Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C@H:36]([NH:38][CH:39]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40]2)[CH3:37])[CH:33]=[CH:34][CH:35]=1.[ClH:51]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:51].[ClH:51].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C@H:36]([NH:38][C@@H:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)[CH3:37])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)N[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 25 g of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]([C:26]#[CH:27])([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.CO.[OH-].[Na+].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>O>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[C:26]([C:13]1([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)#[CH:27]
Reactant: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Yield: 43 %

Procedure:
A suspension of 1.00 g of 1-phenoxycarbonyl-4-ethynyl-4-(2-nitrophenoxy)piperidine, 14 ml of methanol, and 6 ml of 15% sodium hydroxide solution was heated at reflux for 2.5 hrs under nitrogen and allowed to cool to room temperature. The mixture was poured into water, extracted twice with chloroform, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Evaporation of solvent provided an oil. Treatment of a solution of the oil which ethereal maleic acid provided 0.43 g (43%) of product, mp 155°-157°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.Cl.Cl.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][NH:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:24]3[CH2:29][CH2:28][C:27]4([C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][NH:30]4)[CH2:26][CH2:25]3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CNC21CCNCC1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)NCc1ccccc12
Reaction time: 16 h
Yield: 24.1 %

Procedure:
To a solution of 0.10 g (0.51 mmol) 6-chloro-1H-indole-3-carboxylic acid in 5 ml dichloromethane were added 0.074 ml (0.56 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. The reaction mixture was concentrated in vacuo after 1 h. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A suspension of 0.147 g (0.56 mmol) 2,3-dihydrospiro[isoindole-1,4′-piperidine]dihydrochloride and 0.285 ml (2.04 mmol) triethylamine in 2 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 16 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane/methanol) to give the title compound (0.045 g; 24%) as an off-white solid. MS m/e (%): 366 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(Cl)(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:22]3[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A solution of 32.4 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, in 300 ml of dimethyl sulfoxide, is stirred and heated at 140° for 6 hours with 12.8 g of 4-methylpiperidine and 35.8 g of anhydrous potassium carbonate, cooled and poured into water. The solid obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-5-[4-methylpiperidin-1-yl]-6-nitrobenzothiazole melting at 116°-120°.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:3]=1.[CH3:29][C:30]1([CH3:46])[C:42]2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:4]2[C:5]3[C:16]4=[C:17]5[C:8](=[CH:7][CH:6]=3)[CH:9]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[C:12]5[CH:13]=[CH:14][C:15]4=[C:2]([C:40]3[CH:39]=[CH:38][C:37]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]([CH3:29])([CH3:46])[C:42]=4[CH:41]=3)[CH:3]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc2ccc3c(-c4ccc(Cl)cc4)cc(-c4ccc5c(c4)C(C)(C)c4ccccc4-5)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A mixed solution of 10.0 g of 1-bromo-7-t-butyl-3-(4-chlorophenyl)pyrene, 5.86 g of 9,9-dimethylfluoren-2-yl boronic acid, 0.016 g of bis(triphenylphosphine)palladium dichloride, 33 ml of an aqueous 1.5M sodium carbonate solution and 112 ml of 1,2-dimethoxyethane was heated and stirred for 3 hours under a nitrogen stream and under refluxing. After the mixture was cooled to room temperature, 223 ml of water was added, and this was extracted with 236 ml of toluene. The organic layer was washed with 640 ml of an aqueous sodium chloride solution two times, dried with magnesium sulfate, and evaporated, 50 ml of 2-propanol was added, and the mixture was stirred for 2 hours, and filtered. After the mixture was vacuum dried, 9.5 g of 1-(4-chlorophenyl)-3-(9,9-dimethylfluoren-2-yl)-7-t-butylpyrene was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1C#N
Temperature: 60 °C
Yield: 51.8 %

Procedure:
To a solution (10 ml) of ethyl 5-chloro-1-(3-cyano-4-isobutoxyphenyl)-pyrazole-4-carboxylate (1.05 g) in ethanol was added 1 N aqueous sodium hydroxide solution (3.6 ml) with string, and the mixture was heated at 60° C. for 1 hour. After the completion of the reaction, the reaction mixture was pouted into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.5 g of 5-chloro-1-(3-cyano-4-isobutoxyphenyl) pyrazole-4-carboxylic acid, melting point 216-218° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].C1C=C(Cl)C=C(C(OO)=[O:51])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][S:25](=[O:51])[CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a cooled solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (200 mg, 0.34 mmol) in 2 ml of DCM, m-CPBA (70 mg, 0.41 mmol) was added at 0° C. and stirred at room temperature for 2 h (monitored by TLC). The reaction was quenched with sat. NaHCO3, compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel (100-200) column chromatography to obtain the title compound (60 mg, 29.3%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)NS(C)(=O)=O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4-H-pyrido -[1,2-a]pyrimidin-3-yl}-2-propenoic acid (24 mg) was dissolved in dimethylformamide (2 ml), added with methanesulfonamide (15 mg), dimethylaminopyridine (20 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg), and then the mixture was stirred at room temperature for 24 hours. The reaction solution was added with ethyl acetate and hexane, washed with 0.2 M hydrochloric acid, and dried over sodium over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (14 mg) as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=O)=[C:11]([CH:16]=2)[C:12](OC)=[O:13])=[CH:4][CH:3]=1.[NH2:23][C@@H:24]1[C@@H:29]([OH:30])[CH2:28][CH2:27][O:26][CH2:25]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:11]3[C:10]([CH2:17][N:23]([C@@H:24]4[C@@H:29]([OH:30])[CH2:28][CH2:27][O:26][CH2:25]4)[C:12]3=[O:13])=[C:9]([CH3:19])[C:8]=2[CH3:20])=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)cc2)c(C)c(C)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2)cc2c(c1C)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of methyl 5-(4-chlorobenzyl)-2-formyl-3,4-dimethylbenzoate (0.02 g) in THF (1.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (8.14 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with methanol (1.00 mL). Sodium triacetoxyborohydride (0.02 g) was added thereto under argon atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC. The fractions were combined, saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.60 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2=[C:9](C(O)=O)[S:10][C:11](C(O)=O)=[C:6]2[O:5][CH2:4]1.C(OCC)(=O)C>CN(C)C(=O)C.N1C2C(=CC=CC=2)C=CC=1>[O:8]1[CH:3]([CH2:2][OH:1])[CH2:4][O:5][C:6]2=[CH:11][S:10][CH:9]=[C:7]12
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCC(CO)O2
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Solvent: CC(=O)N(C)C
Product: OCC1COc2cscc2O1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-Hydroxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid (48 g, 0.184 mol) was dissolved in N,N-dimethylacetamide (500 mL), and Cu2Cr2O7 (8.6 g) and quinoline (15 drops) were added. This mixture was subsequently stirred for 2 hours at 150° C., after which it was cooled to 25° C. It was then poured into ethyl acetate, the catalyst was removed by filtration and the filtrate was washed with acidic water and an aqueous saturated sodium chloride solution. Subsequently, the solvent was removed after which pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol was isolated by vacuum distillation (115–120° C.; 0.05 mm Hg).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2O)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:18]=[O:19].[ClH:20]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:11][Cl:20])[C:18]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cl
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
2-(2H-Benzotriazol-2-yl)-4-methyl-phenol (2.3 g, 10 mmol) is dissolved in acetic acid (30 mL) at 80° C. Zinc chloride (140 mg, 1 mmol) and paraformaldehyde (390 mg, 13 mmol) are added and HCl gas is passed through the reaction mixture for 12 hours at 80° C. The product, which precipitates after cooling to room temperature, is filtered off, washed with small amounts of cold ethyl acetate and dried at 60° C. under vacuum to yield 1.9 g of 2-(2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][C@H:15]2[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.Cl.O1CCOCC1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([O:14][C@H:15]2[CH2:19][NH:18][C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1
Temperature: 20 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution (0.62 M) of 1-tert-butyl 2-methyl (2S,4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate in CH2Cl2 was treated with a solution (4 M) of HCl in dioxane (5 eq). The mixture was stirred at 20° C. for 2 h, then treated with a solution (4 M) of HCl in dioxane (2 eq). After 5 h, the reaction was judged complete and the mixture was concentrated under reduced pressure. The residue was triturated with Et2O to give the title compound (95%) as a solid. MS (ES+) m/z 338 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[Cl:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[Cl:56])CN1C=CC(N)=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:53]3[CH:45]=[CH:44][C:43]([Cl:42])=[C:55]([Cl:56])[CH:54]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Nc1ccn(Cc2ccc(Cl)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(Cl)c(Cl)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-(3,4-dichloro-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3,4-dichloro-benzyl)-1H-pyrazol-3-yl]-propionamide (133 mg, 79%) as a white solid: ESI-LRMS m/e calcd for C25H26Cl3N3O3S [M+] 553.1, found 554.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.22 (m, 2H, CH2), 1.42-1.90 (m, 8H, 4×CH2), 2.09-2.28 (m, 1H, CH), 3.24 (s, 3 H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 5.07 (s, 2H, NCH2), 6.71 (d, J=2.3 Hz, 1H, Ar), 6.95 (dd, Jo=8.2, Jm=2.0 Hz, 1H, Ar), 7.21 (d, Jm=2.0 Hz, 1H, Ar), 7.31 (d, J=2.3 Hz, 1H, Ar), 7.36 (d, Jo=8.2 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.14 (s, 1H, NH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][CH:27]=1)([CH3:25])[CH2:23][OH:24]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:22]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:20])=[CH:31][CH:30]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(CO)(CO)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (103 mg, 0.33 mmol, 1.0 eq) in DMF (5 mL) was added TEA (0.092 mL, 0.66 mmol, 2.0 eq) followed by phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) at 0° C. and the mixture was stirred for 16 h at RT. The reaction mixture was concentrated under vacuum and the residue purified by neutral alumina column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxy-2-methylpropan-2-yl)phenyl)urea (105 mg; 65%) as a white solid (TLC system: MeOH/CHCl3 (1:9), Rf: 0.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a stirred solution of 3-[4-(1-t-butyloxycarbonyl piperidin-4-yloxy)phenyl]prop-2-ene-1-oic acid (38 grams, 0.109 moles, obtained in above step) and triethylamine (38.4 mL, 0.273 moles) in dichloromethane (500 mL) was added ethylchloroformate (13.6 mL, 0.142 moles) at 0° C. The reaction mass was further stirred for 2 hours at 0-5° C. Morpholine (19.2 mL, 0.219 moles) was added to above mass at 0-5° C. and the resulting mixture were stirred for 2 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was quenched by adding water (100 mL). Layers were separated and the organic layer was washed with brine solution (100 mL) and dried over sodium sulphate. The organic phase was concentrated under vacuum to obtain the crude residue, which was further purified by flash chromatography using methanol:triethylamine:chloroform in the ratio of 1:1:98 to afford the title compound (34 grams).