Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:28][C:29](O)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:28][C:29]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCCCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCCCC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Triethylamine 0.24 ml was added in a methylene chloride 10 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo (3.2.1]octane hydrochloride 0.28 g, and stirred at 0° C. for 30 min. Cyclooctyl acetic acid 0.25 g and WSC 0.40 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 21 hours. The reaction mixture was washed wits saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-cyclooctylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THP 15 ml solution of lithium aluminum hydride 0.12 g and refluxed for 1 hour. The reaction mixture was cooled, then added water and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: acetone=10:1) to obtain the product. Yield: 0.26 g (Yield 61%)
Reaction SMILES: [Na].COS([O-])(=O)=O.[CH:8]([N+:11]1[CH2:15][CH2:14][CH2:13][C:12]=1N(C)C)([CH3:10])[CH3:9].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21]>C(O)C>[CH:8]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[CH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21])([CH3:10])[CH3:9]
Reactant: COc1cccc(C(C)=O)c1
Reactant: CC(C)[N+]1=C(N(C)C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C(=O)C=C2CCCN2C(C)C)c1
Reaction time: 4 h

Procedure:
A solution of 7.6 g of sodium in 100 ml of ethanol is added dropwise(*) at 90° within 2 hours to a mixture of 88 g of 1-isopropyl-2-dimethylamino-1-pyrrolinium methyl sulfate and 42 g of 3-methoxyacetophenone. Stirring is continued for a further 4 hours at this temperature; the solvent is distilled off in a vacuum; and the residue is distributed in 250 ml of dichloromethane and 250 ml of water. The organic phase is collected, dried over sodium sulfate and concentrated. The oil remaining behind is freed from excess 3-methoxyacetophenone by heating under a high vacuum. Yield: 42.8 g (59% of theory) of the title compound as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH2:27][O:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[C:39]([O:41][CH3:42])=[O:40])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 4-[N′-(2-methylphenyl)ureido]phenylacetic acid (2.32 g, 5.15 mmol), dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (1.51 g, 5.15 mmol) in DMF (20 mL) was added Et3 N (1.0 mL, 6.65 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc. The solution was washed with brine, dried over MgSO4, and evaporated off in vacuo. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (10:1, v/v) as eluent to give 1.58 g (55%) dimethyl 4-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow crystalline solid. 1H-NMR (CDCl3) δ 1.87–2.25 (m, total 7 H), 3.50–3.65 (m, 4 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 4.18–4.31 (m, 2 H), 4.44 (m, 1 H), 6.95–8.45 (m, total 13 H).
Reaction SMILES: [NH3:1].CO.Br[CH2:5][C:6]1[C:7]([F:23])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:17]#[N:18])[C:9]([F:12])=[CH:10][CH:11]=1>C1COCC1>[NH2:1][CH2:5][C:6]1[C:7]([F:23])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:17]#[N:18])[C:9]([F:12])=[CH:10][CH:11]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2F)c1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A 7M solution of ammonia in MeOH (45.8 mL, 321 mmol) was added to a solution of 3-{[3-(bromomethyl)-2,6-difluorophenyl]oxy}-5-chlorobenzonitrile (2.3 g, 6.41 mmol) in THF (30 mL) at RT. The reaction was capped and stirred for 16 h at RT then concentrated to dryness under vacuum. Ethyl acetate (200 mL) and saturated aqueous NaHCO3 solution (300 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (2×200 mL), water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated to give a white solid. The crude product was purified on silica gel (10% MeOH/DCM) to give the title compound (1.63 g, 86%) as a white solid (N4011-13-100). 1H NMR (400 MHz, DMSO-d5) δ ppm 7.82 (s, 1H), 7.40-7.66 (m, 3H), 7.31 (t, 1H), 3.75 (s, 2H), 1.86 (br. s., 2H).
Reaction SMILES: C(C1N=[C:7]([N:22]2C[CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].COC[C@@H]1CCCN1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C@H:23]2[CH2:24][O:25][CH3:26])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-2-(methoxymethyl)pyrrolidine and isolated as light-yellow gum (12.0 mg, 61%). MS(m/e): 415.4 (MH+).
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].Cl.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:5]1([CH3:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@:3]([CH3:17])([C:1]2[N:26]=[N:27][NH:28][N:2]=2)[CH2:7][O:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C#N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)c1nn[nH]n1
Temperature: 103 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a mixture of 6.96 g of tert-butyl (4R)-4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate, 12.5 g of triethylamine hydrochloride, and 105 ml of toluene was added 5.84 g of sodium azide, followed by stirring at 103° C. for 3 hours. The insoluble materials were separated by filtration and the filtrate was concentrated. The obtained residue was purified twice by silica gel column chromatography to obtain 7.65 g of tert-butyl (4R)-2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([Cl:29])=[CH:24][C:23]=2[F:30])([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:25]1[C:26]([F:28])=[CH:27][C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:23]([F:30])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1cc(F)c(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1cc(F)c(Cl)cc1F

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 109b (1.5 g, 2.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.5 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:6]([OH:7])[CH:5]=1.C(=O)([O-])[O-].O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][C:6]=1[O:7][CH2:26][C:27]([F:30])([F:29])[F:28]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a mixture of isovanillic acid methyl ester (33.0 g, 0.18 mol) and potassiuin carbonate (41.4 g, 0.30 mol) in DMF (100 ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.0 g, 0.28 mol) in CH2Cl2. The mixture was stirred at room temperature for 18 h then evaporated to 50 ml, the mixture partitioned between ether and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55 g, 90%). Rf 0.47 (CH2Cl2). MS m/z 265 (MH+).
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCCc1ccccc1Cl
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccccc1Cl)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 27 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(2-chlorophenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(2-chlorophenyl)ethyl]-isonicotinamide was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.91-10.82 (m, 1H), 8.91-8.85 (m, 1H), 8.56-8.44 (m, 2H), 8.06-7.98 (m, 2H), 7.63-7.17 (m, 8H), 3.55-3.48 (m, 2H), 3.03-2.92 (m, 2H); MS (ES+) m/z 380.5 (M+1), 382.3 (M+2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58 mg), 2-hydroxybenzophenone (271 mg), and 4-dimethylaminopyridine (166 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively give 110.4 mg of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1>ClCCl>[C:1]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](N)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-n3cc(C)c4c(-c5cnc6ccccc6c5)ccnc43)ccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.012 mL) and triethylamine (0.021 mL) were added to a solution of compound (61) (0.050 g) prepared in Example 61 in dichloromethane (10 mL), followed by stirring at room temperature for 1 hr. The solvent was distilled away under reduced pressure, and water was added to the residue. The precipitate was collected by filtration, washed by sprinkling water and ether, and dried under reduced pressure to obtain (62) (0.043 g, 78%) as a white solid.
Reaction SMILES: C12BC(CCC1)CCC2.[F:10][C:11]([F:33])([F:32])[CH2:12][NH:13][C:14]([C:16]1([CH2:29][CH:30]=[CH2:31])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15].[OH-:34].[Na+].OO>C1COCC1.O>[F:10][C:11]([F:32])([F:33])[CH2:12][NH:13][C:14]([C:16]1([CH2:29][CH2:30][CH2:31][OH:34])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15]
Reactant: [OH-]
Reactant: C=CCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)C1(CCCO)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12 ml of 9-borabicyclo[3.3.1]nonane are added dropwise to a solution of 1.5 g (4.52 mmol) of 9-allyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide in 40 ml of THF under nitrogen. Then the mixture is stirred for three hours at ambient temperature. 6 ml of 1M sodium hydroxide solution and 4 ml of 33% hydrogen peroxide solution are then added successively and the resulting mixture is stirred for one hour. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:4].C(=O)(O)[O-].[K+].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1OS(C)(=O)=O.O>C(#N)C>[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH:26]3[CH2:25][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(C3Cc4ccccc4C3)CC2)cc1
Yield: 33.4 %

Procedure:
To a suspension of 4-piperazin-1-yl-benzoic acid ethyl ester dihydrochloride (1 g) and potassium bicarbonate (1.57 g) in acetonitrile (10 ml) was added methanesulfonic acid indane-2-yl ester (0.69 g) and the mixture was stirred under refluxing for 8 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried over under reduced pressure. The powder was purified by column chromatography on silica gel using methanol/dichloromethane (50:1) as the eluent to give 4-(4-indan-2-yl-piperazin-1-yl)benzoic acid ethyl ester (0.38 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH2:73][CH2:74][O:75][CH2:76][CH2:77]2)[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: COc1cc(N2CCOCC2)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCOCC2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 46.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 2-methoxy-4-morpholinoaniline (Bionet) (0.14 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide as a light yellow solid (Yield 0.13 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:26]([CH:29]1[CH2:31][CH:30]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:27]=[O:28].O>CN(C=O)C>[C:32]1([CH:30]2[CH2:31][CH:29]2[NH:26][C:27]([NH:1][C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NC1CC1c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CC1c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (123 mg, 0.35 mmol) in DMF (20.0 mL) was added (2-isocyanatocyclopropyl)benzene (111 mg, 0.7 mmol). The mixture was stirred at 60° C. overnight. After cooling, the mixture was poured into water (120 mL). The white solid, which precipitated, was filtered off and dried in vacuum to give the title product (162 mg) as a white solid in 90% yield. 1H NMR (300 MHz, CDCl3) δ 8.01-7.97, 7.73, 7.60, 7.55, 7.32, 7.22-7.10, 7.06, 4.00-3.95, 3.87-3.86, 3.62-3.52, 3.43-3.41, 3.25-3.22, 2.85-2.82, 2.14-2.10, 0.91-0.86. MS (ES+) m/z 511.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([OH:29])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[OH-:32].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18](=[O:19])[N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[C:16]([CH:15]=2)[O:29][C:17]([CH3:27])([CH3:16])[C:18]([OH:19])=[O:32])=[CH:30][CH:31]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C

Procedure:
A stirred, refluxing mixture of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol), sodium hydroxide (480 mg, 1.2 mmol), and 50 mL of acetone is treated with chloroform (125 μL, 1.6 mmol) in 20 mL of acetone. The reaction is refluxed for 4 hours and concentrated in vacuo. The resulting material is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (20 g) with 40-100% ethyl acetate/hexane followed by 10% MeOH/ethyl acetate as the eluent to afford 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid as colorless foam. A stirred, 0° C. solution of 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid (210 mg, 0.411 mmol) in 2.0 mL of anhydrous dichloromethane and 150 mL of anhydrous ethanol at 0° C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting ethyl 4-[5-[3-ethoxycarbonyldimethylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with anhydrous ammonia for 5 minutes at 0° C. The pressure tube is sealed and heated to 100° C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/dichloromethane as the eluent to afford ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride as colorless foam; CHN calculated for C31H46CIN3O6 -1.25 H2O: