Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:30][CH3:31])=[C:10]([C:12]([CH3:29])([CH3:28])[CH2:13][C:14](=[O:27])[CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[CH:18]=[CH:17]2)[CH:11]=1.[CH:32]1([Mg]Br)[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([C:14]([OH:27])([CH2:13][C:12]([C:10]2[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=2[O:30][CH3:31])([CH3:29])[CH3:28])[CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[CH:18]=[CH:17]2)[CH2:34][CH2:33]1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)Cn1ccc(=O)c2ccccc21
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 1 %

Procedure:
An oven-dried round-bottomed flask charged with cerium chloride (0.27 g, 1.08 mmol) was dried under vacuum and at 140° C. for 1 hour followed by vacuum at room temperature for an additional 14 hours. The flask was sealed with a septum, evacuated under vacuum, and charged with argon. THF (3 mL) was added and the slurry was sonicated for 1 hour to give a yellow suspension. To this slurry was added 1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]-1H-quinolin-4-one (0.20 g, 0.54 mmol) dissolved in 1 mL of THF resulting in the formation of a dark brown solution. This was stirred for 1 hour at room temperature followed by the addition of the cyclopropylmagnesium bromide (2.18 mL, 0.5 mol/L) at 0° C. The reaction was allowed to stir at this temperature for 3 hours followed by quenching through the addition of saturated ammonium chloride (10.0 mL) resulting in the formation of a white precipitate. The biphasic system was filtered and the aqueous layer was separated. The organic layer was washed with one 25 mL portion of brine, dried over anhydrous sodium sulfite, filtered, and the solvent was evaporated in vacuo to give a yellow oil. The pure product, 1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one (2.0 mg, 1%) was obtained by flash chromatography on silica gel using mixtures of EtOAc-hexanes as the eluent.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C[O:10][CH:11](OC)[CH2:12][NH2:13].O.[BH4-].[Na+]>C1C=CC=CC=1>[OH:10][CH:11]1[CH2:12][NH:13][CH2:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: COC(CN)OC
Reactant: Cc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc2c(s1)CNCC2O
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 5-methyl-thiophene-2-carboxaldehyde (30 g; 0.237 mole) and aminoacetaldehyde dimethylacetal (27.4 g; 0.261 mole) in benzene (250 ml) is refluxed for 2 hours in a flask provided with a Dean-Stark water separator with overhead condenser. After evaporating to dryness, the residue is dissolved in ethanol (250 ml). Sodium borohydride (13.5 g; 0.355 mole) is added portionwise, and the resulting material is left aside overnight at room temperature. Excess sodium borohydride is destroyed by addition of acetone and the mixture is evaporated to dryness. The residue is taken up into water and extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated to dryness. The resulting residual oil is distilled under reduced pressure; b.p.2 =127° C.; Yield: 90% The resulting N-(5-methyl-2-thienyl)methyl aminoacetaldehyde dimethylacetal is heated at 60° C. for 1 hour in 6N hydrochloric acid (250 ml). After evaporating to dryness, the residue is triturated with acetone. The off-white crystals of the desired hydrochloride are recrystallized from acetonitrile; M.p.=120° C. Overall yield: 61%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1.O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[O:31][CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C>[CH3:32][O:31][C:23]1[CH:24]=[C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=2)[CH:26]=[CH:27][C:22]=1[NH2:21]
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Reactant: COc1cc(B(O)O)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)ccc1N
Temperature: 90 °C

Procedure:
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (700 mg, 2.29 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 DME:water:ethanol (7 mL). (4-Amino-3-methoxy-phenyl)boronic acid (574 mg, 3.43 mmol), 2M sodium carbonate solution (4 mL) and dichlorobis(triphenylphosphine) palladium (81 mg) was then added to the solution and refluxed at 90° C. for 1 hour. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (50 mL) and water (50 mL), the organics dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and filtered to remove insoluble material. The filtrates were purified using a companion.
Reaction SMILES: N#N.[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([Si:36]([CH3:53])([CH3:52])[O:37][CH:38]([C:40]1[O:41][C:42]([CH2:45][N:46]2[N:50]=[C:49]([NH2:51])[CH:48]=[N:47]2)=[CH:43][N:44]=1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:32]([Si:36]([CH3:53])([CH3:52])[O:37][CH:38]([C:40]1[O:41][C:42]([CH2:45][N:46]2[N:50]=[C:49]([NH:51][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:5]3[CH:4]=[C:3]([CH3:17])[CH:8]=[CH:7][CH:6]=3)=[O:16])[CH:48]=[N:47]2)=[CH:43][N:44]=1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-m-tolyl-oxazole-4-carboxylic acid (31 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.20 min, [M+H]+=509.55.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([Sn:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:20]1([SnH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triphenyl tin hydride was prepared as follows: a 4-neck flask equipped with magnetic stirring was charged with 600 ml of ether and 3.1 g (81 mmol) of LiAlH4 and cooled to 0° (ice+salt bath). 62.6 G (0.16 mol) of triphenyl tin chloride were added by means of a dropping funnel adapted for powder introduction. No exothermic reaction was observed. The mixture was allowed to warm up to room temperature and stirred for 1 h. It was then poured on ice, extracted with ether, washed 3 times with water, dried and concentrated. The raw product thus obtained (56.8 g) was used as such in the synthesis described above.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:34](Cl)(=[O:40])[O:35][CH2:36][C:37]#[C:38][CH3:39]>C(#N)C.CO>[CH3:1][N:2]([CH3:26])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:15][CH2:16][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:34]([O:35][CH2:36][C:37]#[C:38][CH3:39])=[O:40])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOC(=O)Cl
Reactant: CN(C)C(=O)N1CCC2(CCN(C3CCNCC3)CC2)c2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC#CCOC(=O)N1CCC(N2CCC3(CCN(C(=O)N(C)C)c4ccccc43)CC2)CC1
Reaction time: 1 h

Procedure:
N,N-dimethyl-1-(piperidin-4-yl)-2′,3′-dihydrospiro[piperidine-4,4′-quinoline]-1′-carboxamide 2ae (35.7 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL) and triethylamine (100 uL) and treated with but-2-ynyl carbonochloridate (26.5 mg, 0.2 mmol). The reaction was stirred for 1 hour, then diluted with methanol (0.5 mL) and purified by HPLC (2-99% CH3CN gradient, 0.05% TFA) to yield compound no. 5. LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 453.2, retention time 2.31 minutes. 1H-NMR (CDCl3, 400 MHz): δ 12.65 (br s, 1H), 7.69 (d, J=6.9 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H), 7.02 (t, J=8.1 Hz, 1H), 6.83 (d, J=9.2 Hz, 1H), 4.66 (s, 2H), 4.38 (br s, 2H), 3.58 (m, 2H), 3.45 (m, 2H), 3.31 (m, 1H), 3.08 (m, 5H), 2.85 (s, 6H), 2.37 (m, 2H), 1.97 (m, 2H), 1.86 (t, J=2.3 Hz, 3H), 1.81 (m, 3H), 1.42 (t, J=7.3 Hz, 2H).
Reaction SMILES: [Br:1][CH:2]([CH:7]1[CH:9]([C:10]([OH:12])=[O:11])[C:8]1([CH3:14])[CH3:13])[C:3]([Br:6])([Cl:5])[Cl:4].[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26]O)[CH:22]=2)=[CH:18][CH:17]=1>>[Br:1][CH:2]([CH:7]1[CH:9]([C:10]([O:12][CH2:26][N:23]2[CH:24]=[CH:25][C:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:29][CH:28]=3)=[CH:22]2)=[O:11])[C:8]1([CH3:14])[CH3:13])[C:3]([Br:6])([Cl:4])[Cl:5]
Reactant: OCn1ccc(Cc2ccc(F)cc2)c1
Reactant: CC1(C)C(C(=O)O)C1C(Br)C(Cl)(Cl)Br
Product: CC1(C)C(C(=O)OCn2ccc(Cc3ccc(F)cc3)c2)C1C(Br)C(Cl)(Cl)Br

Procedure:
Following the procedure of Example 1, 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanecarboxylic acid is reacted with [3-(4-fluorobenzyl)-1-pyrrolyl]methanol to give the final product [3-(4-fluorobenzyl)-1-pyrrolyl]methyl 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH:23]=2)[C:10]=1[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])C.[OH-].[Na+]>>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:29])=[O:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Yield: 58.5 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(propane-1-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (87 mg, 0.12 mmol) and 1.0 N aqueous sodium hydroxide (1.22 mL) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(propane-1-sulfonyl)-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (46 mg, 57%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C35H42O10S (M+Na)+ 677.2391, found 677.2388.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([CH:22]([OH:24])[CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: CC=O
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 from Example 19 (0.3 mmol) dissolved in THF (3 mL) at −78° C. was added 1.6M solution of n-butyllithium (0.39 mmol). The reaction mixture was stirred for 30 mins at which point acetaldehyde (1.2 mmol) was added. The reaction was stirred for one hour and quenched with ice and allowed to warm to room temperature. The aqueous layer was extracted with methylene chloride and the organic layer was filtered through sodium sulfate. The organic phase was concentrated to yield 1-(2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-yl)ethanol (72 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:28])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[C:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH:26]=2)[CH:11]=1>CO.C(O)(=O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:28])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:11]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1

Procedure:
To a de-gassed solution of 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine (example I-61, 130 mg, 0.27 mmol) in methanol (50 mL) and acetic acid (5 mL) was added 10% Pd/C (50 mg). The solution was degassed and charged with hydrogen for three times, and then was stirred under hydrogen balloon for over night. The mixture was filtered through a celite pad, washed with methanol, and then condensed. The residue was dissolved in ethyl acetate, washed with sat. NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine as a white solid.
Reaction SMILES: N=[CH:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:6]1=[O:20].CC1(C)O[O:24]1>CC(C)=O>[O:21]=[C:3]([CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:6]1=[O:20])[CH:2]=[O:24]
Reactant: N=CC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Product: O=CC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-(3-imino-2-oxopropyl)-3-pyridin-2-yl-1,3-dihydro-2H-benzimidazol-2-one from Step A (54 mg, 0.19 mmol) in acetone (2 mL) at 0° C. was added a solution of dimethyldioxirane (0.02 M in acetone, 9.6 mL, 0.19 mmol). The reaction mixture was stirred for 90 min then concentrated in vacuo to give the title compound in sufficient purity for use in the next step.
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[NH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>CN(C)C=O>[C:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]([CH3:31])[NH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 80.4 %

Procedure:
With ice-cooling and stirring, a solution of tetradecanoyl chloride (2.83 g) in dimethylformamide (25 ml) was added dropwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.34 g) and N,N-dimethylaniline (1.53 g) in dimethylformamide (23 ml) over a period of 10 minutes. After completion of the addition, the mixture was stirred at room temperature for an additional 1.5 hours. The solvent was then distilled off under reduced pressure and 10% hydrochloric acid was added to the residue. The resulting crystalline powder was collected by filtration, washed with water and dried to give 6-(4-tetradecanoylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3.82 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH2:32])=[O:31])[C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH2:32])=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(N)=O)C(=O)NC3=O
Agent: BrB(Br)Br
Product: NC(=O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Yield: 77 %

Procedure:
Demethylation of (118) prepared as described in example 231 with BBr3 using the procedure described in example 80 gave (119) as a yellow/orange powder (77%), mp 319–322° C. 1H NMR δ [(CD3)2SO] 11.06 (br s, 1H), 9.36 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.77 (s, 1H), 7.60–7.55 (m, 2H), 7.52–7.43 (m, 3H), 7.35 (br, 1H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 6.87 (br, 1H), 4.65 (t, J=6.7 Hz, 2H), 2.57 (t, J=6.7 Hz, 2H). FABMS found M+: 435.0833, 433.0828. C23H16ClN3O4 requires 435.0800, 433.0829.
Reaction SMILES: C([N:8]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:9]1[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][CH2:13]2)C1C=CC=CC=1>CCO.[Pd]>[C:18]([N:11]1[CH2:12][CH2:13][CH:14]2[NH:8][CH:9]([CH2:17][CH2:16][CH2:15]2)[CH2:10]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC2CCCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2CCCC(C1)N2
Yield: 96 %

Procedure:
A solution of 10-benzyl-3-Boc-3,10-diazabicyclo-[4.3.1]decane obtained in Example 11 (3.50 g) in EtOH (52 ml) underwent hydrogenation at 45 psi and 30° C. for 19 hours in the presence of Pd/C 10% (1.13 g). At the end the mixture was filtered on celite and the catalyst washed with EtOH. The solution was then concentrated. 2.44 g of a light oil corresponding to the compound 3-BOC-3,10-diazabicyclo[4.3.1]decane (12a) are obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][S:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>>[CH2:7]([C:8]1[C:10]2[CH2:11][S:12][CH2:13][CH2:14][C:15]=2[N:32]=[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])=[CH:24][CH:25]=2)[N:31]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCSCC1C(=O)Cc1ccccc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CSCC3)cc1
Yield: 28 %

Procedure:
4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (74 mg, 28%) was synthesised from 3-(2-phenylacetyl)dihydro-2H-thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 414.2 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])C=O>N1CCCCC1>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:21]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 33.6 %

Procedure:
The title compound was prepared from p-nitrophenylacetic acid (25.0 g, 0.14 mol), and 3,4-dimethoxybenzaldehyde (21.0 g, 0.14 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A, to yield a yellow solid, 13.4 g (0.047 mol, 34%) of the desired product. mp: 133-134° C.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([C:15]#[CH:16])#[N:14]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:15]([C:13]#[N:14])[CH:16]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: C#CC#N
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: N#Cc1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
6.0 g (0.04 mole) of 3-diazooxindole and 2.2 g (0.045 mole) of cyanoacetylene are taken up in benzene (250 ml) and refluxed overnight under N2. The mixture is cooled and the beige-colored precipitates are filtered off. The crude product is dried in a vacuum oven at room temperature for 3 hours. Yield: 5.2 g, m.p. 302°-304°. Percent yield: 65.6.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1)(=O)C.[OH-].[Li+].O>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1nc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 61.4 %

Procedure:
A mixture of 227a (131 mg, 0.20 mmol) and lithium hydroxide.1 water (120 mg, 2.0 mmol) in i-propanol/THF/water (4 mL/4 mL/2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with dichloromethane (3×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 227 as a white solid (75 mg, 62%). MS-ESI: [M+H]+ 611.2. 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.64 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 4.82 (s, 1H), 4.60-4.57 (m, 1H), 4.38-4.36 (m, 1H), 4.29-4.19 (m, 2H), 4.10-4.05 (m, 1H), 3.93-3.90 (m, 1H), 3.80 (s, 3H), 3.60-3.50 (m, overlap, 8H), 2.66-2.54 (m, 2H), 2.48-2.46 (m, 2H), 1.81-1.66 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([CH:18]=[CH:19][CH2:20]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(=O)(O)(O)O>>[C:12]1([CH:18]=[CH:19][CH2:20][O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC=Cc1ccccc1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: O=P(O)(O)O
Product: Cc1cccc(C(=O)OCC=Cc2ccccc2)c1O
Yield: 89.1 %

Procedure:
Using the method of example 1, 15.24 g of 2-hydroxy-3-methylbenzoic acid (0.1 moles), 40.251 g of 3-phenyl-2-propen-1-ol (0.3 moles) of 4.9 g of anhydrous phosphoric acid (0.05 moles) give 23.9 g (yield 89%) of (3-phenyl-2-propenyl)-2-hydroxy-3-methylbenzoate, m.p. 154°-154.5° C.