Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:7][C:6]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]=2[N:4]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>O1CCCC1>[CH3:20][N:4]1[CH:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8][CH:6]2[N:7]=[C:3]1[C:2]([F:1])([F:18])[F:19]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2nc(C(F)(F)F)[nH]c2C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(C(F)(F)F)=NC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-(trifluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (90 mg) in tetrahydrofuran (3 mL) at −20° C. was added potassium bis(trimethylsilyl)amide solution (0.714 mL 0.5M in toluene). The mixture was stirred at −20° C. for 30 min at which point methyl iodide (0.04 mL) was added and the reaction slowly was warmed to ambient temperature over 1 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL). The phases were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and the resulting product used without further purification. LC/MS 292.2 (M+1).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]([CH2:42][CH2:43][CH2:44]O)[CH2:30][N:31]([CH3:41])[S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:27][CH:28]=1>C(#N)C>[Br:1][CH2:44][CH2:43][CH2:42][CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[CH2:30][N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CN(CC(CCCO)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CN(CC(CCCBr)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Bromine was added to a solution of triphenylphosphine (41.4 mg, 0.158 mmol) in 0.50 mL of acetonitrile until the red color persisted, and a small additional quantity of triphenylphorsphine was then added to consume the excess bromine. A solution of N-(2-(3-chlorophenyl)-5-hydroxypentyl)-N-methylbenzenesulfonamide (38.7 mg, 0.105 mmol) in 0.3 mL of acetonitrile was added. After stirring for 1 h, the reaction was quenched by a solution of sodium sulfite (20 mg) dissolved in 1.0 mL of water. The mixture was diluted with 15 mL of sodium bicarbonate and extracted with 2×20 mL of ethyl acetate. The organic layers were washed with 15 mL of brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with of 10% ethyl acetate in hexane to give 23 mg the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([CH3:19])([S:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:5].C(N(CC)CC)C.[CH3:27][OH:28]>>[Cl:1][CH2:2][CH2:3][C:4]([CH3:19])([S:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:28][CH3:27])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:5]
Reactant: CO
Reactant: CC(C)(CCCl)Sc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SC(C)(C)CCCl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-2-methylbutan-2-ylthio)-3-nitrobenzoyl chloride (3.48 g, 10.8 mmol) in MeOH (200 mL) was added triethylamine (15.05 mL, 108 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The resulting paste was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (75 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH2:9][CH2:10][CH3:11].[C:14]1(/C=C/C(=O)C)[CH:19]=CC=C[CH:15]=1>>[NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[C:9]1[CH:19]=[CH:14][CH:15]=[CH:11][CH:10]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(=O)/C=C/c1ccccc1
Product: Cc1cc(-c2ccccc2)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 5) using (3E)-4-phenyl-3-buten-2-one (20 g, 137 mmol). LCMS E-S(M+H)=215.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.2-12.3 (br s, 1H), 7.88-8.00 (br s, 3H), 7.43-7.51 (m, 3H), 7.29-7.38 (m, 2H), 6.08 (s, 1H), 3.67-3.70 (m, 2H), 2.23 (s, 3H).
Reaction SMILES: O.O.O.[NH2:4][CH2:5][CH2:6][CH2:7][C:8]([P:14](=[O:17])([OH:16])[OH:15])([P:10](=[O:13])([O-:12])[OH:11])[OH:9].[Na+].[OH-].[Na+].[C:21]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>O.CN(C)C1C=CN=CC=1.[I-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.C(OCC)C>[C:21]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([CH:5]([NH2:4])[CH2:6][CH2:7][C:8]([P:14](=[O:15])([OH:16])[OH:17])([P:10](=[O:11])([OH:12])[OH:13])[OH:9])=[O:28])(=[O:23])[CH3:22]
Reactant: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1C(=O)C(N)CCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.18 g (9.8 mmoles ) of sodium trihydrogen 4-amino-1-hydroxybutylidenediphosphonate trihydrate are added in 30 ml of water to 1.8 g (45 mmoles) of sodium hydroxide, 100 mg of p-dimethylaminopyridine and 200 mg of tetrahexylammonium iodide. The resulting solution is cooled to 0° C., and added with 2.03 g (10.2 mmoles) of 2-acetoxybenzoic acid chloride dissolved in 10 ml of diethyl ether. The reaction mixture is stirred for 2 hours at room temperature, then it is extracted with ethyl ether and the aqueous solution is acidified with concentrated HCl under stirring, with cooling. [4-(2-Hydroxybenzoyl)-amino-1-hydroxybutylidene]-diphosphonic acid precipitates, which is filtered, washed and dried at 70° C. and transformed into the title product by means of acetylation with acetic anhydride.
Reaction SMILES: Cl[C:2]1[C:3]2[C:19]([CH3:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:17][C:4]=2[N:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:7]=1.NC(N)=[S:28].C(O)C>O>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[CH2:8][C:6]1[NH:7][C:2](=[S:28])[C:3]2[C:19]([CH3:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:17][C:4]=2[N:5]=1
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)nc(Cl)c2c1C
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=S)c2c1C
Temperature: 25 °C
Reaction time: 35 h
Yield: 94 %

Procedure:
A mixture of 1.23 g of ethyl 4-chloro-2-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate, 594 mg of thiourea and 50 mL of ethanol was stirred at room temperature for 35 hours. Then 50 mL of water was added, followed by 30 minutes' stirring. Crystals were recovered by filtration and washed with water. Drying the same under aeration, 1.15 g of the title compound was obtained.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CC1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCc2cc(OCc3c(-c4ccc(CC)cc4)nsc3C(F)(F)F)ccc21
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate (160 mg, 0.44 mmol, 1.00 equiv), ethyl 2-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate (97 mg, 0.44 mmol, 1.01 equiv), potassium carbonate (183 mg, 1.32 mmol, 3.02 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 30° C. The resulting solution was diluted with 20 mL of H2O. The resulting mixture was washed with 3×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:85). This resulted in 200 mg (93%) of ethyl 2-(5-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dihydro-1H-inden-1-yl)acetate as colorless oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Mg]Br)C.[I:19]I>CCOCC>[I:19][C:1]#[C:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: II
Reactant: C#CCOCCCCCCCCCC
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCCCCCCCCCOCC#CI
Yield: 71 %

Procedure:
Following the procedure described in Vaughn, T. H., J. Am. Chemical Soc'y 55 3456 (1933), 4-oxatetradecyne (13 g, 66.2 mmol) was reacted with ethylmagnesium bromide (73 mmol) in dry ether. The resulting alkynyl magnesiumbromide was reacted with iodine and provided 15 g of 1-iodo-4-oxa-tetradecyne as viscous liquid (71% yield). The sample was analyzed with 1H-NMR in CDCl3, and the observed chemical shift peaks were at δ=0.88 (t, 3H, --CH3), 1.23-1.4 (br singlet, 14H, --CH2 --), 1.57 (pentate center, 2H, --CH2 --), 3.51 (t, J=7.0 Hz, 2H, --CH2 --O), and 4.28 (s, 2H, O--CH2 --C≡C). Observed IR (KBr) peak was at 2120 (--C≡C--) cm-1 ; no peak was observed at 3298 (--C≡CH) cm-1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1.S(Cl)(Cl)=O.[CH3:26][C@H:27]1[NH:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1>C1COCC1>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]([N:32]3[CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][C@H:27]3[CH3:26])=[O:18])[CH2:14][CH2:15]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid hydrochloride (0.5 g, 1.487 mmol) in thionyl chloride (10.86 mL, 149 mmol) was heated at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure and dried under high vacuum for 1 hour. The resulting solid was suspended in THF (14.87 mL) and cooled to 0° C. under nitrogen atmosphere. To this mixture was added (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.357 g, 1.785 mmol) as a solution in THF (5 mL). The ice bath was removed, and the reaction mixture was stirred overnight at RT. The resulting mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 solution (30 mL) and then with saturated aqueous ammonium chloride solution (2×). The organic phase was collected, dried over sodium sulfate, and concentrated under reduced pressure to afford (R)-tert-butyl 4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate as a light yellow solid (0.55 g, 77% yield). MS m/z=482.2 [M+H]. Calc'd for C22H32ClN5O5: 481.2.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][C:8]([CH3:12])([CH3:11])[C:9]#[CH:10])=[CH:5][CH:4]=1)#[N:2]>CCN(C1C=CC=CC=1)CC>[CH3:12][C:8]1([CH3:11])[O:7][C:6]2[CH:13]=[CH:14][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH:10]=[CH:9]1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: CCN(CC)c1ccccc1
Product: CC1(C)C=Cc2cc(C#N)ccc2O1
Yield: 70 %

Procedure:
Cyclisation of the 3-(p-cyanophenoxy)-3-methybut-1-yne (9.77 g) was accomplished by heating in diethylaniline at 210°-220° C. under nitrogen. Purification by distillation, and extraction with dilute hydrochloric acid gave 2,2-dimethyl-6-cyano-2H-benzo[b]pyran as a colourless oil (6.84 g), which slowly crystallised on standing, having a nmr spectrum showing signals at δ 1.46, 6.25 (d, J=10), 5.67 (d, J=10,), 6.74 (d, J=8), 7.18 (d, J=2), 7.34 (q, J32 8, 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 569.4 %

Procedure:
To a solution of ethyl (2E)-3-(4-{[2-(4-fluorophenyl)-6-hydroxy(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoate (0.16 g, 0.37 mmol) in tetrahydrofuran (6 mL) was added a solution of lithium hydroxide monohydrate (0.20 g, 4.77 mmol) in water (3 mL). After it stirring at room temperature for 20 hours, the tetrahydrofuran was evaporated. The aqueous solution was neutralized with 5% aqueous HCl and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 75-100% ethyl acetate/hexane) to provide the title compound (0.85 g, 57% yield): 1H NMR (CDCl3) 7.72 (d, 1H), 7.40 (d, 2H), 7.02 (d, 2H), 6.93 (m, 2H), 6.76 (m, 2H), 6.61 (m, 2H), 6.56 (dd, 1H), 6.42 (d, 1H), 4.75 (t, 1H), 3.55 (m, 1H), 3.46 (m, 1H), 3.16 (m, 1H), 2.87-3.00 (m, 2H), 2.64 (dt, 1H); ES-MS m/z 404 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:19])=[O:18])=[C:4]([C:9]([O:14][CH3:15])=[C:10]([CH2:12][CH3:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O1CCOCC1.C(#N)C>O>[Br:1][C:2]1[C:3]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:18])=[O:19])=[C:4]([C:9]([O:14][CH3:15])=[C:10]([CH2:12][CH3:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCc1cc(Br)c(NS(=O)(=O)c2ccccc2F)c(C(=O)OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Br)c(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1OC

Procedure:
A mixture of Example 470F (75 mg, 0.2 mmol), lithium hydroxide (70 mg, 2.0 mmol), dioxane (1.5 mL), and water (0.75 mL) was sealed in a vial and microwaved at 160° C. for 15 minutes. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired compound. MS (ESI(+)) m/e 432, 434 (M+H)+; (ESI(−)) m/e 430, 432 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.68 (m, 1H), 7.57 (m, 1H), 7.28 (m, 3H), 3.65 (s, 3H), 2.49 (m, 4H), 1.09 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (450 mg, 68%).
Reaction SMILES: Cl.[N:2]1([S:8]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:44][S:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])([C:38]2[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=2)[CH2:34][CH2:35][CH:36]=O)=[CH:29][C:28]=1[F:51])#[N:26].[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:44][S:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])([C:38]2[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=2)[CH2:34][CH2:35][CH2:36][N:5]2[CH2:4][CH2:3][N:2]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)(=[O:10])=[O:9])[CH2:7][CH2:6]2)=[CH:29][C:28]=1[F:51])#[N:26]
Reactant: O=S(=O)(c1cccc(O)c1)N1CCNCC1
Reactant: Cn1cncc1C(CCC=O)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1cncc1C(CCCN1CCN(S(=O)(=O)c2cccc(O)c2)CC1)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(Piperazin-1-ylsulfonyl) phenol hydrochloride (0.065 g, 0.231 mmol) was dissolved in MeOH (5 mL), neutralized with Et3N (0.032 mL, 0.231 mmol), then treated with N-[1-(4-cyano-3-fluorophenyl)-4-oxo-1-(1-methyl-1H-imidazol-5-yl)butyl]-2-methylpropane-2-sulfinamide (0.086 g, 0.220 mmol). The pH of the solution was adjusted to 5 with HOAc, then NaCNBH3 (0.021 g, 0.330 nunol) was added, and the pH was adjusted again to 5. After stirring at ambient temperature for 18 h, the reaction mixture was concentrated in vacuo, partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution, the aqueous layer washed with CH2Cl2 (2×), the organic layers combined and dried (MgSO4), filtered and concentrated to give the title product. MS(M+1) 617.
Reaction SMILES: [C:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][C:21](=[O:23])[CH3:22])[C:10](=[O:24])[C:9]=2[CH:8]=[C:7]([C:25]([NH:27]C(C)(C)C)=O)[CH:6]=1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][C:21](=[O:23])[CH3:22])[C:10](=[O:24])[C:9]=2[CH:8]=[C:7]([C:25]#[N:27])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)NC(C)(C)C)cc1C2=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C#N)cc1C2=O
Temperature: 105 °C

Procedure:
A stirred mixture of 4,5-diacetoxy-9,10-dihydro-N-(1,1-dimethylethyl)-9,10-dioxoanthracene-2-carboxamide (337.0 g) and toluene was warmed to 105° C. and then filtered through a pre-warmed glass sinter funnel. The stirred filtrate was heated back to 100° C. and phosphorus pentachloride (278.0 g) was added portionwise over 15 minutes. The heat was removed and the mixture allowed to cool to room temperature. The mixture was cooled further to 15° C. and the material isolated by filtration and washed in turn with toluene, aqueous sodium bicarbonate (1.5 liters) and water (2×1.5 liters). The green solid was then dried in vacuo at 45° C., m.p. 218°-220° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:13]O)[CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>ClCCl>[C:1]([O:4][CH2:5][CH:6]([CH2:13][Br:34])[CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(CO)COC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OCCC(CBr)COC(C)=O
Reaction time: 20 h
Yield: 82.5 %

Procedure:
A solution of 4-acetoxy-2-hydroxymethylbutyl acetate (11.04 g, 0.054 mol) and triphenylphospine (21.27 g, 0.081 mol) in dry dichloro methane (150 ml) was stirred at 0° C., and N-bromo-succinimide (14.43 g, 0.081 mol) was added in portions. The mixture was kept at 0° C. for 20 h, evaporated to small volume and stirred with 50 ml of ethyl acetate+n-hexane (1+1). The white triphenylphospine oxide was filtered off and washed with a little ethyl acetate+n-hexane (1-1). The combined filtrate was evaporated and purified on a 200 g SiO2 column with ethyl acetate+n-hexane (1+1) as eluent. The 250-550 ml fraction was evaporated in vacuum to give 11.90 g (82%) of pure 4-acetoxy-2-bromomethylbutyl acetate. TLC on silica (ethyl acetate+n-hexane 1+1): Rf 0.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:21]=[C:14]2[CH:15]=[N+:16]([O-])[CH:17]=[C:18]([F:19])[C:13]2=[N:12]1.P(Br)(Br)([Br:24])=O>C(Cl)Cl>[Br:24][C:15]1[C:14]2=[CH:21][N:11]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([CH:8]=[CH2:9])=[CH:5][C:4]=3[Cl:10])[N:12]=[C:13]2[C:18]([F:19])=[CH:17][N:16]=1
Reactant: C=Cc1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Product: C=Cc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a suspension of 2-(2,6-dichloro-4-vinylphenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (1.0 g, 3.1 mmol) in DCM (15 mL) under an atmosphere of nitrogen at 0° C., was added phosphorus oxybromide (2.6 g, 9.0 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then allowed to reach room temperature over 30 minutes. The resultant mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and diluted with DCM. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (304 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (d, J=2.5 Hz, 1H), 8.19 (d, J=3.3 Hz, 1H), 7.99 (s, 2H), 6.85 (dd, J=17.6, 11.0 Hz, 1H), 6.25 (d, J=17.6 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([Sn](C)(C)C)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.Br[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1.[Cl-].[Li+]>O1CCOCC1>[C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:16]2[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH2:6][C:7]3[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:15]=2)=[CH:26][CH:27]=1)(=[O:30])[NH2:31]
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc([Sn](C)(C)C)c1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(C(N)=O)cc2)c1OC
Temperature: 0 °C
Yield: 7.1 %

Procedure:
1.0 g of 5-(3,4-dimethoxy-5-trimethylstannyl-benzyl)-pyrimidine-2,4-diamine (Example 1o) and 0.472 g of 4-bromobenzamide are dissolved in 50 ml of dioxan, treated with 0.3 g of lithium chloride and 0.15 g of tetrakis-triphenylphosphine-palladium and held at reflux under argon for 14 hrs. The mixture is poured on to ice-water, extracted with methylene chloride, dried over magnesium sulphate and, after concentration, the residue is chromatographed on silica gel with methylene chloride/methanol 2:1. 64 mg (7%) of 5-(4'-carbamoyl-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a colourless solid. M.p. 199° (decomposition).