Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COCCNc1ccc(C(=O)c2cc(Br)cnc2N)cn1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCNc1ccc(C(=O)c2cc(-c3ccc(OC)c(OC)c3)cnc2N)cn1
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To (2-amino-5-bromo-pyridin-3-yl)-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone, 3,4-dimethoxyphenylboronic acid (1.3. equiv.) and dichlorobis (triphenylphosphino)palladium (ii) (6 mol %) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water, and a 2 m solution of sodium carbonate in water to achieve an overall concentration of the starting material of 0.10 m. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone as a yellow solid (74% yield). 1H NMR (DMSO-d6): δ 8.49 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.58 (broad s, 1H), 7.14 (s, 1H), 7.05 (m, 3H), 6.98 (d, J=8.5 Hz, 1H), 6.59 (d, 9.0 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.50 (broad t, J=5.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.26 (s, 3H); HPLC/MS m/z: 409.2 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])[CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[O:44][CH3:45]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.20 mmol) (Aldrich), followed by the addition of 5-isocyanato-1,2,3-trimethoxy-benzene (33 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide (Yield 35 mg, 44.9%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[F-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:4]2[C:3]=1[N:14]([CH:15]1[CH2:17][CH2:16]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(Br)c1F
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate (1.35 g) in anhydrous dimethylformamide (5 ml) was added sodium fluoride (0.23 g). The mixture was stirred at 97°-108° C. for 7.5 hours, and then poured into ice water (50 ml) and the resulting precipitate was collected by filtration, washed with water and recrystallized from dichloro-methane-n-hexane to give the title compound (1.05 g), mp 163.5°-168° C. as colorless prisms.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])=[N:13]2.Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>C(OCC)(=O)C.C1CCCCC1>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:11]1[C:10]([O:9][CH3:8])=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])=[N:15][C:16]=2[NH2:19]
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCBr
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 18 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane with purification on an aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient.
Reaction SMILES: [CH2:1]([N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=2)[C:27]1=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:7]1=[O:25]>C(Cl)(=O)C>[CH2:5]([N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:29](=[O:33])[CH3:30])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=2)[C:7]1=[O:25])[CH2:4][CH2:3][CH2:2][CH2:1][N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:9](=[O:13])[CH3:10])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=2)[C:27]1=[O:45]
Reactant: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)C1(C)C
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(N2C(=O)N(CCCCCN3C(=O)N(c4ccc(NC(C)=O)c(C(F)(F)F)c4)C(=O)C3(C)C)C(C)(C)C2=O)cc1C(F)(F)F
Temperature: 23 °C
Yield: 52 %

Procedure:
The compound of Example 8 (161 mg, 0.25 mmol) is mixed under an argon atmosphere with acetyl chloride (10 ml) and stirring is maintained for 15 hours at 23° C. The reaction mixture is then evaporated to dryness (entrainment with toluene) and the residue obtained is purified on a silica column (eluent: CH2Cl2/EtOH from 99/1 to 90/10). After evaporation, the expected compound is obtained in the form of a cream coloured foam with a yield of 52%.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](S(C2C=CC=CC=2)(=O)=O)[N:8]=1>C1COCC1>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[N:8]=1)#[C:2][CH3:3]
Reactant: CC#C[Mg]Br
Reactant: O=S(=O)(c1ccccc1)c1cccc(F)n1
Solvent: C1CCOC1
Product: CC#Cc1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.06 mol of propynylmagnesiumbromide and 25 ml of THF is added at 40°-40° C. [sic] to a mixture of 0.05 mol of 2A and 15 ml of THF. The mixture is stirred at room temperature for 2 hours and subjected to customary work-up. The unpurified product is processed further as in 10B.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[O:11])=[O:9])=[O:5])[CH3:2].Br([O-])(=O)=O.[Na+]>O.C(OCC)(=O)C.[Cl-].[Na+].O.O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]([C:10]([NH:12][CH2:13][C:14](=[O:16])[CH3:15])=[O:11])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)C(=O)NCC(C)O
Agent: Cl[Ru](Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CNC(=O)C(=O)NCC(C)=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of N-(ethoxycarbonyl-methyl)-N′-(2-hydroxy-1-propyl)oxamide (8.0 g, 34.5 mmol), as prepared in the preceding step, in water (50 mL) under nitrogen at 50° C. was added ruthenium (III) chloride hydrate (75 mg, 0.35 mmol). The reaction flask was removed from the heating bath, and a solution of sodium bromate (5.2 g, 34.5 mmol) in water (40 mL) was added dropwise. The reaction mixture was allowed to cool to room temperature, and then diluted with ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate (2×), then saturated with sodium chloride and extracted again (×2). The combined ethyl acetate layers were washed with brine, dried over Na2SO4, and treated with activated carbon. Evaporation of the solvent and drying under high vacuum provided the title compound as a white solid (7.3 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.99 (s(br), 1H), 7.84 (s(br), 1H), 4.24 (q, 2H, J=7.1 Hz), 4.19 (d, 2H, J=5.2 Hz), 4.10 (d, 2H, J=5.7 Hz), 2.24 (s, 3H), 1.30 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[S:42][N:41]=[C:40]([C:43](=[N:67][O:68][CH3:69])[C:44]([NH:46][C@@H:47]2[C:65](=[O:66])[N:49]3[C:50]([C:62]([O-:64])=[O:63])=[C:51]([CH2:54][N+:55]4([CH3:61])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:52][S:53][C@H:48]23)=[O:45])[N:39]=1.C[Si](C)(C)NC(=O)C.C(OC(C)C)(C)C>CS(C)=O>[NH2:37][C:38]1[S:42][N:41]=[C:40]([C:43](=[N:67][O:68][CH3:69])[C:44]([NH:46][C@@H:47]2[C:65](=[O:66])[N:49]3[C:50]([C:62]([O-:64])=[O:63])=[C:51]([CH2:54][N+:55]4([CH3:61])[CH2:60][CH2:59][N:58]([C:9]([C:4]5[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][N:5]=5)=[O:11])[CH2:57][CH2:56]4)[CH2:52][S:53][C@H:48]23)=[O:45])[N:39]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Reactant: O=C(O)c1cc(O)c(O)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)N[Si](C)(C)C
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a solution of 4,5-dihydroxy-2-pyridinecarboxylic acid (3.1 g) and 1-hydroxybenzotriazole (4.0 g) in dimethyl sulfoxide (30 ml) was added N,N'-dicyclohexylcarbodiimide (6.2 g). After being stirred at room temperature for 1 hour, the reaction mixture was added to a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (10.0 g) and N-trimethylsilylacetamide (3.0 g) in dimethyl sulfoxide (50 ml), and the stirring was continued for 30 minutes. The mixture was added dropwise to diisopropyl ether (1.5 l) and the resulting precipitate was collected by filtration, which was dissolved in an aqueous solution of sodium bicarbonate, After the insoluble material was filtered off, the filtrate was adjusted to pH 3.0 with 1N hydrochloric acid and subjected to column chromatography on "Diaion HP-20" with 5% aqueous isopropyl alcohol as an eluent. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (0.5 g).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31]([O:38][C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:45])[CH:40]([NH:41][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH:42]([CH3:44])[CH3:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)NC(C(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.8 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.417 g (1.1 mmol) of L-valine benzyl ester p-toluenesulfonic acid salt, 0.227 g (1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a glassy solid (0.20 g).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([C:33]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:23]=[CH:24][CH:25]=[CH:26]5)=[O:34])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2ncccc2c1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol), quinoline-6-carboxylic acid (0.11 g, 0.63 mmol), 1-hydroxybenzotriazole (0.10 g, 0.74 mmol) were dissolved in N,N-dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.78 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the title compound (0.13 g, yield 57%).
Reaction SMILES: [Mg].C[O-].[Mg+2].C[O-].[CH2:7]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26](O)(=[O:28])C>CO.C1(C)C=CC=CC=1>[CH2:7]([C:19]1[CH:20]=[C:21]([CH:26]=[O:28])[C:22]([OH:25])=[CH:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium turnings (12.2 g, 0.50 mole), methanol (133 ml), toluene (60 ml), and magnesium methoxide solution (10 ml of an 8% w/w solution of magnesium methoxide in methanol). The reaction mixture was heated to 45° C. at which point the magnesium dissolution became vigorous. The temperature of the reaction mixture was maintained between 45 and 55° C. Para-dodecyl phenol (128.0 g, 0.50 mol) dissolved in toluene (125 ml) was added in one portion to the reaction mixture which was then maintained at 65° C. for one hour. Glacial acetic acid (30.1 g, 0.50 mol) was added over a 1 hour period, while maintaining the reaction mixture at reflux (65-66° C.). The reaction flask was then rigged for fractional distillation and the methanol/toluene azeotrope was distilled off until an internal temperature of 85° C. was reached. A total of 117 g of distillate, assaying 65% methanol and 35% toluene, was collected. Toluene (130 g) was added to the reaction mixture in one portion. Paraformaldehyde (45.0 g) slurried in toluene (90 g) was then added over a 90 minute period. During the addition, the reaction mixture was maintained at a temperature of 85-90° C. allowing a continuous distillation of the volatile reaction by-products. When the paraformaldehyde addition was complete, the reaction mixture was maintained at 90° C. for an additional 90 minutes. The reaction mass as then cooled to 35° C. and 500 ml of 20% v/v sulfuric acid was added. The hydrolysis mass was then stirred for an additional 45 minutes. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-dodecyl salicylaldehyde. A 65% yield was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH2:6][CH2:5][C:4]1=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1C(=O)CCNc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN1CCCNc2ccccc21

Procedure:
1-Ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 23A (1.7 g, 8.94 mmol) was reduced with lithium aluminium hydride according to the procedure in Example 15A; yield 1.55 g (98%).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH2:44][C@@:42]2([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[OH:45])[C@@:37]2([CH:46]=[O:47])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:48][CH3:49])=[CH:33][C:34]=1[CH2:35][CH2:36]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH2:44][C@@:42]2([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[O:45][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C@@:37]2([CH:46]=[O:47])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:48][CH3:49])=[CH:33][C:34]=1[CH2:35][CH2:36]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@@]2(C)[C@H]1CC[C@@H]2O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]21
Temperature: 25 °C
Yield: 93.2 %

Procedure:
4.46 g of imidazole and 9.66 g of tert-butyldimethylsilyl chloride are added in succession at 0° C. to a solution of 12.49 g of alcohol 5 in 160 ml of N,N-dimethylformamide and stirred at room temperature until the reaction is completed. For working-up, the aqueous phase is mixed with water and extracted several times with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography (cyclohexane/ethyl acetate) and yields 14.36 g of silyl ether 6 as a yellow, viscous mass (GC-MS: m/z theor.: 602, pract.: 602).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:51])=[C:17]([N:19]([CH2:36][C:37]([N:39]([N:41]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[C:46]([F:50])[CH:47]=4)[CH2:42]3)[CH3:40])=[O:38])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH3:28])=[O:22])[CH:18]=2)[N:9]=1.[C:52]([O-:55])(=[O:54])[CH3:53].[Na+].C(OCC)(=O)C.CCCCCC>O>[C:52]([O:55][CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:51])=[C:17]([N:19]([CH2:36][C:37]([N:39]([N:41]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[C:46]([F:50])[CH:47]=4)[CH2:42]3)[CH3:40])=[O:38])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH3:28])=[O:22])[CH:18]=2)[N:9]=1)(=[O:54])[CH3:53]
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(-c2noc(CCl)n2)ccc1C)C(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(-c2noc(COC(C)=O)n2)ccc1C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To N,N-dimethylformamide (40 ml) were added the compound (3.39 g, 5.15 mmol) of step A and sodium acetate (1.37 g, 16.7 mmol), and the mixture was stirred at 60° C. for 5 hr. After cooling to room temperature, ethyl acetate-hexane=1:1 mixed solvent and water were added to the reaction mixture, and the organic layer was extracted. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (3.15 g, yield 90%) as a pale-yellow amorphous solid
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:42])[NH:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)[N:18]=3)[CH2:10]1.C([O:46][CH2:47][C:48](Cl)=[O:49])(=O)C.C[O-].[Na+].CO>C(Cl)Cl.CO.O1CCCC1.C(Cl)Cl.CO>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([N:11]4[CH2:12][CH2:13][N:14]([C:47](=[O:46])[CH2:48][OH:49])[C:9]([CH3:42])([CH3:8])[CH2:10]4)[N:16]3[CH2:37][C:38]([F:41])([F:39])[F:40])=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:20]=2)=[CH:31][N:32]=1
Reactant: CC1(C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: CC(=O)OCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Triethylamine (63.1 μl, 0.45 mmol) was added to a methylene chloride solution (3.0 ml) of 5-[8-(3,3-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (101.3 mg, 0.21 mmol) at room temperature followed by the addition of acetoxyacetyl chloride (27.4 μl, 0.25 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 1 hour followed by the addition of triethylamine (17.2 μl, 0.13 mmol) and acetoxyacetyl chloride (6.8 μl, 0.06 mmol) with ice cooling and the resulting mixture was further stirred at room temperature for 16 hours. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (94.1 μl, 0.41 mmol) was added to a methanol-tetrahydrofuran (3:1) mixture solution (8.0 ml) of the resulting residue, and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into methylene chloride and washed with water and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (94.2 mg, 83%) as a pale yellow solid.