Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (35 g, 194 mmol) and pyridine (17.5 ml) in dry dichloromethane (200 ml) at 0° C. was added methanesulfonyl chloride (20 ml, 258 mmol) dropwise. The mixture was stirred for 3 hours at room temperature. The mixture was washed with water and extracted with dichloromethane (2×100 ml). The organic layers were dried with MgSO4 and evaporated in vacuo. The residue was triturated and washed with methanol to give 1-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:10])[O:13][CH2:12][CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2cccc(Br)c2)OCCO1

Procedure:
30.1 g (151 mmol) of (3-bromophenyl)methyl ketone and 13.8 g (222 mmol) of ethylene glycol are dissolved in 120 mL of benzene, mixed with 60 mg of 4-toluenesulphonic acid and boiled under reflux at a water separator (Dean-Stark apparatus) until no more water is separated off. The reaction solution is washed with 50 mL of a 0.5 M NaHCO3 solution, the organic phase is separated off and dried over anhydrous MgSO4. After removal of the benzene in a rotary evaporator, the residue becomes the product with a purity (GC) of 97% in nearly quantitative yield as colorless oily liquid. C10H11O2Br.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1>O1CCCC1.C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[C:19]1([OH:22])[CH2:20][CH2:21][S:17][CH2:18]1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Reactant: O=C1CCSC1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)CCSC2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at −78° C. under N2 is treated with see-butyllthium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at −78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at −78° C., allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf=0.37 by TLC, ethyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf=0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>C(#N)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) in acetonitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of p-fluorobenzaldehyde (1.6 mmol, 0.2 g) in dimethylformamide (8 mL) was added phenol (3.52 mmol, 0.33 g) and cesium carbonate (3.52 mmol, 1.15 g). The reaction mixture was headed to 90° C. for 3 hours at which time the reaction mixture was cooled to room temperature and filtered through a medium fritted funnel. The reaction mixture was then diluted with 125 mL of ethyl acetate and extracted with eight 15 mL portions of water followed by one 10 mL portion of brine. The organic layer was then dried with magnesium sulfate and evaporated to dryness. The title product was purified by column chromatography and 0.237 g (1.2 mmol) was recovered. 1H NMR (300 MHz, CDCl3) δ 9.91 (s, 1H), 8.02 (s, OH), 7.92-7.79 (m, 2H), 7.49-7.37 (m, 2H), 7.23 (t, J=8.0, 2H), 7.14-7.01 (m, 4H), 6.89 (t, J=8.3, 2H). 13C NMR (75 MHz, CDCl3) δ 191.28, 163.56, 156.41, 155.26, 132.28, 131.38, 130.41, 129.79, 125.23, 120.69, 120.45, 117.79, 115.61.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:20]C(OC(C)(C)C)=O)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1>C(Cl)Cl>[NH2:20][C@@H:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:9][CH:10]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 139.2 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to a solution of (S)-methyl 3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoate (30 mg) in methylene chloride (2 mL). The reaction was stirred for 1 h, and was concentrated under reduced pressure to give the crude product methyl (2S)-2-amino-3-biphenyl-4-ylpropanoate (30 mg, 100%). Analytical LCMS (M+H)+: m/z=256.1.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=NO)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
4-Methylbenzaldehyde (20 g, 166 mmol), hydroxylamine hydrochloride (12.7 g, 183 mmol), and sodium acetate (23.1 g, 282 mmol) were dissolved in a mixed solvent of ethanol (400 ml) and water (150 ml), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20.6 g, 152 mmol, 91.8%).
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[CH3:12][C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>OS(O)(=O)=O>[Br:1][C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:13]([CH3:12])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 176.7 %

Procedure:
1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (13.0 g, 45.7 mmol) was added to a mixture of 2-methyl-3-nitrobenzoic acid (15 g, 82.8 mmol) in conc. H2SO4 (60 mL), and the reaction mixture stirred at room temperature for 5 h. After completion of reaction, the mixture was slowly poured onto ice cold water (400 mL). The precipitated was filtered and dried under vacuum to obtain desired 5-bromo-2-methyl-3-nitrobenzoic acid (21 g, 98.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].N>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: N#CCc1cccc(N)c1
Temperature: 85 °C
Yield: 96.3 %

Procedure:
A mixture of (3-nitro-phenyl)-acetonitrile (2.00 g, 12.35 mmol), iron dust (2.07 g, 37.03 mmol) and ammonia chloride (1.96 g, 37.03 mmol) in EtOH (20 mL) and water (4 mL) was refluxed at 85° C. for 1 h. The reaction mixture was filtered through cellite and rinsed with EtOH. The combined filtrate was concentrated and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (1.57 g, 11.89 mmol, 96% yield) as a pale-yellow solid. MS (ESI) m/z 133.1 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH2:26][CH3:27]>C(#N)C>[CH2:24]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Agent: Cl
Solvent: CC#N
Product: CCCCN1CCC(NC(=O)c2nn(CCC)c3ccccc23)CC1
Yield: 69 %

Procedure:
To a suspension of N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.52 g) obtained in Example 20 in acetonitrile were successively added 50% potassium fluoride-Celite (1.10 g) and 1-bromobutane (0.22 ml), and the mixture was heated under reflux for 11 hours. The reaction solution was filtered off, distilled off under reduced pressure, and to the residue was added chloroform and saturated aqueous sodium hydrogencarbonate. After extraction with chloroform, the chloroform layer was dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (0.42 g) as a yellow oily substance. Yield=69%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 3-(4-bromophenyl)propan-1-ol (1 eq.) in DMF (0.25 M) was added imidazole (1.2 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.). The resulting solution was stirred at RT for 13 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with hexanes. The combined organic extracts were washed further with water and brine. Concentration of the organic extracts in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.COC(OC)(C)C>>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][C:11]([CH3:13])([CH3:10])[O:5][CH2:4]1
Reactant: OCC(CO)(CBr)CBr
Reactant: CC(C)=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(CBr)(CBr)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TsOH monohydrate (0.1 eq) was added at 0° C. to a 0.2M solution of 2,2-bis(bromomethyl)propane-1,3-diol in acetone/2,2-dimethoxypropane (10:1) and the solution was stirred for 2 h at RT. Filtration over a pad of neutral alumina with EtOAc afforded the title compound as a white solid after evaporation of the solvent in vacuo (quant). 1H NMR (300 MHz, CDCl3, 300 K) 3.80 (s, 4H), 3.58 (s, 4H), 1.42 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].C(O)C.Cl.[NH2:16][OH:17]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:16][OH:17])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(C=NO)c1

Procedure:
To a solution of 3-nitrobenzaldehyde (5.0 g; 33.1 mmol) in abs. ethanol (40 ml) was added hydroxylamine, hydrochloride (3.45 g; 49.6 mmol) and the resulting suspension was heated to reflux overnight. The cooled mixture was poured into water (100 ml) and the product was filtered off and dried. Yield: 4.5 g (82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Br:19])=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C)cs1
Solvent: CC#N
Product: CCOC(=O)c1nc(C)c(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methyl-thiazole-2-carboxylic acid ethyl ester (171 mg, 1.0 mmol) in acetonitrile (5 ml) is added NBS (180 mg, 1.0 mmol). The reaction mixture is stirred at rt for 2 hr followed by the addition of a second portion of NBS (180 mg, 1.0 mmol). After stirring at rt for 3 hr, the solvent is removed. The resulting residue is purified by PTLC to give the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=1)[NH2:20].N12CCN(CC1)CC2>CS(C)=O.O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=2)[NH2:20])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C

Procedure:
A solution of t-butyl 1-piperazine carboxylate 38 (1.0 g., 5.4 mmole), 5-chloro-2-nitroaniline 54 (0.93 g., 5.4 mmole) and 1,4-diazabicyclo[2.2.2]octane (0.61 g., 54 mmole) in DMSO (10 mL.) was heated 16 hours under argon, cooled to r.t. and diluted with water (150 mL.) and extracted with ethyl acetate (3×50 mL.). The combined organic layers were washed with water (3×30 mL.) and dried over Na2SO4. Solvent was removed and the residue chromatographed (40% EtOAc/Hexane, silica) to give the title compound as a yellow solid, (0.5 g., 30%). MS (M+H)+ 323.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:26]CC.Cl>ClCCl.CCCCCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CCOCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-(trifluoromethyl)benzonitrile (10.0 g, 40 mmol) in dichloromethane (100 mL) was dropwise added a 1.0 M solution of diisobutylaluminum hydride in hexane (48 mL). The resulting solution was stirred under nitrogen at ambient temperature for 1 h and was then diluted by addition of ether (100 mL). After cooling in an ice bath, a 3 N solution of HCl was carefully added, and the mixture was vigorously stirred at ambient temperature for 15 min. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting oil was purified by flash chromatography (5% EtOAc/hexane) affording 5 g of 2-bromo-5-trifluoromethylbenzaldehyde. 1H NMR (CDCl3) δ 10.39 (s, 1H), 8.18 (d, J=2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.5 Hz, 2 Hz, 1H).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:18]1([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:7]2[CH:8]=[C:4]([CH2:3][OH:2])[N:5]=[CH:6]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 20 h

Procedure:
To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vccuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A suspension of 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (11.6 g, 60 mmol) and 10% Pd/C (1.2 g) in MeOH was stirred overnight at RT under H2 (40 psi). The mixture was filtered through Celite® and washed with MeOH. The filtrate was evaporated under vacuum to afford 8.2 g of 7-amino-3,4-dihydro-2H-isoquinolin-1-one, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@@H](CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (2.0 g, 17.2 mmol) in DCM (20 mL) was added Et3N (4.8 mL, 34.44 mmol) followed by p-toluenesulfonyl chloride (3.61 g, 18.94 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane as eluent) to provide compound A94-1 (4.06 g, 87%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH3:1][C:2]1[N:7]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1cccc(N)n1
Solvent: CCO
Product: CCOC(=O)c1cn2c(C)cccc2n1
Yield: 100 %

Procedure:
A solution of 6-methyl-2-pyridinamine (10 g, 93 mmol) [Aldrich, A75706] and ethyl bromopyruvate (15 mL, 110 mmol) in ethanol (93 mL) was heated at 90° C. for 4 h. The reaction mixture was concentrated, diluted with dichloromethane (250 mL), and washed with 10% aqueous potassium carbonate (200 mL). The aqueous layer was separated and extracted with additional dichloromethane (100 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude solid. The solid was treated with diethyl ether (300 mL) and, after several minutes, the diethyl ether was decanted to give the desired product (19 g, quantitative) as a solid after drying under reduced pressure. This material was used without further purification. LCMS for C11H13N2O2 (M+H)+: m/z=205.1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:5]([O:4][C:2]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
Benzyl chloroformate (19 g, 111.1 mmol) in THF (20 mL) was added dropwise over 15 min to a stirred solution of 2-(methylamino)ethanol (10 g, 133.3 mmol) in THF (100 mL) and aqueous sodium carbonate (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 12 h and then extracted with EtOAc (2×200 mL). The organic layer was washed with aqueous sodium carbonate (200 mL) and dried (potassium carbonate) and solvent was removed under reduced pressure to give the title compound (22.5 g, 97% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14](=[O:15])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Product: CN(CCO)C(=O)OCc1ccccc1

Procedure:
N-methylethanolamine was treated with benzylchloroformate to give (2-hydroxy- ethyl)-methyl-carbamic acid benzyl ester. The product was treated with methanesulfonyl chloride and Et3N in CH2Cl2 to give methanesulfonic acid 2-(benzyloxycarbonyl-methyl-amino)-ethyl ester. The resulting mesylate is used to alklylate 3 as described for the preparation of 4. The isopropenyl group is removed with acid as described for 6. The product is alkylated as described for compound 7 and the benzyloxy group was removed with catalytic hydrogenation (Pd/C) to give compound 99.