Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(C#N)cc23)CC1
Reaction time: 18 h

Procedure:
A solution of 3-[1-(t-butoxycarbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-cyanoindole (15.3 g, 47.3 mmol) in ethanol was treated with 10% palladium on carbon (2.38 g). The mixture was hydrogenated on a Parr shaker at 50 psi for 18 hours and then filtered through celite to remove inorganics. Evaporation gave the desired product as an off white solid (15.2 g, 98%). 1H-NMR δ(CDCl3) 8.33 (br s, 1 H), 7.99 (s, 1 H), 7.42 (s, 2 H), 7.07 (s, 1 H), 4.22 (m, 2 H), 2.82 (m, 3 H), 1.98 (br d, 2 H), 1.66 (m, 2 H), 1.48 (s, 9 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11]C1C=CC=C2C=CC=CC=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[CH2:22]1N(P(OC2C=CC(OP(N3CC3)(NCCC(C3C=CC=NC=3)=O)=O)=CC=2)(NCCC(C2C=CC=NC=2)=O)=O)C1.C(C1SC=CC=1)(=O)C.CNC.C=O>>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([C:6]1[S:10][CH:9]=[CH:8][CH:7]=1)=[O:11]
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Reactant: O=C(CCNP(=O)(Oc1ccc(OP(=O)(NCCC(=O)c2cccnc2)N2CC2)cc1)N1CC1)c1cccnc1
Agent: C=O
Agent: CC(=O)c1cccs1
Agent: CNC
Product: CN(C)CCC(=O)c1cccs1

Procedure:
Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][C:5]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[N+:26]([O-:28])=[O:27])([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:56].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1([CH3:29])[O:7][CH2:6][C:5]([CH2:8][F:56])([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[N+:26]([O-:28])=[O:27])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OCC(CF)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
30 mg (0.0705 mmol equivalents) of 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1.0 mL of acetonitrile, 39.8 mg (0.106 mmol equivalents) of Kryptofix 222 (trade name, Merck), 5.1 mg (0.088 mmol equivalents) of potassium fluoride, and 2.0 mg (0.014 mmol equivalents) of potassium carbonate were added thereto, and the mixture was stirred under reflux by heating for 3 hours. After completion of the reaction, the reaction liquid was cooled to room temperature (25° C.), the solvent was then removed by distillation, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=2/1) to give 9.2 mg (0.034 mmol equivalents) of 2,2-dimethyl-5-fluoromethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:12])[CH2:10]Cl)[CH:3]=1.[CH3:13][P:14](=[O:25])([O-:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1.[K+]>CC(C)=O>[CH3:13][P:14](=[O:24])([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[O:25][CH2:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:12]
Reactant: Cc1ccnc(NC(=O)CCl)c1
Reactant: CP(=O)([O-])Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccnc(NC(=O)COP(C)(=O)Oc2ccc(Cl)c(Cl)c2)c1

Procedure:
N-(4-Methyl-2-pyridyl)-α-chloroacetamide (18.5 grams), potassium O-(3,4-dichlorophenyl) methylphosphonate (29.5 grams) and acetone (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is stirred and heated at reflux for a period of about 18 hours. After this time the reaction mixture is cooled, filtered and stripped of acetone on a steam bath to yield a residue. The residue is extracted with chloroform and the chloroform solution is washed with water. The washed solution is dried over magnesium sulfate, is filtered and evaporated to yield the desired product O-[2-(4-methyl-2-pyridylamino)-2-ketoethyl] O-(3,4-dichlorophenyl) methylphosphonate as the residue.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C@H:9]2[CH2:13][O:12][C@H:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C@@H:10]2[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)=[CH:3][CH:2]=1>CO.Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C@H:9]2[CH2:13][O:12][C@H:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C@@H:10]2[CH2:20][CH2:21][CH2:22][OH:23])=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1
Agent: Cl
Solvent: CO
Product: OCCC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.37 g (0.00272 mole) of (2S,3S,4R)-4-(biphenyl-4-ylmethoxy)-3-(3-t-butyldimethylsilyloxyprop-1-yl)-2-(3-pyridyl)tetrahydrofuran in 14 ml of methanol, hydrogen chloride gas is bubbled until the pH of the solution is brought to 3. The mixture is stirred at room temperature for 1 h and evaporated. The residue is triturated with ethyl acetate and neutralized with concentrated aqueous sodium bicarbonate. The aqueous layer is extracted once more with ethyl acetate and the combined organic extracts are dried (MgSO4) and evaporated. The residue is purified by flash chromatography using methylene chloride-methanol-ammonium hydroxide (300:25:1) as eluent to give (2S,3S,4R)-4-(biphenyl-4-ylmethoxy)-3-(3-hydroxyprop-1-yl)-2-(3-pyridyl)tetrahydrofuran as an oil having [α]D25 =+89.78° (MeOH).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C1CSC(=O)C1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a stirring solution of 695 mg (6.04 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.97 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.37 g (7.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.19 mmol) of γ-linolenic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.8 g (79%) of 4-hydroxy-3-[(Z,Z,Z)-1-oxo-6,9,12-octadecatrienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:64])[CH2:36][C:37]1[C:38](=[O:63])[N:39]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53]([NH2:55])=[NH:54])[CH:41]=2>>[CH2:56]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53]([NH2:55])=[NH:54])[CH:41]=2)[CH:46]=[C:37]([CH2:36][C:35]([OH:64])=[O:34])[C:38]1=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: COC(=O)Cc1cc2ccc(OCCCCNC(=N)N)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCCOc1ccc2cc(CC(=O)O)c(=O)n(Cc3ccccc3)c2c1

Procedure:
The title compound is prepared according to the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester trifluoroacetate is replaced with [1-benzyl-7-(4-guanidino-butoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: Cl.O[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([Cl:12])[CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([Cl:12])[CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)ccnc1CO
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1c(Cl)ccnc1CCl

Procedure:
A 1000 ml round-bottom flask is loaded with 67 g (0.319 mol) of 2-hydroxymethyl-3-methoxy-4-chloro-pyridine hydrochloride and 469 ml of toluene. 73 g (0.606 mol) of thionyl chloride are then dropped therein, under stirring and at inner temperature of about 15–25° C. After completion of the addition, the mixture is washed with 35 ml of toluene, keeping the suspension at this temperature for at least 1 hour. After completion of the reaction, approx. 200 ml of solvent are distilled off under vacuum. The suspension, containing 2-chloromethyl-3-methoxy-4-chloro-pyridine, is then subjected to the subsequent step.
Reaction SMILES: [OH:1][C@@H:2](C)[C:3](N1CCNCC1)=O.[OH:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15]>>[C:2]([O:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15])(=[O:1])[CH3:3]
Reactant: C[C@H](O)C(=O)N1CCNCC1
Reactant: C[C@H](O)C(=O)O
Product: CC(=O)O[C@@H](C)C(=O)O

Procedure:
Scheme 3 shows the synthesis of intermediate, oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V from (S)-2-hydroxypropanoic acid (L-lactic acid) 1. Acetylation of 1 gave (S)-2-acetoxypropanoic acid 2, followed by treatment with a chlorinating reagent, such as oxalyl chloride, to give acid chloride, (S)-1-chloro-1-oxopropan-2-yl acetate 3 (Example 6). Reaction of 3 with the dihydrochloride salt of 1-benzylpiperazine in dichloromethane in the presence of triethylamine gave (S)-1-(4-benzylpiperazin-1-yl)-1-oxopropan-2-yl acetate 4 (Example 7). Hydrolysis of the acetate of 4 with lithium hydroxide gave (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 5 (Example 8), followed by hydrogenation to remove the N-benzyl group to give (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one 6 (Example 9). The oxalate salt was formed from 6 with oxalic acid in ethanol and tetrahydrofuran to give V (Example 9).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:20]([CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.C(#N)C>[Pd].CO>[CH2:29]([C:20]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:30]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CC#N
Solvent: CO
Product: CCc1nc2cnc3cc(O)ccc3c2n1CC1CCOCC1
Reaction time: 16 h
Yield: 94.6 %

Procedure:
7-(Benzyloxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (8.3 g, 20.7 mmol) was added to a Parr vessel containing 10% palladium on carbon (1.5 g) wetted with acetonitrile. Methanol (160 mL) was added and the vessel was placed on the hydrogenator. The vessel was degassed three times and charged with 50 psi (3.4×105 Pa) hydrogen. The vessel was allowed to shake for 16 hours, replenishing the hydrogen as needed. The catalyst was removed by filtration through glass fiber filter paper. The catalyst was washed with 3:1 chloroform/methanol. The filtrates were combined. Evaporation under reduced pressure afforded 6.1 g of 2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol as a gray solid.
Reaction SMILES: CO.[CH3:3][NH2:4].C(O[C:8]([C:10]1[C:11]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9])C>O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:11]3[C:10]([C:8]([NH:4][CH3:3])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To the solution of methanol with 40% methylamine (30 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (1.5 g) obtained by by preparation example 1, and the solution was reacted at 25-30° C. for 1 hr. The reaction mixture was cooled at 20-25° C., added H2O (90 ml) and stirred for 0.5hr. The reaction mixture was filtered, washed with 25% aqueous methanol solution (10 ml), obtained a solid product. The solid product was dried in vacuo to obtain the desired compound (1.26 g, 88%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22].C(N(CC)CC)C>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[C:25]#[N:26])=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC#N
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 144 h

Procedure:
To 1 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 930 mg of methylsulfonylacetonitril and 1.6 g of triethylamine. After 24 hours another 1 g of methylsulfonylacetonitril and 0.3 g of triethylamine was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (4a). Yield 1.1 g of (4a), m.p. 206° C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([S:9]([CH2:12][C:13]([OH:15])=[O:14])(=[O:11])=[O:10])[CH3:8])=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[CH3:27]O>>[CH3:27][O:14][C:13](=[O:15])[CH2:12][S:9]([CH:7]([C:4]1[CH:3]=[CH:2][C:1]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)[CH3:8])(=[O:11])=[O:10]
Reactant: CO
Reactant: CC(c1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CS(=O)(=O)C(C)c1ccc(-c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
17.0 gm (56 millimols) of [1-(4-biphenylyl)-ethylsulfonyl]-acetic acid were dissolved in 100 ml of methanol, and 3 ml of phosphorus oxychloride were added to the solution while cooling on ice. The mixture was heated to 35° C. and was then allowed to stand overnight at room temperature. The crystalline reaction product which had separated out was suction-filtered off and recrystallized from 50 ml of isopropanol. Yield: 14.8 gm (83% of theory); m.p. 79°-80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>C(O)CO.O>[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]3[C:22]([N:25]=[C:5]4[C:4](=[N:26]3)[C:3]3[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6]4)=[N:23][N:24]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C)c2c1NC(=O)C2=O
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Solvent: OCCO
Solvent: O
Product: Cc1ccc(C)c2c1[nH]c1nc3nnc(Cc4ccc(F)cc4)n3nc12
Temperature: 125 °C
Reaction time: 18 h

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4,7-dimethyl-1H-indole-2,3-dione (105 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (18 hr). The mixture was cooled to room temperature, diluted with water (10 mL), stirred for 15 min. The precipitated product was collected by filtration, washed with MeOH+water 1:1. Dried on high vacuum. The crude product (187 mg) was suspended in anhydrous ethanol (6 mL), heated to reflux, sonicated while hot, allowed to cool overnight, filtered, washed with ice-cold methanol, filtered and dried on high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[S:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][N:19]=1>N1C=CC=CC=1>[C:20]([C:17]1[S:16][C:15]([NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:19][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cnc(N)s1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.336 g, 6.681 mmol) in anhydrous pyridine (30 mL) was treated with 2-amino-5-tert-butylthiazole (1.044 g, 6.681 mmol) and the reaction stirred at room temperature under a nitrogen atmosphere. The solvent was removed by rotary evaporation in vacuo and the residue dried on a vacuum pump. The residue was taken up in ethyl acetate (100 mL) and washed with water (4×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 5% ethyl acetate/methylene chloride provided the title compound (1.76 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]=[O:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br.O>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH2:19][C:18]2[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:17]=2[Cl:16])[C:3]=1[CH:8]=[O:9]
Reactant: Clc1cc(I)ccc1CBr
Reactant: Cc1nc(C=O)c(Cl)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C=O)n1Cc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-chloro-2-methylimidazole-4-carbaldehyde (433 mg) in N,N-dimethylformamide (4.3 ml) were added potassium carbonate powder (616 mg) and 2-chloro-4-iodobenzyl bromide (1.2 equivalents) under ice-cooling and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture were added water and saturated brine, and the resulting product was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give 4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazole-5-carbaldehyde (1.01 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=N[CH:13]=2)=[CH:4][CH:3]=1.[CH2:31]([C@@H]1COC(=O)N1C(=O)[C@H](CS(N1CCN(C2C=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=O)=O)C(C)C)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:31][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Yield: 59 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluoro-phenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine-1-sulfonyl methyl}-3-methylbutyryl)-oxazolidin-2-one (0.167 g), to yield the title compound as a white solid (0.072 g, 59%).
Reaction SMILES: [OH:1][C@H:2]([CH3:21])[C@@H:3]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].CO>C1COCC1.O>[OH:1][C@H:2]([CH3:21])[C@@H:3]([CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@H](CC1CCC(c2ccccc2)CC1)[C@@H](C)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of methyl (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoate (4.17 g, 0.014 mol) and lithium hydroxide monohydrate (0.59 g, 0.014 mol) is stirred at 25° C. in a mixture of THF (30 mL), methanol (15 mL) and water (15 mL) for 72 h. The reaction is not complete and an additional 0.88 g (0.021 mol) of lithium hydroxide monohydrate in water (10 mL) is added. After 6 h an additional 0.59 g (0.014 mol) of solid lithium hydroxide monohydrate and the mixture is stirred at 25° C. for 18 h. The mixture is concentrated in vacuo and the residue is taken up in water, chilled in an ice-bath and the pH is adjusted to 2 with sodium bisulfate. The mixture is extracted with dichloromethane. The combined extracts were washed with saturated sodium chloride, dried over sodium sulfate and concentrated in vacuo to give 3.43 g (89%) of (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoic acid as a yellow solid.
Reaction SMILES: C1(NC(C)C)CCCCC1.[Li]CCCC.[C:16]([O:20][C:21](=[O:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[C:16]([O:20][C:21](=[O:23])[CH2:22][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][CH:27]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of cyclohexyl-isopropyl-amine (1.0 eq.) in THF (2.0M) at −78° C. was added dropwise n-BuLi (0.95eq.). The mixture was stirred at −78° C. for 20 min then a solution of acetic acid tert-butyl ester (1.0 eq.) in THF (5.0M) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h. A solution of 4-bromobenzyl bromide (0.9eq.) in THF (5.0M) was then added dropwise and the final mixture was warm slowly to rt and stirred for 12 h. The reaction was quenched with cold aqueous HCl (1M), diluted water and extracted with Et2O (2×). The combined organic extracts were washed with HCl (1M), brine, dried over Na2SO4, filtered and concentrated. The residue was distilled under vacuum (95° C., 0.4 mmHg) to afford the title compound as a colorless oil.