Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](O)[CH3:5].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([Cl:14])[CH3:5]
Reactant: CC(O)c1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
2,6-Difluoro-alpha-methylbenzyl alcohol of (B) (14.9 g, 0.094 mol) is dissolved in chloroform (50 ml) and warmed to 60° C. Thionyl chloride (22.4 g, 0.19 mol) is now added dropwise. The whole is kept at 60° C. for 4 hours then stirred overnight at room temperature. Excess thionyl chloride and chloroform are then removed on a rotary evaporator, resulting in pure title product (16.6 g, 99.8%).
Reaction SMILES: [CH3:1][C:2]([O:32]C1CCCCO1)([CH2:27][CH2:28][C:29]#[C:30][CH3:31])/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][C@H:6]1[O:20]C1CCCCO1>C(O)(=O)C.O.C1COCC1>[OH:20][C@H:6]1[C@H:5](/[CH:4]=[CH:3]/[C:2]([OH:32])([CH3:1])[CH2:27][CH2:28][C:29]#[C:30][CH3:31])[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7]1
Reactant: CC#CCCC(C)(/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC#CCCC(C)(O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
500 mg. of (5Z,13E)-(11R,15RS)-15-methyl-9-oxo-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated for 16 hours at 20° with 15 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), then evaporated under vacuum, and the remainder purified by column chromatography on silica gel. With methylene chloride/5% methanol, 260 mg. of the title compound is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-1-fluoro-2-nitrobenzene, 1-Boc-piperazine, and TEA yielding tert-butyl 4-(4-chloro-2-nitrophenyl)piperazine-1-carboxylate (95%). LCMS (m/z): 342.0 (MH+); LC Rt=3.50 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:19]=[C:18]([NH:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:17][N:16]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7]1.Cl.[Cl-].[NH2:42][C@@H:43]1[C:60](=[O:61])[N:45]2[C:46]([C:57]([OH:59])=[O:58])=[C:47]([CH2:50][N+:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:48][S:49][C@H:44]12.C[Si](C)(C)NC(=O)C>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[NH2:20][C:18]1[S:17][N:16]=[C:15]([C:11](=[N:10][O:9][CH:6]2[CH2:7][CH2:8]2)[C:12]([NH:42][C@@H:43]2[C:60](=[O:61])[N:45]3[C:46]([C:57]([O-:59])=[O:58])=[C:47]([CH2:50][N+:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH2:48][S:49][C@H:44]23)=[O:14])[N:19]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Reactant: O=C(O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)ns1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
Phosphorous oxychloride (0.31 ml) was added to a mixture of N,N-dimethylformamide (0.25 ml) and ethyl acetate (1 ml) under ice-cooling. The mixture was stirred at the same temperature for 10 minutes to give a suspension. To the suspension was added 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.18 g) and tetrahydrofuran (15 ml) and the mixture was stirred under ice-cooling for 30 minutes to give an activated acid solution. On the other hand, to a suspension of 1- [(7β-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride (1.3 g) in tetrahydrofuran (20 ml) was added N-trimethylsilyl-acetamide (8.5 g). The suspension was stirred at ambient temperature for an hour to give a clear solution. To the solution was added the activated acid solution prepared above at -30° C. and the mixture was stirred at -20° C. to -5° C. for 30 minutes and under ice-cooling for an hour. The mixture was poured into ethyl acetate (300 ml) to give precipitates. The precipitates were collected. To the precipitates was added a mixture of anisole (14 ml) and trifluoroacetic acid (4.3 ml) under ice-cooling. The mixture was stirred for 1.5 hours at ambient temperature. The mixture was concentrated in vacuo and poured into ice-water (50 ml). The mixture was adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water, the elution was carried out with 2% isopropyl alcohol. The fractions containing the object compound were collected, combined, evaporated to remove isopropyl alcohol in vacuo, and finally lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol- 3-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)(260 mg).
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([CH:6]([OH:12])CS(C)(=O)=O)=[CH:4][C:3]=1[CH3:16].[NH2-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([CH:6]=[O:12])=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1cc(C(O)CS(C)(=O)=O)cc(C)c1N
Agent: [NH2-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C=O)cc(C)c1N

Procedure:
A solution of 14.6 g. of 4-amino-3,5-dimethyl-α-[(methylsulfonyl)-methyl]-benzyl alcohol in 50 ml. of absolute dimethylsulfoxide was treated with 1.17 g. of sodium amide, stirred for 2 hours at room temperature, diluted with 500 ml. of water and extracted with two 500 ml. portions of ethyl acetate. The ethyl acetate extract was washed with two 200 ml. portions of water and evaporated under vacuum. After recrystallization of the residue from cyclohexane, there was obtained 4-amino-3,5-dimethyl-benzaldehyde having a melting point of 75°-76° C.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=2
Reactant: C[O-]
Reactant: CCCCCNc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 8-bromo-N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (607 mg) in dry MeOH (4.75 mL) was added sodium methoxide solution (0.906 mL, 30% wt. MeOH) and the mixture was stirred at 60° C. for 48 h. The reaction was concentrated in vacuo. The residue was taken up in EtOAc (25 mL) and washed with saturated ammonium chloride (25 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a red/brown viscous oil (520 mg) which was used crude in the next step.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:25])([C@H:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[CH3:18])[CH2:15]O.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[N:44][CH:43]=[N:42]1>O1CCCC1.CO.CN(C)C=O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:25])([C@H:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[CH3:18])[CH2:15][N:41]1[CH:45]=[N:44][CH:43]=[N:42]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](c1ccncn1)[C@](O)(CO)c1ccc(F)cc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](c1ccncn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (1.15 g) was added to a stirred solution of the product of part (iv) (2.35 g) and diisopropylethylamine (2.38 g) in dry tetrahydrofuran (30 ml) at -10° to -20° under an atmosphere of dry nitrogen. The solution was stirred at the same temperature for 1 hour and then anhydrous potassium carbonate (7.0 g) and dry N,N-dimethylformamide (25 ml) were added. The mixture was stirred at room temperature for 1.5 hours and then partitioned between water and ether. The organic layer was separated, washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was immediately dissolved in methanol (50 ml). 1H-1,2,4-Triazole (6.0 g) and anhydrous potassium carbonate (6.0 g) were added and the mixture was heated at 60° with stirring for 40 hours, then evaporated. The residue was partitioned between ethyl acetate/ether (1:1) and water, the organic layer was separated and washed with water, then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Initial elution with ethyl acetate gave impurity-containing fractions, and subsequent further elution with ethyl acetate/methanol (20:1) gave, after combination and evaporation of appropriate fractions, the title compound, (0.87 g), m.p. 55°-58°, [α]25/D -65.1° (0.55% in methanol).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1>CO.[OH-].[Na+]>[ClH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCCCCN1CCC(OC(c2ccccc2)c2ccc(C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(OC2CCN(CCCCCC(=O)O)CC2)c2ccccc2)cc1
Yield: 96.3 %

Procedure:
A mixture of 8.29 g of (±)-methyl 4-[(4-methylphenyl)-phenylmethoxy]-1-piperidinecaproate hydrochloride in 40 ml of methanol and 28 ml of 2N sodium hydroxide aqueous solution was refluxed for 1 hour and concentrated. Water was added to the residue, made acidic with hydrochloric acid and extracted with chloroform. The extract was dried and concentrated. The residue was solidified by treatment with ethyl acetate and ether. The precipitate was collected by filtration to give 7.73 g of colorless crystals. The crystals were then recrystallized from a mixture of water and acetone to give 5.80 g of colorless prisms, mp 168°~170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7]OC.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:19][CH:7]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC=Cc1cccc(OC)c1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(-c2c[nH]c3ccccc23)c1
Temperature: 25 °C

Procedure:
A 90 g portion of the abovementioned methyl (3-methoxystyryl) ether was dissolved in 100 ml of ethanol. Then the solution was added dropwise to a mixed solution of 59.3 g phenylhydrazine, 800 ml ethanol and 53 ml concentrated hydrochloric acid under reflux, and after the addition, reflux heating was continued for 2 more hours. The reaction mixture was then cooled to room temperature, and after adding water, sodium chloride and a small amount of ethyl acetate, the mixture was stirred and the precipitated crystals were collected by filtration. The crystals were dissolved in chloroform and washed with dilute hydrochloric acid and sodium bicarbonate aqueous solution. And the solution was dried and concentrated to obtain a residue. Then toluene was added to the residue, and after refluxed for one hour. After cooling, precipitated crystals were then collected by filtration to obtain 89.6 g of 3-(3-methoxyphenyl)indole.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].C(C1C=C(C=CC=1)C(O)=O)(=O)C>>[N:10]1([C:8]([C:5]2[CH:4]=[C:3]([C:15](=[O:17])[CH3:16])[CH:2]=[CH:7][CH:6]=2)=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)c1cc(C(=O)N2CCCC2)ccc1O
Agent: CC(=O)c1cccc(C(=O)O)c1
Product: CC(=O)c1cccc(C(=O)N2CCCC2)c1

Procedure:
The title intermediate was synthesized as described for Compound 18 except 3-acetylbenzoic acid was used instead of 3-acetyl-4-hydroxy benzoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.Cl>C(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Yield: 78.9 %

Procedure:
A mixture of 0.20 g (0.66 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 0.11 g (0.79 mmole) of 4-aminobenzoic acid in a 1:4 mixture of 5 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.21 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-131).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CC(N(C)C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[CH3:9])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1cc(N)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(N)ccc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of 4-amino-2-methyl-phenol (4.25 g, 34.5 mmol) in dimethylacetamide (50 mL) was degassed in vacuo and blanketed with argon. Potassium tert-butoxide (5.0 g, 44.6 mmol) was added and the reaction mixture was de-gassed a second time and stirred at RT under argon for 30 min. 2,4-Dichloro-pyridine (4.6 g, 31.3 mmol) was added and the mixture was heated to 100° C. overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine (4.5 g, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=5.2 Hz, 1H), 6.75-6.80 (m, 3H), 6.45-6.50 (m, 2H), 5.15 (s, 2H), 1.92 (s, 3H); MS (ESI) m/z: 235.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: COC(=O)c1ccc(F)cc1
Product: O=C(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 15 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (900 mg, 3.0 mmol), using methyl 4-fluorobenzoate instead of 4-fluoroacetophenone, was converted to the title compound (190 mg, 15%) which was obtained as a white solid. MS: m/e=416.3 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[C:32]([Cl:34])[CH:33]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:37][CH2:36][N:35]([C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[C:32]([Cl:34])[CH:31]=3)[CH2:40][CH2:39]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([O:11][C@H:12]([C@@H:14]([N:17]1[C:21](=[O:22])[N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:19]=[N:18]1)[CH2:15][CH3:16])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC1C=CC(S(O[CH2:53][C@H:54]2[CH2:58][C@:57]([CH2:67][N:68]3[CH:72]=[N:71][CH:70]=[N:69]3)([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=3[F:66])[O:56][CH2:55]2)(=O)=O)=CC=1>CS(C)=O>[N:68]1([CH2:67][C@@:57]2([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=3[F:66])[O:56][CH2:55][C@@H:54]([CH2:53][O:41][C:38]3[CH:39]=[CH:40][C:35]([N:32]4[CH2:31][CH2:30][N:29]([C:26]5[CH:27]=[CH:28][C:23]([N:20]6[C:21](=[O:22])[N:17]([C@H:14]([CH2:15][CH3:16])[C@@H:12]([O:11][CH2:4][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=7)[CH3:13])[N:18]=[CH:19]6)=[CH:24][CH:25]=5)[CH2:34][CH2:33]4)=[CH:36][CH:37]=3)[CH2:58]2)[CH:72]=[N:71][CH:70]=[N:69]1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC[C@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 52.5 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium hydroxide (9.2 g) and water (10 ml) was cooled to 25-35° C. and added dimethyl sulfoxide (350 ml), followed by 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (50 gms) compound of formula-20 at 25-35° C. The reaction mixture was stirred for 45 minutes at the same temperature. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (50 μms) compound of formula-10 was added to the above reaction mixture and heated to 45-60° C. The reaction mixture was stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and neutralized with hydrochloric acid. The reaction mixture was stirred for 1 hour at 25-35° C. Filtered the solid and washed with water. Dried the solid to get the title compound. Yield: 79 g
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:13]([CH3:31])[CH:12]=1>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[C:13]([CH3:31])[CH:12]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(F)ccc1Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 241 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.380 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-fluoro-2-methylphenoxy)phenyl)pyridin-2-amine (354 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give the title compound (375 mg) as a slightly yellow solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[Na].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1CBr.[OH-].[K+]>O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[CH:24][CH:25]=[CH:26][C:27]=1[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: BrCc1ccccc1-c1ccccn1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1ccccn1)C(=O)O
Temperature: 130 °C

Procedure:
148 g (0.85 mol) of diethyl methylmalonate were added dropwise at room temperature to 19.5 g (0.85 mol) of sodium in 400 cm3 of H2 O-free EtOH. Subsequently, 211 g (0.85 mol) of 2-(2-pyridyl)benzyl bromide were added dropwise and the mixture was heated under reflux for 3 hours. At room temperature, 143 g (2.55 mol) of KOH dissolved in 500 cm3 of H2O were added and the mixture was heated under reflux for a further 4 hours. The EtOH was distilled off and the residue was admixed with H2O until completely dissolved and subsequently acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated for 1 hour at 130° C. This gave 193 g (94%) of 2-(2-(2-pryridyl)benzyl)propionic acid as solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:21])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccc(Br)cc1)C1CCNC1
Yield: 82.4 %

Procedure:
Stir a solution of 3-(4-bromo-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.79 g, 10.7 mmol) in 4 M HCl in dioxane (21.4 mL) at 0° C. for one hour. Concentrate the reaction mixture, dilute the mixture with CH2Cl2, wash with 5 N NaOH (15 mL), and back extract the aqueous with CH2Cl2. Wash the combined organic layer with brine, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatograph, eluting with 5-10% in MeOH (2N NH3)/CH2Cl2 to give 2.24 g (82%) of the title compound. LC-MS m/z (79Br) 254.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CCO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: CC(C)(CC=O)NC(=O)OC(C)(C)C
Yield: 54 %

Procedure:
(3-Hydroxy-1,1-dimethyl-propyl)-carbamic acid tert-butyl ester (6.0 g, 30 mmol) was dissolved in CH2Cl2 (50 mL) and treated with Dess-Martin periodinane (20.0 g, 44 mmol). After stirring overnight 50 mL of water was added followed by NaHCO3 and Na2S2O3. The resultant mixture was stirred vigorously for 30 min and then was extracted with CH2Cl2 (3–50 mL). The extracts were dried with MgSO4 and concentrated to give 3.26 g (54%) of an orange oil. This material was used in the next step without purification.