C=C(C)c3ccc(C(=O)O)cc3)cnc2n1
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(C)=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 50 mL of N-methylpyrrolidinone containing 0.18 g of N-methylmorpholine was added 0.22 g of phenyl N-phenylphosphoramidochloridate in a single portion. After stirring the mixture at room temperature for 1 hour, 0.20 g of diethyl L-glutamate was added. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure and the residue was triturated with chloroform. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel using a 5% methanol in chloroform mixture as the eluent. This gave 74.6 mg (25%) of the title compound as a pale yellowish solid; NMR (CDCl3, 250 MHz) d 1.22 (t, 3H, J=7.1 Hz), 1.30 (t, 3H J=7.1 Hz), 2.11-2.57 (m, 10H), 4.14 (q, 2H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.75-4.83 (m, 1H), 6.86 (brs, 1H), 7.18 (brs, 1 H), 7.57 (d, 2H, J=8.42 Hz), 7.84 (d, 2H, J=8.42 Hz), 8.50 (d, 1H, J=2.01 Hz), 8.96 (brs, 1H), 10.34 (brs, 1H).