Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13]C)[C:10]([CH3:12])([CH3:11])O2)=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:10]([CH3:11])([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: COC1(c2ccc(F)cc2)OC1(C)C
Reactant: CN1CCNCC1
Product: CN1CCN(C(C)(C)C(=O)c2ccc(F)cc2)CC1
Temperature: 125 °C

Procedure:
29.43 g (0.15 mol) of 2-(4-fluorophenyl)-3,3-dimethyl-2-methoxyoxirane and 60.1 g (0.60 mol) of 1-methylpiperazine are brought together, and the mixture is heated to about 125° C. After 8 hours it is cooled down and the excess 1-methylpiperazine is distilled off. The residue is taken up in toluene, and the mixture is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and concentrated. The residue, 29.4 g of a cognac-coloured oil, is then further reacted.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1)C(OCC)=O)C.[OH-].[Na+]>CO>[Cl:17][C:16]1[C:11]([CH2:5][C:4]([OH:19])=[O:3])=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ncc(Cl)cc1Cl
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 2-(3,5-dichloro-pyrid-2-yl)-malonic acid diethyl ester (118.5 g) (prepared as described in WO 07/101859) in methanol (1 ml) was added aqueous sodium hydroxide (47 g dissolved in 300 ml water). The reaction mixture was heated to 80° C. for 1 hour. The methanol was evaporated and the pH of the aqueous phase adjusted to pH 4 by addition of glacial acetic acid and then extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to give (3,5-dichloro-pyrid-2-yl)-acetic acid as an off-white solid (50 g). 1H-NMR (400 MHz, CDCl3): 4.04 (s, 2H), 7.81 (d, 1H), 8.45 (d, 1H) ppm.
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1)[C:6](=[O:8])[O-:7])(C)C.C(O)(=O)C.[CH3:26][C:27](N(C1CCNCC1)C(=O)[O-])([CH3:29])[CH3:28]>[Pd].C(O)C>[NH:12]1[CH2:11][CH2:10][CH:9]([NH:5][C:6](=[O:8])[O:7][C:27]([CH3:29])([CH3:28])[CH3:26])[CH2:14][CH2:13]1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCNCC1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
A mixture of 1,1-dimethylethyl[1-(phenylmethyl)-4-piperidinyl]carbamate (0.355 mole), 10% palladium-on-carbon (10.0 g.) in 43 ml. of acetic acid and 90 ml. of ethanol was hydrogenated under low pressure at room temperature for a 96 hr. period. The reaction mixture was filtered and concentrated in vacuo. Residual oil was taken up in chloroform, washed with 20% aqueous sodium carbonate solution and the aqueous phase extracted with additional chloroform. The combined chloroform extracts were dried (MgSO4) and evaporated in vacuo to afford 64.2 g. (90%) of 1,1-dimethylethyl4-piperidinylcarbamate, m.p. 153°-157°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18][OH:19])=[CH:5]2>C(Cl)Cl.O>[CH3:13][S:14]([O:19][CH2:18][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)CCCn1c(CO)cc2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)CCCn1c(COS(C)(=O)=O)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-chloro-1-(3-methanesulfonyl-propyl)-1H-indol-2-yl]-methanol (0.60 g, 2.0 mmol) and TEA (0.60 g, 6 mmol) in 20 mL of DCM was added MsC1 (0.45 g, 4 mmol) in an ice bath. The reaction mixture was stirred at RT for 3 hours. The resulting mixture was diluted with 10 mL of water and then extracted with DCM (10 mL×3). The combined organic layers were dried over Na2SO4, and then concentrated in vacuo to afford the crude {5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl methanesulfonate which was used in the next step without any purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][C:26]=1[O:33][CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[OH:30])=[CH:27][C:26]=1[O:33][CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 25.0 g of 3-bromoquinoline is dissolved in 200 ml of dry ether and cooled to -60°. At this temperature there are added dropwise within 15 minutes 75.1 ml of a 1.6 molar solution of n-butyllithium, whereupon the mixture is stirred for 10 minutes. A solution of 26.5 g of vanillin benzyl ether in 250 ml of dry ether is added dropwise thereto at -60°, the mixture is subsequently stirred at room temperature for 3 hours, poured into about 1.5 l of ice-water and extracted three times with 600 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 1 kg of silica gel with methylene chloride/ethyl acetate (1:1). The crystalline crude product obtained is recrystallized from ethyl acetate. There is obtained α-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in the form of colourless crystals of m.p. 124°-125°.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[N:29]1>>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])=[N:29]1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: Cn1ccc(S(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)n1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 1-methyl-1H-pyrazole-3-sulfonyl chloride Off-white solid. MS (ESI): 459.3 (MH+)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[S:12][C:13]=1[CH2:14]O.C(N(S(F)(F)[F:32])CC)C.O>C1(C)C=CC=CC=1>[F:32][CH2:14][C:13]1[S:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[N:10][C:9]=1[CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: FCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (7 mL) of the compound (500 mg, 1.3 mmol) obtained in Example 89c in toluene was added diethylaminosulfur trifluoride (DAST) (650 mg, 4.0 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (350 mg, 70%) as a colorless oil.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>C1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN1CCCC1=N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cccc(Cl)c1

Procedure:
Assuming 100% conversion, 2.94 g. (0.03 mole) of 2-imino-1-methylpyrrolidine is liberated from its Hcl salt using the calculated amount of 50% NaOH (2.4 g., 0.03 mole) and extracting into benzene. The benzene solution is dried over K2CO3. To this solution, 4.6 g. (0.03 mole) of m-chlorophenylisocyanate dissolved in anhydrous benzene is added dropwise with stirring. Solid forms and the mixture is stirred at room temperature overnight. The solid, 1-m-chlorophenyl-3-(1-methyl-2-pyrrolidylidene)urea, is collected, m.p. = 135°-136° C. A second crop is collected from the mother liquors after taking it to dryness, triturating with hot CHCl3, and filtering off that which does not dissolve. The two crops are combined and recrystallized from methanol-ether to give the pure product, m.p. = 137°-138° C.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([N:25]4[CH2:28][CH:27]([S:29][C:30]5[C@H:31]([CH3:54])[C@@H:32]6[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]6[C:34]=5[C:35]([O:37]CC5C=CC([N+]([O-])=O)=CC=5)=[O:36])[CH2:26]4)[S:23][CH:24]=3)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O>O1CCCC1>[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([N:25]3[CH2:28][CH:27]([S:29][C:30]4[C@H:31]([CH3:54])[C@@H:32]5[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]5[C:34]=4[C:35]([OH:37])=[O:36])[CH2:26]3)[S:23][CH:24]=2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N[C@@H]5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)cs4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)N[C@@H]5CCNC5)cs4)C3)[C@H](C)[C@H]12
Reaction time: 4.5 h
Yield: 40.3 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (410 mg, 0.508 mmol) (obtained as described in Example 58(1)) in a mixture of tetrahydrofuran (21 ml) and distilled water (21 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (410 mg) at room temperature for 4.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate and distilled water. The mixture was shaken in a separatory funnel. The aqueous layer was separated, washed with the above-mentioned mixed solvent and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→distilled water:acetonitrile (76:24)) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-((3R)-pyrrolidin-3-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (101 mg, yield 41%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.O.[OH-].[Li+]>C1COCC1.O>[C:12]([O:11][C:9]([NH:8][CH2:7][CH2:6][CH:5]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:4]([OH:23])=[O:3])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)cc1

Procedure:
The 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-butyric acid ethyl ester (5.61 g, 16.4 mmol) was dissolved in 40 mL of THF and 10 mL of water, then cooled to 0° C. The mixture was treated with lithium hydroxide mono-hydrate (1.38 g, 32.8 mmol) to afford a yellow solution. The ice-bath was removed, and the mixture was allowed to stir overnight to room temperature. The reaction mixture was concentrated to approximately 15 mL and diluted with water. The aqueous was washed with ethyl acetate (discarded) then treated with 3M HCl solution until acidic (pH=2-3). The resulting white precipitate was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-butyric acid as a colorless oil. The material was re-dissolved in a minimal amount of warm (60° C.) hexanes and re-concentrated to afford the pure desired product as a white foam. 1H NMR (CDCl3, 400 MHz) δ 12.05-9.51 (brs, 1H), 7.31-7.25 (m, 4H), 4.59 (brs, 1H), 3.61 (d, J=7.6 Hz, 1H), 3.14 (brs, 2H), 2.28 (m, 1H), 1.92 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:24]([O:26]CC)=[O:25])[C:18]2[CH:19]=[CH:20][NH:21][C:22]=2[CH:23]=1)=[O:13].[OH-].[Na+].Cl>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:24]([OH:26])=[O:25])[C:18]2[CH:19]=[CH:20][NH:21][C:22]=2[CH:23]=1)=[O:13]
Reactant: CCOC(=O)c1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc2[nH]ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cc(C(=O)O)c2cc[nH]c2c1)c1c[nH]c2ccccc2c1=O
Temperature: 50 °C

Procedure:
Ethyl 6-(4-oxo-1,4-dihydroquinoline-3-carboxamido)-1H-indole-4-carboxylate (6 mg, 0.02 mmol) was suspended in 1 M NaOH (400 μL, 0.40 mmol) and heated to 50° C. for 30 min. The clear brown solution was diluted with water (1 mL) and acidified with 1N HCl (450 uL). The solution was washed with water (3×1 mL), and purified via reverse phase HPLC (75% acetonitrile/water) to give 6-(4-oxo-1,4-dihydroquinoline-3-carboxamido)-1H-indole-4-carboxylic acid. LC/MS: m/z 347.8 (M+H)+ at 1.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([CH:15]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:4]1)=O.[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12>>[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=5)[CH2:6][N:5]([C@H:15]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:16]([OH:18])=[O:17])[CH2:4]4)[CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12
Reactant: O=C[C@H]1CN(C(C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1cccc(F)c1
Reactant: c1cc(CCCC2CCNCC2)c2nonc2c1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cccc4nonc34)CC2)[C@@H](c2cccc(F)c2)C1

Procedure:
The title compound was prepared from 30 mg (0.071 mmol) 2-(R)-((3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 102, Step A) and 4-(3-(benzofurazan-4-yl)propyl)piperidine. HCl (from EXAMPLE 117, Step B) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: HPLC (Zorbax SB-C8 4.6 mm×7.5 cm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN over 7.5 min, hold for 45 sec, 2.25 mL/min, 220 nm): Retention Time: 4.31 min; ESI-MS 563.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: O
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
As shown in Scheme 3 above, a mixture of 2,6-dichloropurine (1.90 g, 10 mmol) and morpholine (2.34 g, 30 mmol) in water (25 mL) was heated under reflux for 15 min. Solidified reaction mixture was cooled to room temperature. Solid was filtered out and washed with water, methanol and ether. The 2-chloro-6-morpholin-4-yl-9H-purine was obtained in 96% yield (2.30 g). A mixture of 2-chloro-6-morpholin-4-yl-9H-purine (1.92 g, 8 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine (4.35 g, 24 mmol) in sealed tube and under nitrogen was stirred at 190-195° C. for 1 hour. The reaction mixture turned to clear solution initially and then formed a slurry. The reaction mixture was cooled to room temperature diluted with methanol (8 mL) and the solid was collected by filtration, washed with methanol and Et2O and dried to afford 2.30 g (74% yield) of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl)amine.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@@H]1C
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@@H](C)C1

Procedure:
Starting from N-[(1S*,2S*,4S*)-4-amino-2-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f63) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O1CCOCC1.[O:7]=[C:8]1[NH:12][C:11](=[O:13])[C:10](=[CH:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][CH2:21][C:22]3[NH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[S:9]1.II.[NH4+].[Cl-]>CO>[O:7]=[C:8]1[NH:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][CH2:21][C:22]3[NH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[S:9]1
Reactant: COc1ccc2[nH]c(CCOc3ccc(C=C4SC(=O)NC4=O)cc3)cc2c1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2[nH]c(CCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2c1
Temperature: 50 °C
Yield: 39.8 %

Procedure:
Under an argon atmosphere, 70 ml of 1,4-dioxane were refluxed in a suitably equipped flask, 1 g of the product of step (b) was added, to give a clear solution after about 30 minutes, which was cooled to 50° C., followed by addition of 70 ml methanol, this flask being kept at 50° C. In a second flask, there was placed under an argon atmosphere, 1 g Mg turnings covered with methanol; two crystals of iodine were added, and after foaming began the mixture was stirred until the iodine color disappeared. The contents of the first flask were then poured into the second flask, and the temperature raised to 64° C. A further 1.4 g Mg turnings were added over 4 hours, and the reaction mixture was allowed to reflux for 5 days, until conversion as determined by UV was >95%. The mixture was cooled and poured into 500 ml of 20% NH4Cl solution extracted with 3×200 ml dichloromethane, washed with 5% aq. citric acid and water and rotoevaporated to give a solid which was dissolved in methanol and crystallized at −18° C. There were obtained 400 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:28].C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:28])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2cc(C)c(OCCO)c(C)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc(C)c(OCCOS(C)(=O)=O)c(C)c2)cc1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.32 mL) was added to an ice-cooled mixture of ethyl 4′-(2-hydroxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate (1.0 g) and triethylamine (0.67 mL) in methylene chloride (30 mL) with stirring, and the mixture was stirred at room temperature for 1 hr. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-(2-methanesulfonyloxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate (1.46 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[CH3:13][C:4]1([CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[C:3]1=[O:14]
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(C)=CCC1(C)CCCC(C)C1=O

Procedure:
This compound was prepared as a mixture of 2 isomers by reduction of 2,6-dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone with Na2S2O4. 1H-NMR (400 MHz, CDCl3): 5.15-5.12, 4.94-4.89 (2m, 1H, 2′-H), 2.69-1.26 (m, 9H), 1.70, 1.68 (2s, 3H, 3′-CH3), 1.61, 1.60 (2s, 3H, 4′-H), 1.47, 0.98 (2s, 3H, 6-CH3), 1.00, 0.99 (2d, J=6.8 Hz, 2-CH3) ppm. MS (EI): 194 (M+, 19), 179 (17), 126 (100), 111 (52), 95 (26), 69 (72), 55 (39), 41 (56). IR (ATR): 2967m, 2929s, 2868s, 1705vs, 1452s, 1376m, 995m cm−1.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19]1([CH3:37])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[C:25]2[CH:24]=[C:23]([C:31](=[CH2:36])[C:32](OC)=[O:33])[CH:22]=[CH:21][C:20]1=2.C(C(C(C([O-])=O)O)O)([O-])=O.[Na]>ClCCl>[CH3:18][C:19]1([CH3:37])[CH2:28][CH2:27][C:26]([CH3:29])([CH3:30])[C:25]2[CH:24]=[C:23]([C:31](=[CH2:36])[CH2:32][OH:33])[CH:22]=[CH:21][C:20]1=2
Reactant: C=C(C(=O)OC)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 1M diisobutylaluminium hydride solution in toluene (2.78 ml, 2.78 mmol) is added at 78° C., dropwise, to a solution of methyl 2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)acrylate (310 mg, 1.14 mmol) in dichloromethane (3 ml). The solution is stirred for 1 h at 0° C., then treated with a solution of double tartrate of sodium [lacuna] and filtered through silica.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:47][C:48]1[N:53]2[CH:54]=[C:55]([NH2:57])[N:56]=[C:52]2[C:51]([N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)=[N:50][CH:49]=1>C(Cl)Cl>[Br:47][C:48]1[N:53]2[CH:54]=[C:55]([NH:57][C:1]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[O:13])[N:56]=[C:52]2[C:51]([N:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:50][CH:49]=1
Reactant: Nc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cn2c(Br)cnc(N3CCOCC3)c2n1)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinaldic acid (236 mg, 1.36 mmol) in DCM (10 mL) were added HATU (519 mg, 1.36 mmol) and DIEA (201 μL, 1.15 mmol) at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. and treated with compound 21b (313 mg, 1.04 mmol). The resulting mixture was stirred at rt overnight. The solids formed were collected by filtration, and the organic phase was washed with saturated aqueous NH4Cl (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (9:1 DCM/EtOAc) to give compound 21c. Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H17BrN6O2: 453.0 (M+H). Found 453.1.