Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH:24]=[O:25].Cl>C(OCC)(=O)C.O1CCCC1.CCCCCC>[Cl:13][C:14]1[CH:19]=[C:18]([CH:24]([C:23]2[C:22]([F:21])=[CH:29][CH:28]=[CH:27][C:26]=2[F:30])[OH:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=Cc1c(F)cccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OC(c1cc(Cl)ncc1Cl)c1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.60M hexane solution, 2.33 ml, 3.72 mmol) was added to a tetrahydrofuran solution (12 ml) of diisopropylamine (0.520 ml, 3.72 mmol) at −78° C. The resulting mixture was then stirred at −78° C. for 30 minutes. To the reaction mixture was added a tetrahydrofuran solution (2 ml) of 2,5-dichloropyridine (500 mg, 3.38 mmol). The resulting mixture was stirred at −78° C. for 1 hour. A tetrahydrofuran solution (2 ml) of 2,6-difluorobenzaldehyde (395 mg, 3.72 mmol) was then added to the reaction mixture, followed by stirring at −78° C. for 2 hours. To the reaction mixture was added 1N hydrochloric acid (7 ml) and then, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and brine, dried over magnesium sulfate, and concentrated. The solid thus obtained was washed with dichloromethane to give the title compound (746 mg, 2.57 mmol, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[CH:13]=[O:14].CC(=CC)C.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[C:13]([OH:25])=[O:14]
Reactant: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde from Step 1 (492 mg, 0.001726 mol) and 2-methyl-2-butene (300 μL, 0.002832 mol) were stirred in tert-butyl alcohol (2.0 mL). A solution of sodium chlorite (400 mg, 0.003538 mol) and sodium dihydrogenphosphate (450 mg, 0.003751 mol) in water (3.0 mL) was added and reaction mixture was stirred for 12 hours at room temperature. Solvent was evaporated and resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over MgSO4 and evaporated to give the title compound (340 mg, 65.5%) as white solid. This material was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:24][OH:25])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CI.[C:28](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:24][O:25][CH3:28])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:14][CH2:15]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: Cc1ccccc1CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COCC1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (19 mg, 0.80 mmol) in 1.5 ml of THF, at 0° C. was added a solution of N-t-butoxycarbonyl-4-hydroxymethyl-4-(2-methylbenzyl)piperidine (200 mg, 0.63 mmol) in THF (1 ml ). The mixture was allowed to warm to room temperature. To this suspension was added anhydrous DMSO (0.35 ml) and the mixture was heated to 60° C. and stirred 5 hrs until the solution was almost homogeneous. The reaction mixture was allowed to cool to room temperature and methyl iodide (0.070 ml, 1.12 mmol) was added. The resulting heterogeneous mixture was stirred at room temperature for 16 hrs. The reaction mixture was treated with 10% aqueous citric acid and extracted with diethylether. The combined etheral extracts were washed successively with saturated aqueous NaHCO3 brine, dried (MgSO4), and concentrated in vacuo to a yellow gum. Chromatography (SiO2, 9% EtOAc in hexanes) afforded the product as a colorless gum.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[CH:10][O:9][C:8]=2[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:28]([O:13][CH2:12][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[O:9][CH:10]=1)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](CC)(CC)CC)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-phenyl-2-triethylsilyl-4-furanmethanol (345 mg, 1.20 mmol) and triethylamine (182 mg, 1.80 mmol) in tetrahydrofuran (Compound 64, 15 ml) at 0 degrees under argon was added lauroyl chloride (786 mg, 3.60 mmol). This solution was allowed to warm gradually to room temperature. After stirring an additional 2 hours the white precipitate was filtered off. The filtrate was taken up into ethyl ether, washed with saturated ammonium chloride, saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][C:9](=[O:12])[NH:10][O:11][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][C:9](=[O:12])[NH:10][O:11][C:6]=2[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)ONC(=O)C2
Solvent: ClCCl
Product: O=C1Cc2ccc(C(=O)CBr)cc2ON1

Procedure:
0.01 mol of 7-acetylbenzoxazinone, described in Application EP 223,674, is dissolved in 100 cm3 of methylene chloride. 0.011 mol of bromine is added dropwise and with stirring via a dropping funnel, and stirring is maintained for 13 hours. The mixture is filtered and evaporated to dryness and the residue is recrystallized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:24][CH2:23]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([C:14]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[O:35][CH2:36][C:37]([F:38])([F:40])[F:39])[CH2:24][CH2:23]2)=[O:16])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O
Reactant: NCCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described in Example 1, but using 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylic acid instead of 3-phenyl-5-methyl-isoxazole-4-carboxylic acid and Compound 8B instead of Compound 1B. Extraction with diethyl ether followed by purification by flash chromatography (chloroform-2 N ammonia in methanol 100:3) afforded the title compound (38%) as an oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](F)=[CH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)=[CH:18][CH:17]=1)#[N:15]
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: CCN1Cc2cc(C)sc2C(Oc2ccc(C#N)c3ccccc23)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [O:1]([C@@H:12]1[C@@H:29]([OH:30])[C@@H:28]([OH:31])[C@@H:27]([CH2:32][OH:33])[O:26][C@H:13]1[O:14][C@@H:15]1[C@@H:21]([CH2:22][OH:23])[O:20][CH:18]([OH:19])[C@H:17]([NH2:24])[C@H:16]1[OH:25])[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O.CC1OC(OP(OP(OCC2OC(N3C4NC(N)=NC(=O)C=4N=C3)C(O)C2O)(O)=O)(O)=O)C(O)C(O)C1O>>[O:14]([C@@H:15]1[C@@H:21]([CH2:22][OH:23])[O:20][CH:18]([OH:19])[C@H:17]([NH2:24])[C@H:16]1[OH:25])[C@@H:13]1[O:26][C@H:27]([CH2:32][OH:33])[C@H:28]([OH:31])[C@H:29]([OH:30])[C@H:12]1[OH:1]
Reactant: C[C@@H]1O[C@@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](N)C(O)O[C@@H]3CO)O[C@H](CO)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CC1OC(OP(=O)(O)OP(=O)(O)OCC2OC(n3cnc4c(=O)nc(N)[nH]c43)C(O)C2O)C(O)C(O)C1O
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O

Procedure:
Synthesis of Fucα1-2Galβ1-4GlcNH2 βSEt. Galβ1-4GlcNH2 βSEt is prepared as described above and used directly or after isolation as acceptor for a α1-2-fucosyltransferase (e.g. EC 2.4.1.69) reaction with a suitable glycosyl donor such as GDP-Fuc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH:6]=[CH:5]2.[Li]CCCC.Cl[Ge:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[CH3:19][C:14]1[CH:13]=[C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Ge:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:3]=3)[N:8]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(-c2ccc3cc(Br)ccc3n2)c1
Reactant: CC(C)[Ge](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2ccc3cc([Ge](C(C)C)(C(C)C)C(C)C)ccc3n2)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 82.7 %

Procedure:
6-Bromo-2-(3,5-dimethylphenyl)quinoline (5.3 g, 16.98 mmol) and 150 mL anhydrous THF were added in a dry two-necked round bottom flask and cooled down to −78° C. 7.2 mL BuLi (2.5 M) was added dropwise. The solution was stirred for 45 minutes and 4.4 mL (20.37 mmol) of chlorotriisopropylgermane was slowly added with a syringe. The solution was stirred for 4 h and monitored by GC until the reaction was finished. The reaction mixture was purified by column and distillation. ˜6.1 g colorless liquid was obtained after distillation. GC-MS confirmed the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]C)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CO.[OH-].[Na+].Cl>O>[NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(N)c(C(=O)O)nc1Cl
Temperature: 25 °C

Procedure:
A mixture of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate (100 g; 494 mmol), methanol (1 l) and NaOH (6 mol/l in water; 240 mL; 1.44 mol) is refluxed for 3 h. The mixture is allowed to cool to r.t. and then neutralized by addition of hydrochloric acid (6 mol/l in water; approx. 240 mL). Water (200 mL) is added. The precipitate formed is filtered off with suction, washed with water and dried at 60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7]Br)([O-:3])=[O:2].[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])([O-:3])=[O:2]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Cc1ccc(CBr)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1[N+](=O)[O-]
Yield: 32.1 %

Procedure:
Using 0.23 g of 3-nitro-4-methylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.10 g of 2-(3-nitro-4-methylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (30)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH3:42])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH3:42])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (357 mg, 1.23 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (383 mg, 1.23 mmol) according to the general procedure M. Obtained as a light yellow foam (426 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH:43]([NH:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1)=[O:44].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:48]4[CH:49]=[CH:50][CH:51]=[C:46]([NH:45][CH:43]=[O:44])[CH:47]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: O=CNc1cccnc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(NC=O)c3)CS[C@H]12)c1nsc(N)n1
Reaction time: 1.33 h
Yield: 2.9 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-formylaminopyridine [prepared according to the procedure of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 2665 (1972)] (244 mg, 2 mmoles) in DMSO (2 ml) was stirred at room temperature for 1 hour, and poured into ethyl acetate (200 ml). The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg) and sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40°-50° C. for 80 minutes and evaporated to dryness in vacuo. The residue was dissolved in water (40 ml), neutralized with NaHCO3 and then filtered to remove insoluble material. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500/C18 (100 ml), with water and 5% CH3OH, 10% CH3OH, 20% CH3OH and 30% CH3OH. The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the title compound (I-1F) (E) as a tan powder. Mp. >170° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:31]=[C:32]=[O:33])[CH2:28][CH2:29][CH3:30]>O1CCOCC1>[CH2:27]([NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and n-butyl isocyanate (0.014 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.0 (dd), 158.3, 157.9 (dd), 151.1, 141.0, 138.9, 136.1, 135.0, 132.7, 132.1, 128.9, 127.4 (dd), 126.0 (dd), 122.5, 120.9, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 40.6, 33.3, 21.0, 19.7, 14.1
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([OH:26])[C:18]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH2:2][CH2:3][OH:4])[C:18]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCBr
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.2 %

Procedure:
A solution of 2-bromoethanol (0.034 g) in DMF (1 ml) was added to a stirred mixture of ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 36, 0.1 g) and cesium carbonate (0.127 g) in DMF (1 ml). The resultant mixture was stirred at room temperature for 3 hours. Further 2-bromoethanol (0.017 g) was added and the mixture was stirred at room temperature for a further 3 days. Cesium carbonate (0.085 g) and 2-bromoethanol (0.024 g) were added and the mixture was stirred for 1 hour. 2-Bromoethanol (0.015 g) was added and the mixture was stirred for a further 1 hour. The resultant mixture was partitioned between ethyl acetate and water and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-50%. The product was again purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 25-30% to give ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(2-hydroxyethoxy)benzoate (0.037 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].C1CCC(N=C=NC2CCCCC2)CC1.[C:42]([O:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][C:56](O)=[O:57])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[C:42]([O:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][C:56]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=2[CH:16]=1)=[O:57])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCC(=O)O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)CNC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Reaction time: 5 h
Yield: 61 %

Procedure:
A mixture of N-acetyl-colchicinol (0.357 g; 1 mmol), DCCI (0.248 g; 1.2 mmol), DMAP (0.025 g; 0.2 mmol) and (7) (0.246 g; 1 mmol) in dichloromethane (7 ml) was stirred under argon atmosphere for 5 hours. After removal of the insoluble material by filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (92/8) to give (4) as a foam.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1>>[CH3:23][C:24]1[N:25]=[C:26]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:27][CH:28]=1
Reactant: Cc1cscn1
Reactant: CC(C)(O)c1cccc(Cn2nnc3c(Cl)nc(N)nc32)n1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C(C)(C)O)n2)n1

Procedure:
This is prepared from 7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine and 4-methylthiazole by the method of Example 38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C1([C@H](CO)N)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc([C@H]2CCCCN2)cc1
Agent: N[C@@H](CO)c1ccccc1
Product: Fc1ccc([C@@H]2CCCCN2)cc1

Procedure:
(S)-2-(4-Fluoro-phenyl)-piperidine (0.31 g) was prepared by analogous methods to those used in the preparation of (R)-2-(4-fluoro-phenyl)-piperidine but starting from (R)-(−)-2-phenylglycinol. LCMS m/z 180.12 [M+H]+ R.T.=1.75-2.1 min (Analytical Method 6), which was used in the synthesis of EE-50.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12](S(C)(=O)=O)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24]>>[C:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=4)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2ccccc2)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2ccccc2)C3)cc1
Temperature: 175 °C
Yield: 10.1 %

Procedure:
A mixture of 100 mg (0.31 mmol) of 3-phenyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 170-180° C. for 10 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residual solid was purified by crystallisation from cyclohexane/ethyl acetate to give 14 mg (10%) of 3-phenyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 141-144° C.