Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@:19]23[CH2:27][O:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[C@H:24]2[CH2:23][S:22][C:21]([NH2:32])=[N:20]3)[CH:18]=1.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:32][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([C:28]([F:31])([F:29])[F:30])[O:26][CH2:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:2][F:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])[N:20]=1
Reactant: O=C(O)c1cnc(CF)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 42.5 °C
Yield: 70.8 %

Procedure:
5-(Fluoromethyl)pyrazine-2-carboxylic acid (32.6 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (70.0 g, 1.0 equiv)1 were charged to a reactor and ethyl acetate (EtOAc, 630 mL) was added to the mixture to give a suspension. A solution of n-propane phosphonic acid anhydride (T3P, 146 g, 1.10 equiv, 50 wt % in EtOAc) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40−45° C. >3 hours and monitored by HPLC. The reaction mixture was cooled to 15−20° C. and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30° C. EtOAc (245 mL0 was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (490 mL). The organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL). The organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL). The solution was concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide as a white solid (70.0 g). 1 A preparation of (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine is described herein above in step 1-(25) in the alternative preparation of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide (Example 1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.[CH3:14][N:15]([CH2:17][C:18]1[O:22][C:21]([CH2:23]O)=[CH:20][CH:19]=1)[CH3:16]>Cl>[CH3:14][N:15]([CH2:17][C:18]1[O:22][C:21]([CH2:23][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture containing 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1,1-dioxide (1.0 g; 4.5 mmoles) [prepared in Step A] and 5-dimethylaminomethyl-2-furanmethanol (0.82 g; 4.5 mmoles) [prepared according to the procedure in J. Chem. Soc., 4728 (1958)] in 20 ml of concentrated hydrochloric acid was stirred in an ice-water bath for 2 hours and then allowed to stand at 0° for 64 hours. The reaction mixture was stirred at ambient temperature for 23 hours, evaporated without heating under reduced pressure and the residue partitioned between water and methylene chloride. The aqueous phase was made basic with sodium bicarbonate and extracted with methylene chloride. The combined organic phase was washed with saturated brine solution, dried and evaporated under reduced pressure. The residue was placed on 25 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fraction was evaporated and the product crystallized from methanol. Recrystallization from methanol yielded the title compound, mp 92°-96°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: NCCc1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Add dropwise via an addition funnel a solution of ethyl chloroformate (0.74 mL, 7.7 mmol) in tetrahydrofuran (7 mL) to a stirred solution of tyramine (1.0 g, 7.3 mmol), sodium hydroxide (0.7 g, 17.1 mmol), and water (7 mL). Stir at room temperature for 18 hours then pour the reaction into 1N aqueous hydrochloric acid so the pH=1-2. Extract with ethyl acetate (3×25 mL). Dry the combined ethyl acetate extracts over sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 1.3 g, 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester: 1H NMR (CDCl3, 300.00 MHz): 7.01 (d, 2H); 6.78 (d, 2H); 6.26 (s, 1H); 4.78 (s, 1H); 4.14-4.09 (m, 2H); 3.40-3.38 (m, 2H); 2.74-2.69 (m, 2H); 1.24-1.19 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([CH3:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: CNC
Reactant: Cc1ccc(I)c(CC(=O)Cl)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(I)c(CC(=O)N(C)C)c1

Procedure:
Dimethylamine (200 ml of 2 M solution in THF) is added dropwise to a solution of 5-methyl-2-iodophenylacetyl chloride in Et2O (500 ml) which is cooled in an ice bath. After the addition is complete, EtOAc (350 ml) is added and the solution is washed with water (350 ml), brine (250 ml) and dried (MgSO4). Evaporation on a rotovap and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-methyl-2-iodophenylacetamide as a light tan solid, m.p. 47–49°.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:16])[CH2:9][CH2:10][NH:11][CH2:12][CH:13]([F:15])[F:14])=[CH:5][N:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[F:25][C:26]1([F:32])[CH2:28][CH:27]1[C:29](O)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:16])[CH2:9][CH2:10][N:11]([CH2:12][CH:13]([F:15])[F:14])[C:29]([CH:27]2[CH2:28][C:26]2([F:32])[F:25])=[O:30])=[CH:5][N:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1
Reactant: CCN(C(=O)CCNCC(F)F)c1cn(-c2cccnc2)nc1Cl
Reactant: O=C(O)C1CC1(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)CCN(CC(F)F)C(=O)C1CC1(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((2,2-difluoroethyl)amino)-N-ethylpropanamide (0.10 g, 0.28 mmol) in CH2Cl2 (2 mL) were added 2,2-difluoro cyclopropanecarboxylic acid (0.041 g, 0.34 mmol), DMAP (0.034 g, 0.28 mmol) and N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((2,2-difluoroethyl)amino)-N-ethylpropanamide (0.10 g, 0.28 mmol), and the mixture stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NH4Cl and brine, dried over MgSO4, and concentrated under reduced pressure to give pink oil. The residue oil was purified on silica gel eluting with MeOH/CH2Cl2 to give the title compound F34 as a colorless oil (0.079 g, 58%).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C(O[C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)C.Cl>O1CCCC1>[C:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)#[CH:2]
Reactant: C#C[Mg]Br
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.5N ethynylmagnesium bromide in tetrahydrofuran (100 mL) was added under N2 and stirring 3-ethoxy-2-cyclohexen-1-one (3.75 g, 26.8 mmol) in tetrahydrofuran (12.5 mL). The mixture was stirred at RT for 20 h when it was acidified with 1N HCl (200 mL). After stirring for 15 min the acidic phase was extracted with dichloromethane (5×50 mL). The combined organic extracts were washed with water (2×50 mL) and dried (MgSO4). Evaporation of the solvent gave an oil that was purified by column chromatography (silica, ethyl acetate/hexane 1:9) to yield a yellow oil, 2.71 g, 22.6 mmol, 84%). Analysis were in agreement with literature data.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][C:6]=1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[S:3][C:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][C:6]=1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCc1cc(C(=O)c2ccc(OC)cc2)c(N)s1
Solvent: ClC(Cl)Cl
Product: CCCCCCc1cc(C(=O)c2ccc(OC)cc2)c(NC(=O)CCl)s1
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a solution of 28 g of 2-amino-3-(4-methoxybenzoyl)-5-hexylthiophene in 150 ml of chloroform is added 10 g of chloroacetyl chloride and the mixture is refluxed under heating with stirring for 2 hours. After cooling, the mixture is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution, and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from ethanol to give 16.2 g of 2-chloroacetamido-3-(4-methoxybenzoyl)-5-hexylthiophene as crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1.N1C=CC=CC=1.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:5]1[CH:4]=[C:3]([NH:2][C:19](=[O:20])[O:18][CH2:17][C:16]([Cl:23])([Cl:22])[Cl:15])[S:7][N:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(N)sn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of 5-amino-3-methylisothiazole hydrochloride (21.2 g, 127 mmol), pyridine (68 mL, 841 mmol) and DMAP (4.62 g, 38 mmol) in CH2Cl2 (420 mL) was slowly added trichloroethylchloroformate (31 mL, 224 mmol) over a period of 15 min. The reaction mixture was stirred at −78° C. for 30 min and then warmed to room temperature for 1 h. The mixture was partitioned between EtOAc and water, the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was disolved in Et2O (800 mL), charcoal was added and the resulting black suspension was boiled for 15 min and allowed to stand at room temperature for 18 h. The charcoal was removed by filtration on a pad of celite and the filtrate was concentrated in vacuo. The crude product was crystallized from a hot mixture of Et2O/hexane (1:1, 600 mL) to yield 2,2,2-trichloroethyl 3-methylisothiazol-5-ylcarbamate as a light yellow solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31](=O)[CH3:32])[CH:29]=3)[C:24]([CH3:35])([CH3:34])[CH2:23][CH:22]=2)=[CH:17][CH:16]=1>C1COCC1.CCOCC>[CH3:34][C:24]1([CH3:35])[CH2:23][CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=2)[C:30]2[CH:29]=[C:28](/[C:31](/[CH3:32])=[CH:11]/[C:12]#[N:13])[CH:27]=[CH:26][C:25]1=2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(=O)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C/C(=C\C#N)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reaction time: 0.67 h

Procedure:
To a slurry of NaH (48.0 mg, 2.00 mmol) in THF (6 ml), was added diethylcyanomethylphosphonate (450.0 mg, 2.50 mmol). After 40 mins, a solution of 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-acetylnaphthalene (Compound V) 95.0 mg, (0.33 mmol) in THF (4 ml) was added. The mixture was stirred for 16 hours, diluted with ether (100 ml), and washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure, and column chromatography (3% EtOAc/hexanes) afforded the title compound as a solid. 1H NMR (CDCl3): δ 7.39 (1H, d, J=1H), 7.32 (1H, dd, J=2.0, 8.1 Hz), 7.20-7.25 (4H, brs), 7.15 (1H, d, J=2.0 Hz), 6.03 (1H, t, J=6.0 Hz), 5.44 (1H, s), 2.42 (3H, s), 2.36 (2H, d, J=6.0 Hz), 2.35 (3H, s), 1.35 (6H, s).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][CH2:27][CH2:28][OH:29])=[N:24][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C=O)C>[OH:29][CH2:28][CH2:27][NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(NCCO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(NCCO)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (311 mg, 1.21 mmol), 2-(5-amino-pyridin-2-ylamino)-ethanol (84 mg, 0.55 mmol), N-hydroxybenzotriazole (185 mg, 1.38 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg, 1.38 mmol) in a mixture of methylene chloride (5 mL) and DMF (1 mL) was stirred at room temperature for 5 hr. The solvents were removed, and lithium hydroxide hydrate (excess) in a mixed solvent of methanol, tetrahydrofuran, and water (3:1:1, 5 mL) was added. The reaction mixture was stirred at room temperature for overnight. Solvents were removed, and water was added. The resulted mixture was extracted twice with ethyl acetate. The organic layers were collected, and washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in methylene chloride for 30 min), and then preparative HPLC (0-90% acetonitrile in water for 20 min), followed by lyophilization gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide as a light yellow solid. LCMS calcd for C18H15F3N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[CH2:10][CH:9]1[OH:34])([CH3:4])([CH3:3])[CH3:2].[Cl:37][CH2:38][C:39](Cl)=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:37][CH2:38][C:39]([O:34][C@H:9]1[CH2:10][C@H:11]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[O:12][C@@H:8]1[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:36])[CH3:35])=[O:40]
Reactant: O=C(Cl)CCl
Reactant: CCCCCc1ccc(-c2cc3cn(C4CC(O)C(CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)CCl)[C@@H](CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 25 mL flask was added 102 mg (0.2 mmol) of 3-(5-((tert-butyldimethyl silyloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one, 48 mg (0.4 mmol) of DMAP, and 5 mL of DCM. 30 μl (0.4 mmol) of chloroacetyl chloride was added dropwise. The mixture was stirred at rt for 1 h.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24](O)=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>C1COCC1.CO>[OH:25][CH2:24][CH2:23][CH2:22][C:17]12[CH2:16][CH2:15][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:27])[N:3]([CH2:28][CH2:29][CH3:30])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCCO)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 60 h
Yield: 85.7 %

Procedure:
To a solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionic acid (41.7 mg, 1.0 mmol) in THF (25 ml), cooled to 0° C. with the aid of an ice bath, was added BH3 (1.0 M in THF, 3.0 mmol). The resulting mixture was allowed to reach ambient temperature and stirred for a period of 60 h. Following the addition of MeOH (10 ml), the mixture was concentrated in vacuo to afford a white solid that was dissolved in MeOH. (20 ml), stirred at rt for 2 h and evaporated to dryness in vacuo. The resulting white solid was recrystallized from EtOAc to afford 345 mg (86%) of a white powder MS: 403 (MH−).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[S:34]([CH3:33])(=[O:36])=[O:35])[CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(C)(=O)=O
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (7.5 mg, 0.062 mmol), methanesulfonyl chloride (0.05 mL, 0.61 mmol, Aldrich, St. Louis, Mo.), and Hünig's base (0.2 mL, 0.9 mmol). The reaction mixture was stirred at room 20 min and then the solvent was removed in vacuo. The crude product was purified by column chromatography (40 g of silica, 10% to 30% acetone in hexanes) to afford N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide (0.110 g) as a mixture of two isomers:
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:7][C:8]([OH:10])=O)[C:4]([OH:6])=[O:5])[CH3:2].C(Cl)(=O)C.[CH:17]1([C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[S:26][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])(=O)C.[Na+]>COCCOC>[CH:17]1([C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([NH:36][C:8](=[O:10])[CH2:7][C:3]([CH2:1][CH3:2])([CH2:11][CH3:12])[C:4]([OH:6])=[O:5])[CH:33]=[CH:34][CH:35]=3)[S:26][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCC(CC)(CC(=O)O)C(=O)O
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)Cl
Product: CCC(CC)(CC(=O)Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1)C(=O)O
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
A mixture of 9.26 g (53 mmol) of 2,2-diethylsuccinic acid and 30 ml of acetyl chloride was heated under reflux for 1.5 hr, cooled, and concentrated in vacuo. The residue was reconcentrated twice with toluene and then dissolved in 150 ml of 1,2-dimethoxyethane. To this solution was added 7.56 g (26.4 mmol) of the (E)-3-[2-[4-(cyclohexyl)-2-thiazolyl]-ethenyl]benzeneamine and 10.9 g of sodium acetate dissolved in 150 ml of 1,2-dimethoxyethane. This reaction mixture was heated on the steam bath for 3.5 hr and then concentrated in vacuo. The residue was digested with 600 ml of water on the steam bath for 20 min. The solid was collected to give 10 g of crude product. Recrystallization from ethanol gave 3.5 g of product, mp 180°-185°. Further recrystallization from methanol gave (E)-4-[[3-[2-(4-cyclohexyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-methylene-4-oxobutanoic acid as off-white needles, mp 187°-189°.
Reaction SMILES: CN1CCN(C)C1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)=[O:18])[CH:10]=1.[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].CS(O)(=O)=O>O>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:37][C:25](=[O:27])[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([O:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[O:18])=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Reactant: Nc1ccccc1N
Agent: CS(=O)(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
7.78 g (48 mmole) of N,N′-carbonyldiimidazole were added to a 1,3-dimethyl-2-imidazolidinone (50 g) suspension including 11.45 g (40 mmole) of 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid. After stirring at room temperature for 2 hours, 17.30 g (0.16 mole) of 1,2-phenylenediamine were added to the solution. After cooling to 2° C., 9.60 g (0.1 mole) of methanesulfonic acid were added dropwise. After stirring for 2 hours, water was added, and the deposited solid was collected by filtration. Purification was then carried out through silica gel column chromatography to obtain 10.83 g (yield: 72%) of N-(2-aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)[C:8](=[O:31])[CH:7]=[N:6]2.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:31])[CH2:18][CH2:19]1
Reactant: COc1cc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncc(=O)n(CCN3CCC(N)CC3)c2cc1OC

Procedure:
tert-Butyl {1-[2-(6,7-dimethoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 157, 100 mg, 0.23 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 75 mg (quantitative) of the crude product as an oil.