Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC=CC=1)([O-])=O.[NH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].Cl>O.C(#N)C>[C:18]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CC#N
Product: C=C(C)C(=O)NCCC(=O)O
Temperature: 0 °C
Yield: 45.2 %

Procedure:
In a mixture composed of 80 g (2.0 mols) of sodium hydroxide, 400 ml of water and 4 ml of nitrobenzene was dissolved 178 g (2.0 mols) of β-alanine with stirring and the resulting solution was cooled to 0° C. To the aqueous solution, there were simultaneously added dropwise 230 g (2.2 mols) of methacrylic chloride and an aqueous solution containing 96 g (2.4 mols) of sodium hydroxide dissolved in 200 ml of water. After the completion of the reaction, 800 ml of acetonitrile was added to the reaction solution and the mixture was then acidified by adding 160 ml of concentrated hydrochloric acid. 1 Liter of acetonitrile was further added to extract and the acetonitrile layer was separated. The acetonitrile solution was concentrated and the crystals thus deposited were collected and recrystallized from ethyl acetate to obtain 142 g of N-methacryloyl-β-alanine.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CCC(O)[C@H](N)CC
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)[C@@H](CC)Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4R)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 23 mg (75%). (57% de 4R,3S: 43% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.87-1.07 (m, 6H, —NHCH(CH2CH3) CH(CH2CH3)OH), 1.56 (d, 6H, J=6.63 Hz, & —CH(CH3)2), 1.43-1.63 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.44 (d, 1H, J=6.31 Hz, OH), 3.58-3.71 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.89-4.01 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.56-4.70 (m, 1H, —CH(CH3)2), 4.76-4.95 (m, 2H, —HNCH2-Pyr), 5.20-5.29 & 6.17-6.34 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.19-7.38 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.48-7.60 (m, 1H, Pyr-H), 7.72 (d, 1H, J=7.74 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (50), 297 (30). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2500.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](F)[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNC1
Product: COC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 282.8 %

Procedure:
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (7.99 mmol, 22.6 mmol) was diluted with pyrrolidine (18 mL, 215.6 mmol). The resulting mixture was heated to 80° C. After 3 h, the reaction mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with dichloromethane (200 mL). The organic layer was washed with saturated aqueous citric acid (3×50 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (9.14 g, 100%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:25][CH2:26][C:27]1[S:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.O>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[S:31][C:27]([CH2:26][OH:25])=[CH:28][CH:29]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1ccc(B(O)O)s1
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)s4)cc23)CC1
Reaction time: 0.33 h
Yield: 203.8 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.49 mmol) in dioxane (4.5 mL) and H2O (1.5 mL) was added [5-(hydroxymethyl)-2-thienyl]boronic acid (232 mg, 1.47 mmol), potassium carbonate (406 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol). Reaction was run in the microwave at 150° C. for 20 min. Aqueous work-up with EtOAc/H2O gave 447 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1H-indole-7-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].Cl.C([O:50][C:51](=[O:56])[CH2:52][CH2:53][NH:54][CH3:55])(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:27]=3)[C:22]([C:40](=[O:41])[N:54]([CH2:53][CH2:52][C:51]([OH:56])=[O:50])[CH3:55])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CNCCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)N(C)CCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 21 h
Yield: 98.2 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in N,N-dimethylformamide (2 ml), and thereto are added triethylamine (53 μl), 3-methylaminopropionic acid tert-butyl ester hydrochloride (101.14 mg), 1-hydroxybenzotriazole hydrate (65 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg) under ice-cooling. The mixture is stirred at room temperature for 21 hours. The reaction solution is concentrated under reduced pressure, then the residue is partitioned by adding a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer is concentrated under reduced pressure. The resulting residue is dissolved in a solution (2 ml) of 4N hydrochloric acid in 1,4-dioxane and stirred at room temperature for 1 hour. To the reaction solution is added excessive saturated aqueous sodium bicarbonate solution, and the mixture is neutralized with 1N HCl, then extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give (2R,4S)-4-([3,5-bis-(trifluoromethyl)benzyl]-{5-[(2-carboxyethyl)methylcarbamoyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (223 mg). MS (m/z): 713 [M+H]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][C:11]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1>[Br:8][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[C:11]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:10]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
NBS (1.243 g, 6.98 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.47 g, 5.73 mmol) [Prepared according to the procedure of Example 151] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 h. 6N NaOH (20 ml, 120 mmol) was then added and the mixture stirred at 70° C. for an additional 2 h. The mixture was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4 and concentrated affording the title compound which was used without further purification (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=302 (M+H)+.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][C:18]=1N1CCOCC1)=[O:16])([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.C(Cl)Cl.C(O)(=O)C.[BH4-].[Na+]>C(O)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(CCc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C

Procedure:
11.4 g (20 mmols) of 7β-benzylacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 50 ml of ethanol, 50 ml of methylene chloride and 50 ml of glacial acetic acid. The solution is cooled to 0° C. and then, with stirring and under nitrogen, 4.08 g (120 mmols) of sodium borohydride are added in 200 mg portions over 1 hour, with vigorous evolution of gas after each addition. When the addition is complete, the reaction mixture is cooled to room temperature and, after addition of a further 50 ml of glacial acetic acid, stirred for 36 hours at room temperature. The clear, almost colourless solution is concentrated in a rotary evaporator and the residue is partitioned between water and methylene chloride. The organic phase is washed again with two 50 ml portions of water and then concentrated in vacuo, affording crude 7β-benzylacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.N1CCC[C@H:22]1C(O)=O.C=O>C(#N)C>[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH:16]([CH2:22][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][CH:6]=2)[C:14](=[O:15])[O:13]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C=O
Solvent: CC#N
Product: CC1(C)OC(=O)C(Cc2c[nH]c3ccc(Br)cc23)C(=O)O1
Reaction time: 24 h
Yield: 417.3 %

Procedure:
A solution of 5-bromoindole (10.07 g, 51 mmol), Meldrum's acid (7.38 g, 51 mmol), proline (1.24 g), and 5.2 ml of 30% aqueous formaldehyde in 100 ml of acetonitrile was allowed to stand at room temperature for 24 hours. The acetonitrile was removed in vacuo. Crystallization of the product from methanol (50 ml) provided 15.83 g of 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl-5-bromoindole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([CH3:17])[OH:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:16][CH:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1(c2cccc(Cl)c2)CCN(C)CC1
Product: CC(=O)OC(C)C1(c2cccc(Cl)c2)CCN(C)CC1

Procedure:
A mixture of 1.00 g of 4-(3'-chlorophenyl)-α,1-dimethyl-4-piperidinemethanol (Example 1) and 5 mL of acetic anhydride was heated under reflux for 90 minutes. Removal of the excess acetic anhydride and short-path distillation of the residue (170° bath temperature, 1 micron) gave 1.05 g of the title compound as an oil. NMR (CDCl3): δ7.1-7.4 (m,4H); 4.9 (quartet, J=7 Hz,1H); 2.8 (m,2H); 2.2 (s,3H); 2.0 (s,3H); 1.9-2.4 (m,6H); and 0.9 (d,J=7 Hz,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[Na]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc([N+](=O)[O-])ccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122.9 %

Procedure:
5-Nitroindoline (12.18 mmol, 2 g) was stirred in acetic acid (50 mL) in an ice bath. tert-Butyl 4-oxopiperidine-1-carboxylate (14.62 mmol, 2.91 g) was added, followed by the portionwise addition of sodium triacetoxyhydroborate (18.27 mmol, 3.87 g). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated at reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated at reduced pressure to afford the title compound (5.2 g).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].ClCCl.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.[F:22][C:23]1[C:28]([I:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[C:34]([C:35]([OH:37])=O)=[C:33]([CH3:38])[O:32][N:31]=1>CN(C1C=CN=CC=1)C.CC(C)=O.ClCCl>[C:3]1([C:1]([NH:19][CH2:18][C@@H:17]2[CH2:16][CH2:33][CH2:34][C@H:30]([NH:31][C:35]([C:34]3[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([I:29])[C:23]=4[F:22])=[N:31][O:32][C:33]=3[CH3:38])=[O:37])[CH2:24]2)=[O:2])[CH:23]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1onc(-c2cccc(I)c2F)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1onc(-c2cccc(I)c2F)c1C(=O)N[C@H]1CCC[C@@H](CNC(=O)c2ccccc2)C1
Yield: 62 %

Procedure:
In a fashion similar to that described for preparation 108, a compound from preparation 105(0.1 g, 0.3 mmol), TFA (2 mL), dichloro-methane (1.5 mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol), 3-(2-fluoro-3-iodo-phenyl)-5-methyl-isoxazole-4-carboxylic acid (0.125 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the title compound (0.104 g, 62%) after column chromatography (silica gel, acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 562.1 [M+1].
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>CS(C)=O>[CH3:34][N:35]([CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[N:12]=1
Reactant: CNCc1cccnc1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)Cc3cccnc3)c2C1
Reaction time: 8 h
Yield: 53.3 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. N-methyl-1-(pyridin-3-yl)methanamine (8.55 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-(Methyl(pyridin-3-ylmethyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (17 mg, 52%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:12](=[O:15])[CH:13]=[CH2:14])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCc1cccc(CC)c1N
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1c(CC)cccc1CC
Reaction time: 4 h

Procedure:
To a cold solution of 2.6-diethylaniline (60.6 g, 0.07 mole) in ethyl acetate (600 ml) was added a solution of acryloyl chloride (45.2 g, 0.5 mole) in ethyl acetate (50 ml) over a 30 minute period. The ice bath was removed and the solution stirred for 4 hours. 10 Percher hydrochloric acid was added and the solution stirred gently for 15 minutes. The layers were separated and the organic layer washed with water, dried over sodium sulfate, filtered and the solvents removed on a rotary evaporator leaving an orange solid. The solid was recrystallized from ethyl acetate/hexane and the product filtered and dried.
Reaction SMILES: CS([O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=[CH2:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)(=O)=O.[F:21][C:22]1[C:27]([F:28])=[C:26]([O:29][CH2:30][CH3:31])[CH:25]=[CH:24][C:23]=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([O:5][CH2:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH:19]=[CH2:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[C:22]([F:21])[C:27]=1[F:28])[CH3:31]
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
9.8 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethyl methanesulfonate and 5.96 g of 2,3-difluoro-4-ethoxyphenol were dissolved in 90 mL of DMF. 10.4 g of tripotassium phosphate was added, followed by stirring at 90 to 100° C. for 3 hours. The reaction mixture was poured into water, extracted with toluene, washed in turn with water, 10% hydrochloric acid, water, and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified in turn by subjecting to column chromatography (silica gel/toluene), recrystallization (methanol/acetone), column chromatography (alumina/acetone), washing with ion-exchange water, silica treatment, and recrystallization (methanol/acetone) to obtain 8.5 g of 4-ethoxy-2,3-difluoro-1-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxybenzene (IIIa) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=C1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:27][C:21]3[C:26]([C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]=[CH:6]2
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: CCO
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)[nH]c2ccccc12
Yield: 102.6 %

Procedure:
To a stirred suspension of the 1-(6-methoxy-2-naphthyl)heptan-1-one (81.5 g, 301.44 mmol) in ethanol (2000 mL) under N2 was added phenylhydrazine (35.857 g, 331.58 mmol) and p-toluene sulfonic acid monhydrate (120.41 g, 633.02 mmol). The mixture was refluxed. Warming gave a homogenous solution. (A modification of this Fisher indole reaction to incorporate varied substitution on the indole ring utilizes an N-arylhydrazone in place of the aryl hydrazine-details of hydrazone preparation in a recent JACS, S.Wagaw; B. H. Yang; S. L. Buchwald. JACS, 121, 1999, 10251-10263). After 92 h reflux, heating was stopped and the reaction mixture cooled and rotovap'd to a residue. The residue was partitioned between EtOAc (1700 mL) and 1 N HCl (500 mL). The layers were shaken, separated, and the organic layer washed with 1 N HCl (2×300 mL), sat. aq. NaHCO3 (3×250 mL), H2O (3×250 mL), brine (2×250 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give a dark viscous oil (106.2 g). The residue was triturated with hexane to give an off-white solid which was collected, rinsed and dried in vacuo to give the product as an off-white solid (95.9 g, 279.21 mmol, 93%) which dec. 93-96° C. 400 mg of the crude indole was recrystallized from hexane to give the product as a white solid (298 mg) with mp 95-97° C.; 1H NMR (DMSO-d6) δ 0.82 (t, J=7.0 Hz, 3H), 1.31 (m, 4H), 1.66 (m, 2H), 2.89 (t, J=7.6 Hz, 2H), 3.90 (s, 3H), 6.98-7.02 (m, 1H), 7.07-7.10 (m, 1H), 7.21 (dd, J=2.4, 8.9 Hz, 1H), 7.34-7.37 (m, 2H), 7.54 (d, J=7.94 Hz, 1H), 7.73 (dd, J=1.5, 8.6 Hz, 1H), 7.88 (d, J=9.00 Hz, 1H), 7.93 (d, J=8.55 Hz, 1H), 8.03 (s, 1H), 11.17 (s, 1H); IR (solid) 3350, 2960, 2920, 2840, 1600, 1200, 740, cm−1; mass spectrum [ESI], m/z 344 (M+H)+;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][CH2:14][CH:15](O)[CH2:16][F:17].[CH3:19][O:20][C:21]1[N:26]=[C:25]2[S:27][C:28]([NH2:30])=[N:29][C:24]2=[CH:23][CH:22]=1>>[F:13][CH2:14][CH:15]([CH2:16][F:17])[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:30][C:28]1[S:27][C:25]2[C:24]([N:29]=1)=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[N:26]=2
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: OC(CF)CF
Reactant: COc1ccc2nc(N)sc2n1
Product: COc1ccc2nc(Nc3ncnc4ccc(OC(CF)CF)cc34)sc2n1

Procedure:
The compound of Example 30 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-hydroxy-quinazoline, 1,3-difluoro-2-propanol and 5-methoxy-thiazolo[5,4-b]pyridin-2-yl-amine.