Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:13]([F:20])[C:12]=1[CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(COC)OC.FC(F)(F)S(O)(=O)=O>[F:7][C:24]1[CH2:25][CH2:26][CH:21]([C:12]2[C:11]([F:10])=[CH:16][C:15]([CH2:17][CH2:18][CH3:19])=[CH:14][C:13]=2[F:20])[CH2:22][CH:23]=1
Reactant: CCCc1cc(F)c(C2CCC(=O)CC2)c(F)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COCCOC
Product: CCCc1cc(F)c(C2CC=C(F)CC2)c(F)c1

Procedure:
535 ml of diethylaminosulphur trifluoride (DAST) were added dropwise in 3 portions over 60 hours to a solution of 0.63 g of 4-(2,6-difluoro-4-propylphenyl)cyclohexanone in 15 ml of dimethoxyethane and 50 ml of trifluoromethanesulphonic acid. The reaction solution was subsequently partitioned between sodium carbonate solution and ether. The organic phase was washed twice with water and the aqueous phases were individually extracted twice with ether. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated completely. The resulting crude product (0.8 g) was purified by chromatography and gave 0.36 g of 1-fluoro-4-(2,6-difluoro-4-propylphenyl)cyclohex-1-ene, m.p. (C/I) 62.5° C.
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][C:7]=1[C:19]([O:21]C)=O)=O.OC1C(O)=C(C(OC)=O)N=C(C(O)=O)N=1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1.CCOC(C)=O>CN(C=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:19]([C:7]2[N:8]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[OH:5])=[O:21])=[CH:43][CH:42]=1
Reactant: CCOC(=O)c1nc(C(=O)OC)c(OC(=O)C(C)(C)C)c(=O)n1C
Reactant: NCc1ccc(F)cc1
Agent: COC(=O)c1nc(C(=O)O)nc(O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-Ethyl 4-methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-2,4-dicarboxylate (made by protection and alkylation of the starting material of Example 4, Step 1 using procedures similar to those set forth in Examples 1 or 2) was dissolved in DMF, 4-fluorobenzylamine (3.1 eq.) was added and the mixture was stirred at 90° C. overnight. After concentration of the solvent, the residue was taken into EtOAc, washed with 1 N HCl, dried over Na2SO4 and evaporated to obtain crude N-(4-fluorobenzyl)-2-ethoxycarbonyl-1-methyl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide. To this crude product was added 2-picolylamine (8 eq.), and the reaction was stirred at 90° C. overnight. The title product was obtained as its trifluoroacetic salt by preparative RP-HPLC purification (C18 gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Br:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Br:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccc(F)cc2Br)CCN1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.601 g, 6 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.004 mL, 7.20 mmol). The solution was then cooled to 0° C. before 2-bromo-4-fluorobenzoyl chloride (1.567 g, 6.60 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (40 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL), before being dried over anhydrous sodium sulphate. The sodium sulphate was then removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (40 mL) at 55° C. for 30 minutes. The solid was then removed by filtration to yield the product in 1.625 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:16]C(C)(C)C(C)(C)[O:9]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.[Br:27][CH2:28][C:29](Br)=[O:30]>O.CCCCCC.C(OCC)(=O)C>[Br:27][CH2:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:9])[OH:16])=[O:30]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCCCCC
Product: O=C(CBr)Nc1ccccc1B(O)O
Reaction time: 0.17 h

Procedure:
(50 g, 0.228 mol) of 2-aminophenyl boronic acid pinacol ester and (110 g, 0.798 mole) of potassium carbonate were charged into 10 L, 3 necks RBF connected with overhead stirrer, thermometer and additional funnel, 5 L of Chloroform, synthetic grade was loaded then stirred for 10±5 minutes at 25±5° C. after that (115 g, 50 mL, 0.57 mol) of Bromoacetyl bromide was added drop wise during 10±5 minutes while the mixture stirred. After end of loading, the mixture was stirred for 1-2 hrs at 25±5° C., the reaction completion was monitored by TLC (Ethyl acetate:n-hexane, 15:85 v/v). Afterward, 4-5 L of purified water was loaded then transferred to 10 L separatory funnel and steeled down for 10 minutes, chloroform layer (lower) was separated and dried over 50 g of sodium sulfate and filtered. The filtrate solution was concentrated under vacuum to dryness. The residue was recrystallized from diethyl ether to get pure 2-(bromoacetamido)phenylboronic acid intermediate, the product was characterized by 1H-NMR, 13C-NMR, mass and elemental analysis.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17](OC)=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[N:22]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=5)[CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH2:17][OH:18])=[C:15]([CH3:21])[N:14]=[C:13]4[N:22]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=5)[CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)CCCO3)c1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice cold solution of methyl 4-(chroman-6-yl)-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.019 g, 2.272 mmol) in tetrahydrofuran (THF) (10 mL) was treated with lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (6.82 mL, 6.82 mmol) and the mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 0° C., water (259 uL) was added and the mixture was stirred 5 minutes. Then 15% NaOH (259 uL) was added and the mixture was stirred for 5 minutes. Finally, water (777 uL) was added, the mixture was diluted with ethyl acetate and then stirred 10 minutes. The mixture was filtered over Celite™ and the filtrate was concentrated to afford an off-white residue: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24-7.15 (m, 2 H), 7.14-7.01 (m, 3 H), 6.98 (dt, J=2.0, 4.0 Hz, 1 H), 6.91 (d, J=8.2 Hz, 1 H), 6.26 (d, J=3.5 Hz, 1 H), 5.45 (s, 2 H), 4.74 (d, J=3.9 Hz, 2 H), 4.35-4.21 (m, 2 H), 2.93-2.74 (m, 5 H), 2.18-1.96 (m, 2 H); LC/MS (m/z) ES+=421 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Br:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Br:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH:5]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=4)[CH2:33][CH2:34]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1
Reactant: O=c1[nH]c2cc(Br)ccc2n1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane, 5.9 parts of 5-bromo-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized twice: first from a mixture of 2-propanol and 2,2'-oxybispropane and then from ethanol. The product is filtered off and dried, yielding 5-bromo-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 182° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl)([O-:15])=[O:14].O.Cl>O1CCCC1>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: NCCCO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1CNCCCO
Yield: 33.2 %

Procedure:
3-Aminopropanol (3.94 g, 52.5 mmol) and triethylamine (1.77 g, 17.5 mmol) were dissolved in tetrahydrofuran (30 ml) and added with 2-nitrobenzyl chloride (3.00 g, 17.5 mmol) at room temperature. After heated to reflux for seven hours, the reaction mixture was allowed to cool and poured into 1N hydrochloric acid water and extracted with ether. The aqueous layer was adjusted to pH 9 with a saturated sodium hydrogen carbonate aqueous solution and then extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-(2-nitrobenzylamino)propanol (1.22 g).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:33]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:34])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Reactant: C=CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1
Yield: 60.5 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (100 mg, 0.28 mmol) in anhydrous DCM (3 mL) was added MP-carbonate (3.01 mmol/g; 275 mg, 0.84 mmol) and allyl isocyanate (25 μL, 0.28 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (18 mL), then evaporated to afford the desired product (72 mg, 61%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:22][C:23](=[CH2:25])[CH3:24].[ClH:26].CCOCC>C(Cl)Cl.COCCOC>[ClH:26].[NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([O:6][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
In a Fischer-Porter tube, a mixture of 2-1b (10.2 g, 42 mmol) and DME (150 mL) was sequentially treated with H2SO4 (6.4 mL, 0.12 mol), cooled to -78° C., and then condensed isobutylene (75 mL). The tube was sealed and the cooling bath was removed. After 24 h, ice/water (250 mL) was added followed by washing with ether (2×). The aqueous phase was basified with aq 6N NaOH, then saturated with NaCl, followed by extraction with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a white solid. This was dissolved in CH2Cl2 and treated with 1N HCl/ether (22 mL), and then concentrated to give 2-1 as a glassy yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH:29]OS([O-])=O.[K+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:13]=2)=[CH:5][CH:4]=1)=[O:29]
Reactant: COc1nccc(-c2[nH]c(-c3ccc(SC)cc3)nc2-c2ccc(F)cc2)n1
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc(-c2[nH]c(-c3ccc(S(C)=O)cc3)nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a solution of 2-(4-methylthiophenyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole (0.10 g, 0.25 mmol) in 10 mL of THF at 0° C. was added a cooled solution of Oxone (0.084 g, 0.28 mmol)in 10 mL of H2O. The solution was warmed to room temperature and stirred for 20 min. Next, 20 mL of NaHCO3 sat was added and the mixture was extracted thrice with 20 mL of CH2Cl2. The combined organic layers were washed with 20 mL of 20% NaS2O5 and brine and then dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by silica gel chromatography with 2-6% CH3OH/CH2Cl2 to give the title compound as a light yellow solid (0.084 g, 82%). ES(+) MS m/e=409 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[S:16])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].[CH3:23][C:24]1[CH:25]=[C:26](N)[CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([CH3:39])=[N:36][C:35]=2[CH:40]=1.C(O)(=O)C>C(OC(C)C)(=O)C>[OH:20][CH2:19][C:18]([NH:17][C:15]([NH:14][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[N:9]=[CH:10][N:11]=[C:1]2[NH:2][C:26]1[CH:27]=[CH:28][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([CH3:39])=[N:36][C:35]=3[CH:40]=2)=[C:24]([CH3:23])[CH:25]=1)=[S:16])([CH3:21])[CH3:22]
Reactant: Cc1nc2cc(Oc3ccc(N)cc3C)ccc2o1
Reactant: CN(C)C=Nc1ccc(NC(=S)NC(C)(C)CO)cc1C#N
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Product: Cc1nc2cc(Oc3ccc(Nc4ncnc5ccc(NC(=S)NC(C)(C)CO)cc45)cc3C)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (275 mg, 0.861 mmol) and 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine (241 mg, 0.947 mmol) in isopropyl acetate (2 mL) was added acetic acid (0.2 mL, 3.44 mmol). After stirring at room temperature for 16 hours, hexanes was added and stirred with the mixture for 30 minutes. The mixture was filtered to provide the crude product (281 mg, 62%) as yellow solid.
Reaction SMILES: COC([C:5]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]=2[C:6]=1[OH:26])=O.C(OC(C1CCN(S(C2C=CC(C)=CC=2)(=O)=O)C2C=CC=CC=2C=1O)=O)C.C(O)(=O)C.Cl>C(O)C.O>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:10][CH2:11][CH2:5][C:6](=[O:26])[C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]2=3)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COC(=O)C1=C(O)c2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: CCOC(=O)C1=C(O)c2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester and 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester from Example E5.3 were heated at reflux in a mixture of ethanol (100 ml), acetic acid (300 ml), concentrated HCl (100 ml) and water (50 ml) for 18 h. The mixture was cooled to room temperature, diluted with water (800 ml) and extracted with chloroform. The combined organic ex-tracts were dried, filtered and reduced in vacuo. The residue was crystallised twice from methanol to yield the title compound (44 g, 60% over two steps).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[NH2:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][CH:16]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccnc(NC2CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A solution of 2-bromo-4-methylpyridine (90 mg, 0.523 mmol), sodium tert-butoxide (101 mg, 1.046 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (451 mg, 2.62 mmol) and BINAP (16.3 mg, 0.026 mmol) in anhydrous toluene (7 ml) was purged with argon. Palladium(II)acetate (5.9 mg, 0.026 mmol) was added and the mixture was stirred at 100° C. overnight in a closed vial. After cooling to room temperature the mixture was filtered through kieselguhr and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient from 0.5 to 10% ethyl acetate in heptane) to afford 60 mg of a solid (0.228 mmol, 43%) MS (ESI) m/z=264.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][O:16][CH:17]([C:19]1[S:23][C:22]([N:24]=[C:25]=[O:26])=[N:21][N:20]=1)[CH3:18].CCCCCC>C(OCC)C>[CH3:15][O:16][CH:17]([C:19]1[S:23][C:22]([NH:24][C:25](=[O:26])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:21][N:20]=1)[CH3:18]
Reactant: CNCC(OC)OC
Reactant: COC(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)OC)s1)OC
Yield: 94.2 %

Procedure:
At ambient temperatures, 5.4 grams (0.045 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a 50 milliliter benzene solution containing 8.4 grams (0.045 equivalents) of the 5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes; hexane was added resulting in the formation of an oil, the mixture was topped on a roto-vac at 70° C. to 13.2 grams of a hazy viscous oil which was dissolved in diethylether, and filtered. The diethylether solution was topped on a roto-vac at 70° C. to yield 12.9 grams of a red oil of 3-[5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=1[CH:26]([OH:31])[CH2:27][O:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[ClH:39]>C(OCC)(=O)C.C(Cl)Cl.O1CCOCC1.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=2[CH:26]([OH:31])[CH2:27][O:28][CH2:29][CH3:30])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:39]
Reactant: CCOCC(O)c1c(F)cncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCC(O)c1c(F)cncc1-c1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A 25 mL round bottom flask was charged with 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (74 mg, 0.282 mmol), 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-ethoxy-ethanol (62 mg, 0.235 mmol), 2M aqueous sodium carbonate (0.235 mL, 0.470 mmol) and DMF (5 mL). The reaction mixture was evacuated and flushed with N2 twice, followed by addition of PdCl2(dppf). CH2Cl2 adduct (9.6 mg, 0.012 mmol). The reaction was stirred under N2 at 100° C. for 30 min. The reaction mixture was cooled to room temperature diluted with ethyl acetate and washed with water twice. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in DMF (5 mL) and purified by HPLC using an Xbridge Shield RP18 column and gradient 0.1% aqueous NH4OH in acetonitrile to afford a solid, which was dissolved in DCM (2 mL) and 4N HCl in dioxane (0.5 mL). The solvents were evaporated and the product was lyophilized to afford the product 2-chloro-4-[4-(2-ethoxy-1-hydroxy-ethyl)-5-fluoro-pyridin-3-yl]-benzonitrile as an HCl salt. 1H NMR (400 MHz, MeOD, HCl salt) δ ppm 1.17 (t, J=6.9 Hz, 3H), 3.46-3.57 (m, 2H), 3.81 (dd, J=6.7, 1.4 Hz, 2H), 4.90 (t, J=6.8 Hz, 1H), 7.61 (dd, J=8.0, 1.6 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 8.36 (s, 1H), 8.60 (d, J=2.8 Hz, 1H); HRMS: (ESI) m/z 321.0801 [(M+H)+ Calcd for C16H14ClFN2O2 321.0806].
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)(=O)C>[C].[Pd].CO>[O:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[NH:8][N:9]=[N:10][CH:11]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Cn2nncc2NC2CCOCC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: c1nn[nH]c1NC1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A mixture of 1-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine (450 mg), 10% palladium-carbon (containing water by 50%, 450 mg), ammonium formate (631 mg), acetic acid (1.2 mL) and methanol (12 mL) was stirred at 60° C. for 16 hr under a nitrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a white powder (209 mg, 73%).
Reaction SMILES: O=[O+][O-].[F:4][C:5]1[C:10]2[CH:11]=C(C)[O:13][C:9]=2[C:8]([CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1.FC1C2CC(C)[O:27]C=2C(CCC)=CC=1.CSC>>[F:4][C:5]1[C:10]([CH:11]=[O:27])=[C:9]([OH:13])[C:8]([CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1
Reactant: CCCc1ccc(F)c2cc(C)oc12
Reactant: CCCc1ccc(F)c2c1OC(C)C2
Agent: O=[O+][O-]
Solvent: CSC
Product: CCCc1ccc(F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Ozone was conducted at -78° C. into a solution of 6.6 g (34 mmol) of a 4:1 mixture of 4-fluoro-2-methyl-7-propyl-benzofuran and 4-fluoro-2-methyl-7-propyl-2,3-dihydro-benzofuran until the color became blue. Subsequently, argon was conducted through the solution which was then treated at -78° C. with 13 ml of dimethyl sulfide. After warming to room temperature the solution was concentrated in a vacuum and the residue was dissolved in 50 ml of ethanol. After the addition of 50 ml of 3% sodium hydrogen carbonate solution the mixture was stirred at 70° C. for 30 minutes. Subsequently, the mixture was poured on to 200 ml of ice-water, made acid with 10% HCl and extracted three times with 150 ml of diethyl ether each time. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 2:3). There were obtained 5.0 g (100%) of 6-fluoro-2-hydroxy-3-propyl-benzaldehyde as a pale yellow oil, which was used immediately in the next reaction.