Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:19]([NH:20][C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH:18]=[C:17]([O:16][CH3:15])[C:23]=1[O:24][CH3:25]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C2CSC(c3cccnc3)N2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 630 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 520 mg of 3,4,5-trimethoxyaniline, 650 mg of dicyclohexylcarbodiimide and 430 mg of 1-hydroxybenzotriazole in 8 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with aqueous sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent: ethyl acetate) gave 370 mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in 10 ml of ethyl acetate, and 2 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 130°-132° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)[C:6](=[O:8])[CH3:7].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:25]=1[C:26]([O:28][CH3:29])=[O:27].O.CN1[C:42](=[O:43])N(C)CCC1>C1COCC1>[C:6]([N:5]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH2:4][CH2:3][CH2:2][CH2:42][O:43][CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:25]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:8])[CH3:7]
Reactant: CN1CCCN(C)C1=O
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: CC(=O)N(CCCO)Cc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cccc1COCCCCN(Cc1ccc2ccccc2n1)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-(3-Hydroxy-propyl)-N-quinolin-2-ylmethyl-acetamide (410 mg, 1.5 mmol, EXAMPLE 39a) is dissolved in 20% DMPU in THF (3 mL) and cooled to 0° C. Sodium hydride (60%, 66 mg, 1.65 mmol) is added and the contents are stirred for 10 min. Methyl 2-bromomethyl-6-methyl-benzoate (77%, 365 mg, 1.5 mmol, EXAMPLE 2a) is added. The contents are allowed to come to r.t., and are stirred overnight. The contents are poured into water (100 mL) and extracted with ethyl acetate (3×75 mL). The organic fractions are pooled and washed with water (2×100 mL) and brine (2×100 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 3% methanol in dichloromethane) to give the title compound. MS (ESI) 435 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[C:29]3[CH3:35])=[O:23])[C:3]=1[CH3:36].C([O-])=O.[NH4+]>[Pd].CO>[NH3:4].[CH:17]1([CH2:16][N:11]2[CH2:12][CH2:13][O:14][CH2:15][C@H:10]2[CH2:9][NH:8][C:6]2[C:5](=[O:20])[N:4]([CH2:21][C:22]([NH:24][CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][CH:30]=[C:29]4[CH3:35])=[O:23])[C:3]([CH3:36])=[CH:2][N:7]=2)[CH2:18][CH2:19]1
Reactant: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)c(Cl)nc(NC[C@@H]4COCCN4CC4CC4)c3=O)cc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NC[C@@H]4COCCN4CC4CC4)c3=O)cc12
Product: N
Temperature: 25 °C
Reaction time: 64 h
Yield: 27.3 %

Procedure:
A mixture of 2-[3-chloro-5-({[(3R)-4-(cyclopropylmethyl)morpholinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide (preparation 101) (120 mg, 0.23 mmol), ammonium formate (44 mg, 0.7 mmol) and 10% palladium on charcoal (catalytic) in methanol (5 ml) was stirred at room temperature under a nitrogen atmosphere for 64 hrs. The reaction mixture was filtered through a Whatman® filter, washing through with ethyl acetate. The combined filtrate was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.5) as eluant to give the title compound as a white solid, (15 mg, 14%).
Reaction SMILES: [CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](C3N=CC(O)=CN=3)[CH:17]=2)C1)[CH2:2]CCCCCCCC.C(C1C=CC(C2SC(C3C=CC(O)=CC=3)=CN=2)=CC=1)CCCCC.[C:51]1([CH3:70])[CH:56]=[CH:55][C:54]([S:57]([O:60]CCCC2C=CC=CC=2)(=[O:59])=[O:58])=[CH:53][CH:52]=1>>[C:51]1([CH3:70])[CH:52]=[CH:53][C:54]([S:57]([O:60][CH2:2][CH2:1][CH2:11][CH2:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:58])=[O:59])=[CH:55][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Reactant: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Agent: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccccc2)cc1
Yield: 71.1 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 4-{2-(4-hexylphenyl)thiazole-5-yl}phenol and 3-phenylpropyl p-toluenesulfonate was changed to 4-phenylbutyl p-toluenesulfonate (Yield: 71.1%).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:6][CH:5]=1.N1C=CC=CC=1.[H-].[Na+].Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>CN(C=O)C.C(#N)C>[C:48]([O:47][C:45]([CH2:44][N:10]([C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:34])=[CH:5][CH:6]=1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: COC(=O)c1ccc(NC(=O)CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(15-tert-Butoxycarbonylpentadecanoylamino)benzoic acid methyl ester (235 mg, 0.495 mmol) was evaporated twice from dry pyridine and once from dry acetonitrile, dissolved in dry DMF (4 mL) under nitrogen. 60% NaH (14 mg, 0.594 mmol) was added and the mixture was stirred for 20 minutes at room temperature under nitrogen. tert-Butyl bromoacetate (0.11 mL, 0.742 mmol) was added and the mixture was stirred for 1 hour, the reaction was quenched with ice and separated between water (50 mL) and diethylether (75 mL). The organic phase was dried (Na2SO4) and solvent remove in vacuo. The crude material was dissolved in ethanol (4 mL). NaOH (5 N, 0.15 mL) was added and the mixture was stirred for 1 hour. pH was adjusted to pH=5 with acetic acid and the mixture was separated between water and ethyl acetate. The organic phase was dried (Na2SO4) and solvent removed in vacuo to give the crude product which was purified on RP-HPLC, C-18 with acetonitrile/water gradient (75-95%) containing 0.1% TFA. To give pure 4-[tert-Butoxycarbonylmethyl-(15-tert-butoxycarbonylpentadecanoyl)amino]benzoic acid) (53 mg, 19%)
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11](SC)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([NH2:19])=[O:18])=[N:3]1.O[O:21][S:22]([O-:24])=O.[K+].O.[C:27](OCC)(=O)C>CN(C)C=O.C(OCC)C>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:22]([CH3:27])(=[O:24])=[O:21])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([NH2:19])=[O:18])=[N:3]1
Reactant: CCOC(C)=O
Reactant: CSc1ncc2c(n1)-c1c(c(C(N)=O)nn1C)CC2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(N)=O)c2c1-c1nc(S(C)(=O)=O)ncc1CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
6.00 g (0.022 mol) of 1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 1000 mL of dimethylformamide and 40.18 g of oxone were added. The mixture was stirred 16 hours at room temperature. Water and ethyl acetate were then added and the layers separated. The organic layer was finally dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and 5.40 g (80% yield) of the title compound were collected by filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].II.[Br:14][C:15]1[CH:16]=[C:17]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[N:23]S(C(C)(C)C)=O)[CH:18]=[CH:19][C:20]=1[F:21]>C(OCC)C.O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:22]2([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=3)[C:30]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: COc1ccc(Br)cc1C
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1ccccc1C#N
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (1.21 g, 6.0 mmol) in diethyl ether (10 mL) was added dropwise to magnesium (0.22 g, 9.0 mmol) and iodine. The resulting mixture was heated to reflux for 2 h and was then allowed to cool to room temperature. The prepared reagent was added to a solution of N-((3-bromo-4-fluorophenyl)(2-cyanophenyl)methylene)-2-methylpropane-2-sulfinamide (Scheme #11 F, 0.82 g, 2.0 mmol) in tetrahydrofuran (20 mL) at 0°. The mixture was stirred at 0° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (20 mL) and was treated with hydrochloric acid (2M in diethyl ether, 2 mL) overnight. The solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and evaporated. Purification by flash chromatography using chloroform:methanol (9:1) afforded 0.53 g (63% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.90-7.74 (m, 1 H), 7.74-7.67 (m, 1 H), 7.59-7.42 (m, 3 H), 7.35-7.21 (m, 2 H), 7.12-7.00 (m, 2 H), 6.97-6.71 (m, 3 H), 3.74 (s, 3 H), 2.06 (s, 3 H); MS (ESI) m/z 425, 427 [M+1]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:10](Cl)=[O:11])=[N:7][C:8]=1[CH3:9].[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[CH:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14].[H-].[Na+].O1CCCC1>CCCCCC.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:26])[C:17]([C:10]([C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[C:8]([CH3:9])[N:7]=1)=[O:11])=[CH:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14]
Reactant: Cc1ccc(C(=O)Cl)nc1C
Reactant: CCOC(=O)C=CNc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)n1

Procedure:
Compound 2e was prepared following the procedure outlined in Step 1 of Example 6 using 2.28 g (11.0 mmol) of 5,6-dimethyl-pyridine-2-carbonyl chloride hydrochloride (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351), 1.91 g (10.0 mmol) of 3-phenylamino-acrylic acid ethyl ester, 1.08 g (27.0 mmol) of 60% sodium hydride and 25 mL tetrahydrofuran. Flash chromatography using 10-80% ethyl acetate in hexane yielded 575 mg of the product as yellow solid. LC-MSD, m/z for C19H20N2O3 [M+H]+=325.5, HPLC retention time: 1.9 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH3:26][C:27]([CH3:29])=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:27]([CH3:29])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Temperature: 10 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
4-[1-(3-Amino-2-pyridyl)piperazin4-yl-carbonyl]benzoic acid methyl ester (4 g) was dissolved in methanol (90 ml) and then, acetone (2 ml), acetic acid (5 ml) and sodium cyanoborohydride (2.4 g) were added at 10° C. in order. The reaction mixture was stirred at 10° C. for 4 hours and heated to 20~25° C. and stirred for 1 hour. The solution was neutralized (pH=~8) by addition of aqueous 3N-sodium hydroxide, and excess of water was added gradually for precipitation. The mixture was stirred for 1 hour, filtered, washed with water, methanol and ether in order and dried to give 3.5 g (yield: 78%) of the desired compound as white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[N:20][P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2ccccc2C(C)(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.33 g of N1-(2-tert-butylphenyl)-4-methylbenzamidine (Amidine VI, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow semi-solid was isolated (1.9 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:31])[CH:21]=2)[C:9]1=[O:32])[CH2:6][CH3:7].O.[OH-].[Li+].C(O)(=O)C>O.O1CCOCC1>[O:32]=[C:9]1[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:31])[CH:21]=2)[C:11]2[CH:18]=[CH:17][CH:16]=[N:15][C:12]=2[C:13](=[O:14])[N:8]1[C@H:5]([CH2:6][CH3:7])[CH2:4][C:3]([OH:33])=[O:2]
Reactant: CC[C@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](CC(=O)O)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Yield: 42.3 %

Procedure:
A solution of 1.0 g of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester and 187 mg of lithium hydroxide monohydrate in 20 mL water and 20 mL of 1,4-dioxane is stirred at room temperature for 3 h. The resulting mixture is neutralized with 0.26 mL of acetic acid and the resulting mixture is diluted with water. The product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography on silica gel. The combined fractions are concentrated and the residue is triturated with ether to give 410 mg (42%) of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid; LCMS (ESMS): m/z 435 (M+H+).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.FC(F)(F)S(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 89 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.050 ml of trifluoromethanesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of trifluoromethanesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone to give 135.2 mg (yield 89%) of the title compound, having the same properties as the product of Preparation 17.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:16]=[N:17][C:18]([CH:21]=O)=[CH:19][CH:20]=4)[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]4[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=4[CH3:33])=[O:24])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:16]=[N:17][C:18]([CH2:21][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[CH:19][CH:20]=4)[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]4[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=4[CH3:33])=[O:24])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1H-indazole-4-carboxamide (0.1 g, 0.212 mmol) in methanol (2 mL) was added acetic acid (0.013 g, 0.212 mmol) and morpholine (0.056 g, 0.636 mmol) and stirred it at room temperature for 3 h. Then NaBH3CN (0.014 g, 0.212 mmol) was added to it and the reaction mixture stirred at room temperature overnight. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give corresponding 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-(morpholinomethyl)pyridin-3-yl)-1H-indazole-4-carboxamide (0.049 g, 43.4%). LCMS: 541.30 (M+1)+; HPLC: 94.30% (@ 254 nm) (Rt; 5.379); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.98 (s, 1H), 8.62 (t, 1H, J=4.4&4.8 Hz), 8.39 (s, 1H), 8.21 (s, 2H), 7.90 (s, 1H), 7.56 (d, 1H, J=8.4 Hz), 5.88 (s, 1H), 5.35-5.31 (m, 1H), 4.39 (d, 2H, J=4.8 Hz), 3.65 (s, 2H), 3.60 (t, 4H, J=4&4.4 Hz), 2.44 (bs, 4H), 2.21 (s, 3H), 2.15 (bs, 2H), 2.11 (s, 3H), 2.05-1.98 (m, 2H), 1.89 (bs, 2H), 1.75-1.65 (m, 2H).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[C:6]([CH2:12][C:13]#[N:14])(=O)[C:7]([CH3:10])([CH3:9])[CH3:8]>>[C:7]([C:6]1[CH:12]=[C:13]([NH2:14])[O:1][N:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)c1cc(N)on1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To an aqueous solution of sodium hydroxide solution (40.00 g, 1 mol, in 200 ml of water) was added hydroxylamine hydrochloride (24.00 g, 346 mmol) and pivaloylacetonitrile (40.00 g, 320 mmol). The resulting solution was stirred at 50° C. for 3 hrs. The reaction mixture cooled and the resultant white crystalline solid filtered, washed with water and dried to provide 3-t-butylisoxazol-5-amine as a white crystalline solid (34 g, yield 76% yield). 1H NMR (DMSO-d6) δ 6.41 (brs, 2H), 4.85 (s, 1H), 1.18 (s, 9H): LC-MS (ES, m/z, M+H) 141.3.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[CH2:18]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[CH2:18]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:14](=[O:16])[C:13]([NH:12][C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=3[CH:11]=2)=[O:17])[CH2:28][CH2:27]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: c1ccc(COC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(OCc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid and 4-benzyloxy-piperidine [Tetrahedron Lett., 36 3465. (1995)] according to the method described in Example 1c. Melting Point: 143-146° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1.C(OCC)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1oc2ccccc2c(O)c1C(c1ccccc1)c1ccccc1

Procedure:
To a mixture of 324 mg of 4-hydroxycoumarin and 368 mg of commercially available diphenylcarbinol in 30 mL of dioxane is added 0.37 mL of boron trifluoride etherate. After 100 hours at room temperature the reaction solution is diluted with 40 mL of diethyl ether and washed with water. The organic phase is dried (magnesium sulfate) and concentrated under reduced pressure. The residue is flash column chromatographed with 20% to 80% ethyl acetate in hexanes to give 587 mg of the title product.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20].C(Cl)(=O)C([Cl:26])=O>C(Cl)(Cl)Cl>[C:1]([Cl:26])(=[O:22])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Cl

Procedure:
To a solution of 605 mg of 5,8,11,14,17-eicosapentaenic acid in 6 ml of dry chloroform was added 0.25 ml of oxalyl chloride under argon at room temperature. The mixture was reacted for 2 hours. From the reaction mixture were removed the chloroform and the remaining oxalyl chloride by distillation under reduced pressure to give 5,8,11,14,17-eicosapentaenoyl chloride, which was then dissolved in 6 ml of dry chloroform.