Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([Cl:15])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(O)cc(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Nc1nc(O)c(Cl)c(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To 1.87 g. (10 mM) of 2-amino-6-pheny-4-pyrimidinol is added 50 ml. of glacial acetic acid and 1.46 g. (11 mM) of N-chlorosuccinimide. The mixture is heated with magnetic stirring under nitrogen at 90° C. for 2 hours (solution was complete in less than 20 minutes). The heat is removed and the amber solution is allowed to cool to room temperature. The solution is evaporated to a volume of 10 ml. under vacuum, cooled to 20° C. and filtered. The resulting solids are washed successively with CH3COOH (5 ml.), water (50 ml.), water (50 ml), acetone (100 ml.) and diethyl ether (100 ml.). The solids are dried at 60° C. in a vacuum oven to yield 1.40 g. (63%) of title compound. The solids can be recrystallized from ethanol:DMF by adding DMF to a hot, ethanol slurry of the pyrimidine until solution is complete. Cooling the solution at 5° C. for 18 hours filtering and drying gives analytically pure 2-amino-5-chloro-6-phenyl-4-pyrimidinol.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=NC2CCCCC2)CCCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([OH:35])=O)=[CH:17]1.CNC>CN(C=O)C.C(#N)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([N:7]([CH3:8])[CH3:1])=[O:35])=[CH:17]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccccc1Sc1c[nH]c2ccccc12
Agent: CNC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C(=O)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (875 mg, 4.2 mmol) is added to [2-(1H-Indol-3-ylsulfanyl)-phenyl]-acetic acid (600 mg, 2.1 mmol) in 3 mL dry DMF and 7 mL acetonitril and stirred for 10 minutes at room temperature. 5.3 mL dimethyl amine (2M in THF, 10.6 mmol) is added and the reaction mixture is stirred 16 hours at room temperature. The reaction mixture is concentrated in vacuo. The residue is extracted with ethyl acetate (3 times). The combined orgnic phases are washed with brine, dried with MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gives 116 mg (18%) of the title compound.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18]C)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([OH:18])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OC)ncc1F)C1CC1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cc(O)ncc1F)C1CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 126.2 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(5-fluoro-2-methoxypyridin-4-yl)propanoate (1.38 g) obtained in step A in DMF (2.5 mL) was added pyridinium chloride (5.97 g), and the mixture was stirred at 130° C. for 2 hr. To the reaction mixture was added ethyl acetate at 0° C., and the resulting precipitate was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.65 g) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[O:22]1[C:27]2[CH:28]=[CH:29][C:30](B(O)O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:9])=[C:4]([F:21])[CH:3]=3)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc3c(c2)OCCO3)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2,3-Dihydro-1,4-benzodioxin-6-yl boronic acid. MS (M+H) 411.2
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[N:29][C:28]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:28]1[N:29]=[N:30][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=1
Reactant: CC(C)(C)OC(=O)NCc1nnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CN)n1)c1csc(N)n1)C(=O)O
Yield: 44.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert-butoxycarbonyl)amino)methyl)-2H-tetrazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (185 mg, 0.234 mmol), DCM (2.34 mL) and TFA (1.08 mL, 14.06 mmol) for 1.5 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (55.5 mg, 45%) as a white powder. LCMS: Rt=0.30 min, m/z=533.0 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J=8.8 Hz, 1H), 8.55 (br s, 3H), 7.34 (br s, 2H), 6.73 (s, 1H), 5.37 (dd, J=8.7, 5.5 Hz, 1H), 5.19-5.13 (m, 1H), 5.01-4.94 (m, 1H), 4.62-4.57 (m, 1H), 4.43-4.37 (m, 2H), 1.38 (s, 3H) 1.34 (s, 3H).
Reaction SMILES: [BH4-].[Na+].Cl.Cl.[C:5]1([C:11]2[CH:20]=[C:19]([C:21](=[O:29])[CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[C:5]1([C:11]2[CH:20]=[C:19]([CH:21]([OH:29])[CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12
Yield: 68.2 %

Procedure:
6 g of sodium borohydride were added in 20 minutes, at the ambient temperature, to 16 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanone dihydrochloride in 500 ml of methanol. After reacting for 2 hours at the ambient temperature, 350 ml of water were added and the methanol was removed by distillation under reduced pressure. The residual aqueous suspension was extracted with diethyl oxide, the organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue (13 g) was crystallized from petrol ether. 9 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanol (racemic) were thus obtained, which melted at 147° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])=[CH:7][N:6]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (600 mg, 3.13 mmol) in dry DMF (10 mL) under N2 were added tributyl(1-ethoxyvinyl)stannane (1.09 mL, 3.23 mmol) and Pd(PPh3)2Cl2 (113 mg, 0.161 mmol). The mixture was stirred at 100° C. for 3 h and at rt for 16 h. The mixture was diluted with ether (20 mL), and treated with aqueous KF solution (5 g of KF in 3 mL of water). The mixture was stirred vigorously for 1 h at room temperature before being filtered through diatomaceous earth. The filtrate was washed with satd aq NaHCO3 and brine. The aqueous phase was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 2-chloro-5-(1-ethoxyvinyl)pyrimidine (350 mg, yield 61%).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:10][CH2:9][C:8]([CH3:11])([CH3:12])[C:7]([NH:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)(CO)C(=O)NC1CCCC1
Product: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1

Procedure:
Prepared as in Example 22b from N-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide (Example 29c) and 2-amino-6-fluorobenzonitrile as a white solid (45%). 1H NMR (400 MHz, DMSO-d6) δ 1.19 (s, 6H), 1.40-1.49 (m, 4H), 1.61-1.63 (m, 2H), 1.74-1.79 (m, 2H), 3.95 (s, 2H), 4.03 (m, 1H), 5.98 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H). MS 302 (MH+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[C:56]([F:58])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@H:47]([OH:59])[C@@H:46]1[OH:60])=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:34])[CH3:32])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[ClH:61].C(O)C.[H][H]>C(O)C.CO.[C].[Pd]>[ClH:61].[ClH:61].[NH2:11][C@H:12]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[C:56]([F:58])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@H:47]([OH:59])[C@@H:46]1[OH:60])=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:34])[CH3:32])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: [H][H]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 98.8 %

Procedure:
0.94 Gram (1.11 mmol) of the ester obtained as described above was dissolved in ethanol (100 ml) and methanol (20 ml), and 0.40 g of 10% palladium-carbon and 0.50 g (4.93 mmol) of 36% hydrogen chloride-ethanol were added. The mixture was stirred in a stream of hydrogen under normal pressure for 2 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with ether (20 ml) to obtain 0.71 g (99%) of the desired 5'-O-{N-(N-lysylalanyl)isoleucyl}-5-fluorouridine dihydrochloride as a colorless powdery solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr

Procedure:
Potassium phthalimide (92.5 g) was added in six portions over 4 hours to a boiling solution of 1,5-dibromopentane (230 g) in acetone (670 ml). The mixture was boiled under reflux for 24 hours, then cooled and filtered. The filtrate was evaporated to dryness and the residue dissolved in petroleum ether, b.p. 60°-80° C./ethyl acetate (1:1) and the solution filtered. The filtrate was evaporated to dryness and the residue washed with several portions of petroleum ether, b.p. 60°-80° C. to remove excess dibromopentane. The remaining oil was dried under vacuum at 50° C. The petrol washings were evaporated to dryness and distilled under vacuum to give recovered dibromopentane and a second fraction b.p. 86°-120° C. at 17 mbar. This fraction solidified on cooling and scratching. A little of this solid was used to seed the remaining oil and the combined solids were recrystallised from absolute ethanol (300 ml) to give N-(5-bromopentyl)phthalimide, m.p. 62°-63° C.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25][S:26][CH3:27])[CH:24]=1)[NH:21][CH:20]=[CH:19]2.FC(F)(F)C(O)=O.[Cl-].[NH4+]>ClCCl>[CH:1]1([C:4]2([C:19]3[C:18]4[C:22](=[C:23]([CH2:25][S:26][CH3:27])[CH:24]=[C:16]([F:15])[CH:17]=4)[NH:21][CH:20]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: OC1(C2CC2)CCc2cc(F)ccc21
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
633 mg (2.47 mmol) of the compound from Example 76A with a purity of 75% and 530 mg (2.71 mmol) of the compound from Example 11A were introduced into 12 ml of dichloromethane at 0° C., 0.23 ml (2.96 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 570 mg (63% of theory) of the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([C:16](=[O:19])[NH:17][CH3:18])=[CH:9][N:8]=1)(=O)=O.[NH3:20]>CO>[NH2:20][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([C:16]([NH:17][CH3:18])=[O:19])=[CH:9][N:8]=1
Reactant: CCOc1cc(COS(C)(=O)=O)ncc1C(=O)NC
Reactant: N
Solvent: CO
Product: CCOc1cc(CN)ncc1C(=O)NC
Reaction time: 0.17 h

Procedure:
4-Ethoxy-5-methylcarbamoylpyridin-2-ylmethyl methanesulfonate (436 mg), dissolved in abs. MeOH (7 ml), was added dropwise to a methanolic ammonia solution (7.1 ml; 7N) in a microwave vessel at RT and with stirring in the course of 10 min. After standing overnight, the solvent was stripped off and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed from the acetonitrile and freeze-dried. The product was treated with saturated sodium chloride solution and rendered alkaline with potassium carbonate. After extraction with methylene chloride, the combined organic phases were dried with sodium sulfate, filtered and concentrated. 71 mg of the title compound were obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH:25][C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH3:35])=[O:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: Cc1ccccc1N=C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 71.5 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenylamine (142 mg, 0.4 mmol) and 2-tolyl isocyanate (57 μL, 0.4 mmol) and following the procedure as outlined in Example 60, 140 mg of 1-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenyl}-3-o-tolyl-urea was isolated as an off white powder in 98% purity @ 214 nm; LCMS (APCI): 490 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:15](=[O:17])[CH3:16])[C:6]=1[CH3:18])(=[O:3])[CH3:2].[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:8](=[CH:9][C:10]=1[CH:11]([CH3:13])[CH3:12])[O:14][C:19]1([CH2:22][CH2:21][CH2:20]1)[CH2:16][C:15]2=[O:17])(=[O:3])[CH3:2]
Reactant: O=C1CCC1
Reactant: CC(=O)Oc1c(C(C)C)cc(O)c(C(C)=O)c1C
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C(C)C)cc2c(c1C)C(=O)CC1(CCC1)O2
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of 3-acetyl-4-hydroxy-6-isopropyl-2-methylphenyl acetate (8.5 g) and cyclobutanone (2.6 g) in toluene (150 mL) was added pyrrolidine (1.2 g). The solution was left at room temperature for 16 hours, refluxed for two hours, and then a Dean-Stark was used to remove the water. Work up and chromatography (silica gel, hexane-ethyl acetate 2% to 5%) gave 4 g of 7-isopropyl-5-methyl-4-oxospiro[chroman-2,1′-cyclobutane]-6-yl acetate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:12]=3[S:13][C:14]=2C(O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[C:18]1[C:12]2[S:13][CH:14]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[C:11]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCC(c2c(C(=O)O)sc3c(C(F)(F)F)cccc23)CC1
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2csc3c(C(F)(F)F)cccc23)CC1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A mixture of 3-(1-acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (4.13 g, 11.1 mmol), Cu powder (0.706 g, 11.1 mmol), and quinoline (20 mL) was heated to 200° C. under nitrogen. After 10 min, no gas evolution was observed and the reaction cooled at room temperature. The mixture was diluted with ethyl acetate (100 mL), filtered through a Celite bed and the filtrate washed with 1 N HCl (2×100 mL), 5% aqueous potassium carbonate (100 mL), water (100 mL), and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give an amber oil. The oil was chromatographed on silica, eluting with 10% methanol/ethyl acetate to afford 2.69 g (74%) of the desired product as a tan solid.
Reaction SMILES: C(C[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([OH:12])=O)(O)=O.O.[O:14]1CC[CH2:16][CH2:15]1>>[OH:12][CH2:10][C:9]1([CH2:16][CH2:15][OH:14])[CH:8]=[CH:7][S:6][CH2:5]1
Reactant: O=C(O)Cc1sccc1C(=O)O
Reactant: C1CCOC1
Solvent: O
Product: OCCC1(CO)C=CSC1
Temperature: -2 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
0.45 g of the compound obtained in Example 4 was dissolved in 10 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to −2° C. 3.7 mL of 2M solution of borane-dimethylsulfide complex in tetrahydrofuran was slowly added thereto, and the resulting mixture was allowed to react for at least 1 hour at −1° C. The reaction mixture was warmed to room temperature and further added thereto was 3.7 mL of a 2M solution of borane-dimethylsulfide complex in tetrahydrofuran. The resulting mixture was kept at room temperature for 2 hours, and cooled to 0° C. After adding water thereto, the resulting solution was extracted three times with 15 mL portions of ethyl acetate, and the organic layers were combined, washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.22 g (yield of 57%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].N1C=CC=CC=1>CN(C=O)C>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:27]
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.33 g, 1.0 mmol,) in dry DMF (3 mL) was cooled on an ice-water bath. Chloroacetyl chloride (0.22 g, 2.0 mmol) and pyridine (80 μL) were added. After stirring at room temperature for 18 h, the reaction mixture was concentrated, poured into ice water and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried on MgSO4 and evaporated to dryness. The resulting greenish residue was purified by SiO2 chromatography (1:1 EtOAc/PE) to afford the title compound as a gray solid. Anal. RP-HPLC: tR=20.6 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >97%). 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.03 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.42 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H), 8.01 (m, 1H, Ph-H), 8.41 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.64 (s, 1H, Ph-H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Yield: 63.4 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.38 g, 17.40 mmol), 5-bromo-2-nitro-pyridine (3.52 g, 17.40 mmol), Cs2CO3 (11.34 g, 34.8 mmol), and Pd(PPh3)2Cl2 (1.27 g, 1.74 mmol) in dioxane (50 mL) was stirred at 85° C. under N2 atmosphere overnight. TLC showed a complete reaction. The solution was poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel (petroleum ether:ethyl acetate, 2:1 eluent) afforded the desired product as yellow solid (3.37 g, 64%). 1H NMR (300 MHz, CDCl3): δ 8.63 (d, J=2.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.93 (dd, J=8.4, 2.4 Hz, 1H), 6.31 (s, 1H), 4.17-4.14 (m, 2H), 3.68 (t, J=5.7 Hz, 1H), 2.57-2.54 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7]C1=O.S(=O)(=O)(O)O>O.[OH-].[K+]>[NH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:9][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCN1CC(c2ccccc2)NC1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCNCC(N)c1ccccc1

Procedure:
The racemic 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone (2.2 g) obtained is heated at 140°-150° C. for 20 hours with 60 weight percent sulfuric acid. The solution is cooed to room temperature, diluted with water and 20% potassium hydroxide to attain a pH of 10 and extracted with methylene chloride. The extracts are washed, dried and concentrated to yield racemic N-(2-amino-2-phenylethyl)-2-methoxyethylamine, [α]D20 =-0.00 (c=1, CHCl3).