Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.4 %

Procedure:
To a solution of 1.1 g of sodium hydride in 50 ml of DMF was added 3.4 g of 2-(4-chlorophenyl)ethanol, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred overnight. The mixture was then poured into a mixture of ice in water. Solid was collected and recrystallized from pentane giving 0.149 g of the title product. Yield: 2.4%. M.P. 57°-58° C.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH2:39][CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH2:39][CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: CCO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: Cc1noc(C)c1B(O)O
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CCO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3c(C)noc3C)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in analogy to example 62 using 3,5-dimethyl-isoxazole-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-ethoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 526.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:46]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:46])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(F)c(F)c1C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 77.4 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.45 g, 0.85 mmol) prepared in example 62d was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.6 g, 1.8 mmol) in toluene to give racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.36 g, 78.3%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:19](#N)[CH3:20]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:12][CH2:7][CH2:8][CH2:9][C:20]3[CH:19]=[CH:3][CH:2]=[CH:1][CH:6]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CCCCN2CCC(c3ccccc3)CC2)cc1

Procedure:
4-Phenylpiperidine (1 eq) was reacted with 4-phenylbromobutyl (1 eq) in the presence of K2CO3 in acetonitrile at reflux overnight. The product obtained was treated and purified on a silica column. The 1H NMR at 500 MHz is in accordance with the expected structure.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14](Br)=[C:13]([Br:18])[CH:12]=[N:11]2)=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([NH:2][CH3:1])=[C:13]([Br:18])[CH:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cn2ncc(Br)c(Br)c2=O)cc1
Reactant: CN
Solvent: Cc1ccccc1
Product: CNc1c(Br)cnn(Cc2ccc(OC)cc2)c1=O
Temperature: 90 °C

Procedure:
In a glass pressure reactor vessel equipped with a magnetic stir bar, toluene (100 mL) was saturated with anhydrous methylamine at 0° C. then 2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one (1) (22 g, 59 mmol) was added. The vessel was sealed and the suspension was stirred and heated at 90° C. for 18 h. The resulting suspension was allowed to cool to RT. Anhydrous methylamine was bubbled through the mixture for 15 min, the reactor was sealed again, and the mixture was stirred and heated at 90° C. for an additional 18 h. After cooling to RT, the mixture was concentrated in vacuo to dryness. The resulting brown solid was suspended in MeOH and sonicated. The solid was collected by suction filtration, washed with MeOH, and dried in vacuo to give 2-(4-methoxybenzyl)-5-bromo-4-(methylamino)pyridazin-3(2H)-one as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: NN
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(-c2ccccc2)nc(Cl)n1

Procedure:
To a solution of 2,4-dichloro-6-phenylpyrimidine (224 mg, 1 mmol) in 1 mL of 1,4-dioxane was added 300 uL of hydrazine hydrate. Stirring was continued at room temperature and the reaction monitored by thin layer chromatography (30% ethyl acetate/hexanes). When the starting material was consumed, 2 mL of water was added and the resultant precipitate was collected on a filter to afford 2-chloro-4-hydrazinyl-6-phenylpyrimidine as a yellow solid. The damp solid was suspended in 2 mL of ethanol, to which was added 220 mg of 4-trifluoromethoxybenzaldehyde. Within 5 minutes the solution became clear and then reprecipitated material. The product, 2-chloro-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidine (XX), was collected by filtration and dried to afford 150 mg of a solid. ESI/MS 392.973, 395.002 (M+H).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[C:6](=[NH:12])[NH:5][C:4](=N)[C:3]1=2.Cl.[CH3:15][CH:16]1[N:21]([C:22]2[S:23][CH2:24][C:25](=[NH:27])[N:26]=2)[CH2:20][CH2:19][O:18][CH2:17]1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:12]=[C:6]1[C:7]2[CH2:8][CH:9]([CH3:11])[CH2:10][CH:2]([Br:1])[C:3]=2[C:4](=[C:24]2[S:23][C:22]([N:21]3[CH2:20][CH2:19][O:18][CH2:17][CH:16]3[CH3:15])=[N:26][C:25]2=[NH:27])[NH:5]1
Reactant: CC1COCCN1C1=NC(=N)CS1
Reactant: CC1CC2=C(C(=N)NC2=N)C(Br)C1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: CC1CC2=C(C(=C3SC(N4CCOCC4C)=NC3=N)NC2=N)C(Br)C1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A, but substituting equivalent amounts of 4-bromo-6-methyl-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-methylmorpholino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, there is obtained as the product 1-imino-4-bromo-6-methyl-4,5,6,7-tetrahydro-3-[2-(3-methylmorpholino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH:9]([CH:11]([CH3:17])[C:12](OCC)=O)=[O:10]>>[CH3:17][C:11]1[C:9](=[O:10])[O:7][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: CCOC(=O)C(C)C=O
Reactant: O=C1CCCC(=O)C1
Product: Cc1cc2c(oc1=O)CCCC2=O

Procedure:
Prepared analogously to Example C(a) from cyclohexan- 1,3-dione and ethyl 2-formyl-propionate.
Reaction SMILES: [C@H:1]1([OH:7])[CH:5]=[CH:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.C1COCC1>[C:10]([O:14][C:15](=[O:18])[CH2:16][O:6][CH:3]1[CH2:2][CH:1]([OH:7])[CH:5]=[CH:4]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O[C@@H]1C=C[C@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC1C=CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 2.0 g (20 mmol) of cis-4-cyclopentene-1,3-diol in 1.5 ml of DMF and 15 ml of THF and, at 0° C., add 799 mg (60% strength, approx. 20 mmol) of sodium hydride in portions. After the end of the addition, warm the mixture to RT and stir at RT for a further 1 h, before adding 2.7 ml (18.2 mmol) of bromoacetic acid tert-butyl ester. Then stir the mixture at RT overnight. Then add water, extract with dichloromethane, wash the organic phase with satd. sodium chloride solution, concentrate under reduced pressure and dry the residue under high vacuum. Isolate the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1→2:1). 1.10 g (25.6% of theory) of the target compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1.Cl[C:30](OC)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:30](=[O:31])[NH:22][C:23]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1nc(C)cs1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that t-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that 2-amino-4-methylthiazole was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]1[O:28][CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[B:29]([OH:32])(O)[OH:30]>O>[B:29].[OH:30][B:29]1[O:28][CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:32]1
Reactant: OB(O)O
Reactant: c1ccc(C2CO2)cc1
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN1CC(c2ccccc2)OB(O)OC(c2ccccc2)C1
Product: [B]
Temperature: 25 °C
Yield: 195.7 %

Procedure:
A boron compound of the invention is prepared by adding 17,093 grams of octadecylamine and 15,362 grams of styrene oxide to a 65-liter, round-bottomed flask that contains 13 liters of tollene and 1 liter of water. The flask is fitted with a water-cooled condenser and placed in a heating mantle. The mixture thus formed is refluxed at a moderate rate for 24 hours. The reaction is cooled to room temperature and 4,033 grams of boric acid are added to the flask. Next, the flask is fitted with a Dean-Stark trap, topped with a water-cooled condenser and the reaction mixture is refluxed until water stops collecting in the trap. Toluene is distilled from the reaction product to an end-point temperature of 400° F. The reaction produces 34,183 grams of 1-hydroxy-3,7-diphenyl-5-octadecyl-5-aza-1-bora-2,8-dioxacyclooctane.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:33][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NC1CCCCCC1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(NC3CCCCCC3)ccc12)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=414.3 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonyl chloride and cycloheptylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:8]1.Cl[CH:18]([F:20])[F:19].O>CN(C)C=O>[F:19][CH:18]([F:20])[N:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:8]1
Reactant: FC(F)Cl
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C(F)F)c1
Temperature: 135 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
6.0 g (43.5 mmoles) of anhydrous potassium carbonate was added to a solution of 3.0 g (21.4 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 100 ml of N,N-dimethylformamide. Thereinto was blown chlorodifluoromethane. The resulting mixture was stirred at 130 to 140° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.67 g (yield: 41.0%) of ethyl 1-difluoromethyl-1H-pyrazole-4-carboxylate as a colorless transparent oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:20])=[N:11][N:12]=1>C(O)C.C(O)(=O)C.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:30][CH:31]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH3:20])=[N:11][N:12]=1
Reactant: C=Cc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Yield: 31.4 %

Procedure:
A suspension of 4-[5-amino-6-[5-(2-vinylphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (45 mg, 0.1091 mmol) in a mixture of ethanol (5 mL) and acetic acid (0.5 mL) in the presence of Pd on C, wet, Degussa (116.1 mg, 0.1091 mmol) was hydrogenated at 60 psi overnight using the parr apparatus. The reaction mixture was filtered through a Celite pad and washed with more ethanol (5 mL) and ethyl acetate (5 mL). The filtrate was dried over MgSO4 and filtered and concentrated in vacuo. Purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (14.2 mg, 38% yield); 1H NMR (400 MHz, DMSO) d 1.30 (t, 3H), 2.98 (m, 6H), 3.13 (q, 2H), 7.48-7.55 (m, 4H), 7.62 (m, 1H), 7.78 (br s, 2H), 8.05 (m, 1H), 8.14 (m, 2H) and 8.99 (1H, s) ppm; MS (ES+) 415.27
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:45]=[CH:44][C:18]([C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][S:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:27]([N+:41]([O-:43])=[O:42])[CH:26]=3)(=[O:24])=[O:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>ClCCl.O>[N+:41]([C:27]1[CH:26]=[C:25]([S:22]([NH:21][C:19](=[O:20])[C:18]2[CH:44]=[CH:45][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][CH:2]=[O:1])[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][C:28]=1[NH:31][CH2:32][CH2:33][S:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([O-:43])=[O:42]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCC(CCC3OCCCO3)CC2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CCCC1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1

Procedure:
A solution of Example 203C (250 mg, 0.4 mmol), in dichloromethane (5 mL), TFA (1.5 mL), and 1 drop water was stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane 0.5-1.0% methanol to provide the desired product. MS (APCI) m/e 597 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H), 8.87 (d, 1H), 8.67 (t, 1H), 8.47 (s, 1H), 8.15 (dd, 1H), 7.63 (d, 2H), 7.40 (m, 2H), 7.24-7.34 (m, 4H), 6.87 (d, 2H), 6.82 (m, 2H), 3.87 (d, 2H), 3.58 (m, 4H), 3.21 (t, 2H), 2.86 (m, 2H), 2.50 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.55 (s, 4H) 1.31 (m, 2H).
Reaction SMILES: [OH:1][C@:2]1([CH2:30][OH:31])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[OH:1][C@:2]1([CH2:30][O:31][C:39](=[O:40])[N:38]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(CO)C2)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(COC(=O)N(c1ccccc1)c1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
A mixture of (2R)-2-hydroxy-2-hydroxymethyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g) and N,N-diphenylcarbamoyl chloride (3 g) in pyridine (15 ml) was stirred at 100° C. for 12 hours, cooled to room temperature, and partitioned between ethyl acetate and 1N-HCl. The organic layer was washed with water, sat. NaHO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (2R)-2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.3 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](O)=[O:31])[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.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[CH:66][CH:65]=1>>[CH2:74]([O:73][C:71](=[O:72])[CH2:70][C:67]1[CH:66]=[CH:65][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:69][CH:68]=1)[CH3:75]
Reactant: CCOC(=O)Cc1ccc(N)cc1
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: CCOC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 35.4 %

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 (120 mg, 0.257 mmol), was reacted with diisopropylethylamine (207 mg, 1.60 mmol), diphenylphosphinic chloride (146 mg, 0.618 mmol), then reacted with ethyl 2-(4-aminophenyl)acetate (56 mg, 0.315 mmol) to give rac-(4-{[(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′-carbonyl]amino}-phenyl)-acetic acid ethyl ester (57 mg, 47%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: [NH:1]([C:8]1[C:9]([C:18](O)=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:8]2[C:9]=1[CH:10]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=[CH:17]2
Reactant: O=C(O)c1cc2ccccc2cc1Nc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2ccccc2nc2cc3ccccc3cc12

Procedure:
treating 3-anilino-2-naphthoic acid with phosphorous oxychloride to produce 12-chloro-benz[b]acridine;
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)C>[F:13][C:2]([F:1])([F:14])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(SC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4-(Trifluoromethylthio)phenylacetonitrile (183.4 mg, 0.844 mmol), 0.3 molar in THF, was heated to reflux and then treated with Borane-methyl sulfide complex (88.09 μL, 0.929 mmol). After 1 hour of refluxing, the reaction mixture was cooled to ambient temperature and then treated dropwise with 5.0 molar hydrochloric acid (607.9 μL, 3.040 mmol). The reaction mixture was then heated to reflux for an additional 30 minutes. After 30 minutes the reaction mixture was cooled to 0° C. and then treated with 1.0 molar sodium hydroxide (4644 μL, 4.644 mmol). The reaction mixture was diluted with diethyl ether and partitioned with deionized water. The organic layer was dried with potassium carbonate 98% powder, filtered, concentrated, and dried for one minute under high vacuum to provide the title compound (170.7 mg, 0.772 mmol, 91.2% yield) as a light yellow oil.