Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.FC(F)(F)S(O[CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])(=O)=O>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)C(F)(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 5.9 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30.0 mg, 0.0694 mmol) in acetonitrile (694 μL, 0.0694 mmol) was added triethylamine (38.7 μL, 0.278 mmol) and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (39.1 mg, 0.139 mmol). The reaction mixture was heated to 45° C. for 2 hours. The crude reaction mixture was purified by reverse phase HPLC to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,3,3,3-pentafluoropropyl)azetidin-3-yl)acetonitrile (2.0 mg, 5.9% yield). MS (apci) m/z=492.2 (M+H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:34][CH:35]3[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]3)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(S(C)(=O)=O)n2)C1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(NS(C)(=O)=O)CC3)n2)C1
Yield: 73.3 %

Procedure:
4-[3-(t-Butyl-dimethylsilyloxy)pyrrolidin-1-yl]-1-(2-methylsulfonyl-pyrimidin-4-yl)-1H-indole (about 160 mg, 0.35 mmol), N-(4-amino-cyclohexyl)-methanesulfonamide hydro-chloride (743 mg, 3.255 mmol) and DIEA (0.169 mL, 4.32 mmol) were mixed in NMP (7 mL) under Ar at 130° C. for 2.5 h. The reaction mixture was washed with NH4Cl/H2O and extracted into EtOAc (6×15 mL), and further washed with H2O (6×30 mL). The solvent was removed in vacuo to yield N-[4-(4-{4-[3-(t-butyl-dimethylsilanyloxy)-pyrrolidin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (150 mg).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.06 g, 3.00 mmol), 4-fluoro-benzylamine (0.457 mL, 4.0 mmol), and K2CO3 (0.967 g, 7.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.21 g, 20%). GC-MS: m/z 355 (M)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 4.20 (s, 2H), 4.73 (s, 2H), 7.02 (t, 2H), 7.29-7.31 (m, 2H), 7.44 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]1[C:33]([CH:34]=O)=[CH:32][C:31]2[O:36][CH2:37][O:38][C:30]=2[CH:29]=1>C1COCC1>[CH:34]([C:33]1[CH:28]=[CH:29][C:30]2[O:38][CH2:37][O:36][C:31]=2[CH:32]=1)=[CH2:1]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)OCO2
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
t-BuOK (7.77 g, 69.3 mmol) was added portions to a suspension of compound methyltriphenylphosphonium iodide (28.0 g, 68.3 mmol) in dry THF (250 mL) over 10 min at 0° C. The resulting yellow suspension was stirred for 20 min at this temperature. A solution of piperonal (8.0 g, 53.3 mmol) in dry THF (25 mL) was added dropwise to the above suspension and the mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated and the residue was purified by column chromatograph (petroleum ether) to provide compound 5-vinylbenzo[d][1,3]dioxole (7.4 g, 94%) as colorless liquid. 1H-NMR (DMSO-d6): δ 5.09 (d, 1H, J=11.2 Hz), 5.68 (d, 1H, J=18 Hz), 6.00 (s, 2H), 6.63 (1, 1H, J1=11.2 Hz, J2=18 Hz), 6.85 (m, 2H), 7.11 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([O:9]C)[N:4]=[C:3]1[CH:11]([CH3:13])[CH3:12].Cl>CC(C)=O.CCOCC>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([OH:9])[N:4]=[C:3]1[CH:11]([CH3:13])[CH3:12]
Reactant: COc1cc(=O)n(C)c(C(C)C)n1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)c1nc(O)cc(=O)n1C
Yield: 7 %

Procedure:
6 g (0.33 mol) of 1-methyl-2-isopropyl-4-methoxy-6-oxo-1,6-dihydro-pyrimidine (for preparation, see line 15 this page) were dissolved in 30 ml of acetone and converted to the hydrochloride by adding a solution of hydrochloric acid in ether. The salt was filtered off and after drying was warmed for 20 minutes to 150°-155° C. After the elimination of methyl chloride had ceased, the material was cooled, triturated with ether and filtered off. 3.9 g (92% of theory) of 1-methyl-2-isopropyl-4-hydroxy-6-oxo-1,6-dihydro-pyrimidine were thus obtained in the form of a colourless powder of melting point 159° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH2:18][OH:19]
Reactant: O=Cc1ccc(F)cc1
Reactant: OCc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Br)c(CO)c2)cc1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 4-fluoro-benzaldehyde (5.4 mL, 50.0 mmol, 1.0 eq.), 4-bromo-3-hydroxymethyl-phenol (10.6 g, 50.0 mmol, 1.0 eq.) in DMF (140.0 mL) was added K2CO3 (8.3 g, 60.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (10 mL) and sat. H2O (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×100 mL). Combined organic extracts was washed with brine (100 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzaldehyde as a yellow oil. 1H NMR (CHLOROFORM-d) δ: 9.93 (s, 1H), 7.80-7.89 (m, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.27 (d, J=3.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.89 (dd, J=8.6, 2.9 Hz, 1H), 4.74 (s, 2H). Amount obtained, 15.2 g, 99% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][CH3:28])=[O:26].FC(F)(F)C(O)=O>CC(O)C>[F:20][C:5]1[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=2)[C:25]([NH:27][CH3:28])=[O:26])=[N:3][CH:4]=1
Reactant: Fc1ccc(OC2CN(c3nc(Cl)ncc3F)C2)cc1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cccc(Nc2ncc(F)c(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To 2-chloro-5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (90.0 mg, 0.302 mmol) and 3-amino-N-methylbenzamide (49.9 mg, 0.333 mmol) in a disposable sealed tube in 2-propanol (2.50 mL) was added trifluoroacetic acid (0.070 mL, 0.907 mmol). The resulting reaction mixture was heated at 84° C. for 3 d, cooled to RT and concentrated. The residue was stirred in EtOAc and saturated aqueous NaHCO3 for 10 min and transferred to a reparatory funnel. The organic layer was washed with brine, dried and concentrated giving 3-(5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (124.8 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C[C@H](N)c1ccccc1

Procedure:
2.3 g (11.65 mmol) of (S)-3-amino-3-phenylpropionic acid are introduced in 100 ml of methanol and admixed with a catalytic amount of concentrated sulfuric acid (0.02 eq.). The reaction mixture is heated at reflux for 24 h and then concentrated. The crude product can be used without further purification in the next stage.
Reaction SMILES: N[C:2]1[C:11]2C(=CC=C(OCCNC(=O)OC(C)(C)C)C=2)C=CN=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>Cl.O1CCOCC1.ClCCl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]([O:43][CH2:2][CH3:11])=[O:42])=[CH:44][CH:45]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2ccnc(N)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
648 mg (2.15 mmol) of t-butyl [2-(1-aminoisoquinoline-7-yloxy)ethyl]carbamate was dissolved in a mixture of 2.5 ml of 4 N solution of hydrogen chloride in dioxane and 5 ml of dioxane. The obtained solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 10 ml of DMF. 752 mg (2.36 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 451 mg (2.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 319 mg (2.36 mmol) of 1-hydroxybenzotriazole and 0.99 ml (7.08 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was treated with dichloromethane as the extracting solvent in an ordinary manner, and the obtained crude product was dissolved in a mixture of 2 ml of 4 N solution of hydrogen chloride in dioxane and 1 ml of dioxane. The obtained solution was stirred at room temperature overnight. The title compound was obtained in the same manner as that in step 4 in Example 1.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:7][C:3]=1[C:4]([NH:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=1[CH3:34])=[O:6]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1F
Reactant: Cc1c(O)ccc(F)c1N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2C)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-3-methyl-benzoic acid (intermediate III(f)) (528 mg, 2.1 mmol, 1.0 eq), in CH2Cl2 (20 mL) and DMF (3 drops) was added (COCl)2 (0.5 mL). The reaction was stirred at room temperature for 1 h then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (300 mg, 2.1 mmol, 1.0 eq) and NaHCO3 (536 mg, 6.38 mmol, 3 eq) in THF (20 mL) at 0° C. After addition was completed, the reaction mixture was stirred at room temperature for 30 min. Water was added and the aqueous phase was adjusted to pH 3 by addition of diluted HCl. The aqueous solution was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 1:1) to give the title compound as a white solid (420 mg, 53%).
Reaction SMILES: [OH2:1].O.O.O.O.O.O.O.O.[N+:10]([O-:13])([O-:12])=[O:11].[Al+3:14].[N+:15]([O-:18])([O-:17])=[O:16].[N+]([O-])([O-])=O.NC(N)=O.[Al].C([O-])(=O)C([O-])=O.[K+].[K+].[N+]([O-])([O-])=O.[NH4+]>>[N+:10]([O-:13])([O-:12])=[O:11].[OH:1][Al+2:14].[N+:15]([O-:18])([O-:17])=[O:16]
Reactant: [Al+3]
Reactant: O
Agent: NC(N)=O
Agent: O=C([O-])C(=O)[O-]
Agent: O=[N+]([O-])[O-]
Product: O[Al+2]

Procedure:
Aluminum nitrate nonahydrate (75 g, 0.2 mol) water (75 g, 4.2 mol) and crystal urea (15.5 g, 0.26 mol) were refluxed together for 16 hours. No fumes could be seen coming from the reactor during this period. The clear solution which resulted was analyzed for aluminum content and hydroxyl content and found to have a hydroxyl to aluminum ratio of 2.39:1. The hydroxyl content was determined by direct titration after the addition of potassium oxalate to prevent hydrolysis of the aluminum ion. There was no loss of nitrogen during the process and the final solution contained 186% by weight of ammonium nitrate based on the weight of the Al(OH)2.4 (NO3)0.6 found.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]Br.Cl>CN(C)C=O.O>[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(C)=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
36 g of 3-bromothiophenol were dissolved in 400 ml of dimethylformamide. After the addition of 27 g of finely powdered potassium carbonate and 29 g of 3,3-dimethylallyl bromide, the mixture was stirred at room temperature for 1 hour, diluted with 500 ml of water, acidified with 3N hydrochloric acid while cooling and extracted with ether. The yellow-brown oil obtained after evaporation was distilled in a high vacuum. There were obtained 48 g of m-bromophenyl 3-methyl-2-butenyl sulfide as a colorless liquid, boiling point 85° C./13.3 Pa.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]Br)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[OH:19][CH:20]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>C(#N)C>[OH:18][C:5]1[C:6]([CH2:15][CH2:16][CH3:17])=[C:7]([O:8][CH2:9][CH2:10][CH2:11][O:36][C:33]2[CH:32]=[CH:31][C:30]([CH:20]([OH:19])[CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:35][CH:34]=2)[CH:13]=[CH:14][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: Oc1ccc(C(O)CCCc2ccccc2)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1c(OCCCOc2ccc(C(O)CCCc3ccccc3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
To a solution of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (J. Med. Chem. 29, 1573-1576, 1986) (315 mg) and the phenol of Step 1 (242 mg) in acetonitrile (5 mL) was added cesium carbonate (650 mg) and the mixture was heated to reflux for 5 hrs. The suspension was cooled to 25° C. and poured into 25% aqueous NH4OAc and EtOAc. The organic layer was washed with brine, dried with MgSO4 and the solvents are removed in vacuo. The residue was purified by chromatography on silica gel using EtOAc and hexanes (1:2) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.ClC1C=C(N)C=CC=1OCC1C=CC=CN=1>>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: OCc1cccnc1
Agent: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: Nc1ccc(OCc2cccnc2)c(Cl)c1
Yield: 51.4 %

Procedure:
Compound 2A (0.84 g, 51%) was prepared from 4-amino-2-chloro-phenol (1.0 g, 6.96 mmol), 3-hydroxymethylpyridine (1.52 g, 13.9 mmol) by a route analogous to that used for the preparation of 1C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][C:29]=1[CH3:38].CCN=C=NCCCN(C)C.Cl.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=3[CH3:38])=[O:21])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1ccc(CN)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3ccc(C(=O)O)cc3C)cn2)C1

Procedure:
(R)-4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3-methylbenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl 4-(aminomethyl)-3-methylbenzoate using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 8.81 (m, 1H), 8.78 (s, 2H), 7.75 (m, 2H), 7.31 (d, 1H), 7.05 (d, 1H), 6.91 (m, 3H), 4.48 (d, 2H), 4.33 (m, 1H), 4.18 (app dd, 1H), 3.90 (m, 4H), 3.80 (m, 1H), 2.36 (s, 3H), 2.05 (m, 1H), 1.85 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 491 (M+H).
Reaction SMILES: [OH:1][CH:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.[C:8]1([CH:15]=[CH:14][C:12](O)=[CH:11]C=1)O.C1CC=CC=1>C(Cl)(Cl)Cl>[OH:7][CH:5]1[CH:4]2[C:3](=[C:11]3[CH2:12][CH:14]2[CH2:15][CH2:8]3)[C:2](=[O:1])[O:6]1
Reactant: O=C1C=CC(O)O1
Reactant: Oc1ccc(O)cc1
Agent: C1=CCC=C1
Solvent: ClC(Cl)Cl
Product: O=C1OC(O)C2C1=C1CCC2C1
Temperature: 20 °C
Yield: 61756.5 %

Procedure:
A mixture of 30 g of 5-hydroxy-2(5H)-furanone, 150 ml of chloroform, 50 mg of hydroquinone and 35 ml of freshly distilled cyclopentadiene was stirred at 20° C. under an inert atmosphere and stirred for 17 hours at 20°-45° C. The mixture was evaporated to dryness under reduced pressure and the residue was crystallized from an isopropyl ether-petroleum ether mixture to obtain 46.6 g of 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one melting point at ≃103° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Cl
Reaction time: 5 h

Procedure:
2,3-Dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (25.5 grams, 0.1 mole) is stirred in 250 ml of dimethylformamide. To the stirred solution is added a solution of N-chlorosuccinimide (27 grams, 0.2 mole) in 100 ml of dimethylformamide. The mixture is stirred at 105°-110°C for 5 hours, followed by cooling. The cooled solution is poured into 1.8 liters of cold water and a solid precipitates. The crude product (28 grams) has a melting point of 238°-240°C. The crude product is crystallized from a mixture of 30 ml hot dimethylformamide and 90 ml acetonitrile yielding 26.2 grams of the title compound, melting point 241°-243°C.
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:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH2:27]([NH:34][C:35]([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:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)NCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 mL) and benzyl isocyanate (0.035 mL, 0.28 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a MeOH/CH2Cl2 1:100 as the eluent. This afforded the title compound as slightly coloured solid. 13C NMR (DMSO-d6) δ 195.3, 158.8 (dd), 155.8 (dd), 155.2, 149.1, 140.3, 139.1, 138.2, 133.4, 131.4, 129.0, 128.3, 127.1, 126.7, 126.4 (dd), 124.4 (dd), 120.1, 118.2, 114.9, 112.0 (dd), 111.9, 105.1 (dd), 42.7, 19.1
Reaction SMILES: [C:1]([C:4]1([CH2:13][OH:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CCOCC>[S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)([O:14][CH2:13][C:4]1([C:1]([CH3:3])=[CH2:2])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)C1(CO)Cc2ccccc2C1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C1(COS(=O)(=O)c2ccc(C)cc2)Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
To a mixture of 3.20 g (0.017 mole) of 2-isopropenyl-2-indanemethanol and 3.16 g (0.04 mole) of pyridine, with ice-cooling, was added 3.90 g (0.02 mole) of tosylchloride. The mixture was stirred for 24 hours, with ice-cooling, to complete the reaction. The reaction mixture was poured into ice water, mixed with 50 ml of ether. And then the ether layer was separated, the aqueous layer was extracted twice with 25 ml of ether. The ether layers were combined, washed with 2% aqueous hydrochloric acid solution, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 5.80 g of 2-iso-propenyl-2-indanylmethyl tosylate.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH:6]([N:9]=[C:10]=[N:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7].NC(N)=N>>[CH2:1]([NH:5][C:10]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][CH:6]([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCCN
Agent: N=C(N)N
Product: CCCCNC(=NC(C)C)NC(C)C

Procedure:
A mixture of 33 g of N-butylamine (0.45 mol) and 19 g of diisopropylcarbodiimide (0.15 mol) is refluxed for 3 h 30. GC analysis then shows a conversion of greater than 99.50 of the diisopropylcarbodiimide. The colorless final mixture is concentrated at 60° C. under 20 mbar for 2 h so as to give 29 g of a colorless and virtually odorless liquid of low viscosity, corresponding to the expected guanidine (yield 96.70).