Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.[CH2:12]([O:14][C:15](=[O:35])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29](C(=O)C)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29]([O:10][C:8](=[O:9])[CH3:4])=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)=[O:35])[CH3:13]
Reactant: CCOC(=O)NCCc1ccc(Oc2ccc(C(C)=O)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCc1ccc(Oc2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
Metachloroperbenzoic Acid (1.2 g, 4.1 mmol) was added to a solution of {2-[4-(4-acetyl-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (1.0 g, 3.1 mmol) in chloroform (75 mL). Stirred at room temperature for 72 hours, quenched with saturated aqueous Na2S2O3, then extracted with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (2 g). The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield Acetic acid 4-[4-(2-ethoxycarbonylamino-ethyl)-phenoxy]-phenyl ester (430 mg). 1H NMR (CDCl3, 300.00 MHz): 7.19-6.92 (m, 8H), 4.98 (s, 1H), 4.17-4.07 (m, 2H), 3.42 (q, 2H, J=6.6 Hz), 2.79 (t, 2H, J=7.2 Hz), 2.29 (s, 3H), 1.30-1.20 (m, 3H), 1.30-1.20 (m, 3H), 1.30-1.20 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH3:13])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:31][CH2:30][CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]3[N:10]=[CH:11][N:12]([CH3:13])[C:4]=3[CH:3]=2)=[CH:23][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: CC1(C)OB(c2ccc(CCCO)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cn1cnc2c(C#N)nc(Cl)cc21
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2c(C#N)nc(-c3ccc(CCCO)c(C(F)(F)F)c3)cc21
Temperature: 110 °C
Yield: 62.2 %

Procedure:
6-Chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.29 g), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)propan-1-ol (2.432 g), tris(dibenzylideneacetone)dipalladium (0.307 g), tricyclohexylphosphine (0.225 g) and potassium phosphate (2.417 g) were suspended in dioxane (20 ml) and water (8 ml). The reaction mixture was placed under a nitrogen atmosphere and heated to reflux (110° C.) for 1.5 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc (500 mL), filtered through celite and washed with water (200 mL). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure. The solid residue was washed with ether to afford 6-[4-(3-hydroxypropyl)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.5 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C[OH:35].[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=[O:35])=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 4-[6-(4-cylopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile (2.0 g, 6.3 mmol) dissolved in THF (40 mL) was added DIBAL-H (25 mL, 1 N) at −40° C. The mixture was stirred 2 h at −40° C. and then CH3OH (15 mL), water (100 mL) and 1 N NaOH (15 mL) was added at −40° C. The mixture was extracted with EtOAc (3×300 mL). The combined organic extracts were washed with water (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1.7 g (51%) of 4-[6-(4-cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](O)=[O:22])=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C.[NH:55]1[CH2:62][CH2:61][CH2:60][C@H:56]1[C:57]([NH2:59])=[O:58]>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([N:55]2[CH2:62][CH2:61][CH2:60][C@H:56]2[C:57]([NH2:59])=[O:58])=[O:22])[CH:8]=1)[CH3:20]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cccc(C)c1CNc1cc(C(=O)N2CCC[C@H]2C(N)=O)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol), o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.45 mmol) and triethylamine (0.05 g, 0.5 mmol) were added to methylene chloride (10 ml) and the mixture was stirred for 10 min. (S)-prolinamide (0.016 g, 0.45 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent and crystallization from diethyl ether gave 0.07 g (36%) of the title compound.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:47]=[CH:48][C:49]([CH2:50][OH:51])=[CH:52][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(CO)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(CO)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminobenzylalcohol as the aniline component. (84%, MS=500.2 (M+H))
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[Br:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[Br:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscous yellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#N.C(O)=[O:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:12]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: O=CO
Product: O=Cc1cc(F)cc(F)c1
Yield: 55 %

Procedure:
A mixture of 3,5-difluorobenzonitrile (0.108 mol) and Raney alloy (15 g) was refluxed 2 hours in 90% formic acid (150 ml). The reaction was filtered hot and the filter cake was washed with water, then hexane. The filtrate was extracted three times with hexane, the combined hexane extracts were washed with water and dried over sodium sulfate. Concentration yielded 8.4 g (55%) of a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:46]([O-])=[O:47].[Na+]>>[CH2:1]([N:8]([N:46]=[O:47])[C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a ice-cold solution of 9.50 g (19.79 mmol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-acetamide in 64.53 ml (1128 mmol) acetic acid and 135.84 ml (2395 mmol) acetic anhydride were added in portions over 60 min. 6.83 g (99 mmol) sodium nitrite. The reaction mixture was stirred for 1 h in an ice-bath, then at room temperature overnight. The mixture was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and solid sodium bicarbonate was added to adjust the pH to 7. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining brown foam was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane and ethyl acetate (100:0 to 50:50). Yellow solid (72%). MS (Turbo Spray): m/z=509.2 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][C:4]#[N:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:4](=[NH:5])[CH2:3][CH:2]([CH3:6])[CH3:1])=[CH:14][CH:13]=1
Reactant: CC(C)CC#N
Reactant: Nc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CC(=N)Nc1ccc(Cl)cc1
Yield: 57.6 %

Procedure:
To a solution of 3-methylbutanenitrile (250 mg, 3.0 mmol) and AlCl3 (400 mg, 3.0 mmol) in toluene (6 mL) was added 4-chloroaniline (383 mg, 3.0 mmol). The resulting solution was stirred at reflux for 2 h, diluted with water, and extracted with EtOAc. The aqueous layer was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated. The crude product (364 mg, 58% yield) was used for the next step without purification.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.[OH:31][N:32]1C2C=CC=CC=2N=N1.O(N)C1CCCCO1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C=O)C>[OH:31][NH:32][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=C(O)CCCCNS(=O)(=O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCNS(=O)(=O)c1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.8 %

Procedure:
To a solution of 42 (500 mg, 1.95 mmol) in DMF (20 mL) at room temperature were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 448 mg, 2.33 mmol), and 1-hydroxybenzotriazole hydrate (HOBT, 395 mg, 2.93 mmol). The mixture was stirred 20 min. at room temperature, and then THPONH2 (342 mg, 2.93 mmol) was added. The resulting mixture was heated at 50° C. for 24 h, and then the DMF solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 and washed with brine and a saturated aqueous solution of NaHCO3. The combined organic extracts were dried over (MgSO4) and then evaporated. The crude compound was purified by flash chromatography using hexane-acetone (1:1) as the solvent mixture. The residue was then dissolved in MeOH (10 mL), and 10-camphorsulfonic acid (CSA, 226 mg, 975 mmol) was added. The mixture was stirred for 2 h at room temperature, and then the solvents were evaporated under reduced pressure at room temperature to avoid thermal decomposition. The crude product was purified by flash chromatography using CH2Cl2/MeOH (9:1) as solvent mixture giving compound 43 as a yellowish oil (259 mg, 48% isolated): 1H NMR: (300 MHz, acetone-d6) δ 9.99 (br. s, 1H), 7.87 (br. s, 2H), 7.62 (br. s), 2.90 (br. s, 2H), 2.05 (br. s, 2H), 1.59-1.49 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:35]1[S:36][C:37]2[C:42]([Cl:43])=[N:41][C:40]([CH:44]3[CH2:46][CH2:45]3)=[N:39][C:38]=2[N:47]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:35]3[S:36][C:37]4[C:42]([Cl:43])=[N:41][C:40]([CH:44]5[CH2:45][CH2:46]5)=[N:39][C:38]=4[N:47]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:28][CH2:29]3)=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C2CC2)cc1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a mixture of (R)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide (39 mg) obtained in Example 1100, Step 4 and 2,7-dichloro-5-cyclopropyl-thiazolo [4,5-d]pyrimidine (20 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (20 μl) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was partitioned by adding water. The organic layer was dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (54 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21](O)=[O:22].[Cl:24]C1C(Cl)=C2C(CC(C3CCCC3)(C)C2=O)=CC=1CC(O)=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([Cl:24])=[O:22]
Reactant: CC1(C2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
The preparation is carried out by following substantially the procedures described in Example 1, Step C except that an equimolar amount of (+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetic acid is substituted for the (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid used in Example 1, Step C. There is thus obtained first the (+)-enantiomers of the diastereomers of [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetyl chloride and then (+)-enantiomers of the diastereomers of [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14]CC)=[O:13])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([CH:9]2[CH2:11][CH:10]2[C:12]([OH:14])=[O:13])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1CC1c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CC1c1ncc(Cl)cc1Cl
Reaction time: 8 h
Yield: 91.8 %

Procedure:
1.65 g of ethyl 2-(3,5-dichloropyridin-2-yl)cyclopropanecarboxylate (0.00634 mol) are dissolved in 20 ml of ethanol, 9.5 ml of sodium hydroxide 1M are added to the reaction mixture which is refluxed for 4 hours and left at room temperature overnight. After concentration in vacuo, 30 ml of water are added to the reaction mixture which is extracted twice with ethyl acetate (20 ml). The aqueous phase is acidified with HCl 1M. The precipate which forms is filtered, air-dried to yield to 1.35 g of 2-(3,5-dichloropyridin-2-yl)cyclopropanecarboxylic acid (87%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CN)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A mixture of 4-(methylthio)benzylamine (2.00 mL, 2.20 g, 14.38 mmol) and phthalic anhydride (2.39 g, 15.79 mmol) in acetic acid (40 mL, 42 g, 700 mmol) is heated at reflux for 3 h. The mixture is concentrated under reduced pressure, and the residue is partitioned between water and dichloromethane. The phases are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 9:1 to 7:3). Yield: 3.60 g (88% of theory); ESI mass spectrum: [M+H]+=284; r.t. HPLC: 0.75 min (X001_004).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][Si](C(C)(C)C)(C)C)=[CH2:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:23]([CH3:35])[C@@H:24]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:25](OC)[O:26][CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.B(F)(F)F.CCOCC>ClCCl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@@H:25]([O:26][CH3:27])[C@@H:24]([N:23]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:35])[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(OC)[C@H](C1CCCC1)N(C)Cc1ccccc1
Reactant: C=C(OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C1CCCC1)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To (1-tert-butoxyvinyloxy)(tert-butyl)dimethylsilane (7) (9.9 g, 43.0 mmol) in dichloromethane (80 mL) was added (S)—N-benzyl-1-cyclopentyl-2,2-dimethoxy-(S)—N-benzyl-1-cyclopentyl-2,2-dimethoxy-N-methylethanamine (6) (8.0 g, 28.8 mmol) followed by a solution of BF3. ether (3.6 mL) in DMF (4.9 mL) and dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. After concentrated, the residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate, 10:1) to give product 8 (4.3 g, 66%). LC-MS: 361.3 [M+H+]+.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[N:13]([CH2:23][CH3:24])[CH2:14][CH2:15][NH:16][C:17](=[O:22])C(F)(F)F.CO.C[O-].[Na+]>>[CH2:23]([N:13]1[C:5]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=2[C:17](=[O:22])[NH:16][CH2:15][CH2:14]1)[CH3:24]
Reactant: CCN(CCNC(=O)C(F)(F)F)c1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCNC(=O)c2ccc([N+](=O)[O-])cc21
Yield: 72.1 %

Procedure:
Into a round bottom flask, 2-{ethyl-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-amino}-4-nitro-benzoic acid methyl ester (4.80 g, 13.2 mmol), methanol (60.0 mL, 1480 mmol) and sodium methoxide (0.86 g, 16 mmol) were added. The reaction was heated to 50 degree for 18 hours. TLC suggested 50% conversion. sodium methoxide (0.86 g, 16 mmoles) was added. The reaction was heated to reflux for 4 hours. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The organic was removed under vacuum to afford 1-ethyl-8-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow solid (2.24 g, 71%). 1H-NMR (DMSO-D6, 400 MHz): δ 8.48 (t, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.64 (s, 1H), 3.18-3.32 (m, 6H), 1.15 (t, 3H)
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]=[N:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F-].C[N+](C)(C)C.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31]>O1CCCC1>[CH:1]1([CH2:4][C:5]2([CH:15]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:30]([F:32])([F:31])[F:29])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(C(F)(F)F)C1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid 1-(8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-methylideneamide (19, 1.00 g, 3.05 mmol) in tetrahydrofuran was cooled to −40° C. and was treated sequentially with tetramethylammonium fluoride (313 mg, 3.36 mmol, 1.1 eq.) and (trifluoromethyl)trimethylsilane (587 μL, 3.97 mmol, 1.3 eq.). The mixture was stirred for 2 h at 0° C. before being quenched by addition of saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to give 960 mg of the title compound. Rt=1.63 min (Method B). Detected mass: 398.3 (M+H+).
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].[CH3:5][CH2:6][O:7][CH2:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][S:15]([OH:18])(=[O:17])=[O:16].FC(F)(F)C(O)=O.[BH4-:26].[Na+]>C1COCC1>[B:1]([F:4])([F:3])[F:2].[CH3:5][CH2:6][O:7][CH2:8][CH3:9].[CH3:14][S:15]([OH:18])(=[O:17])=[O:16].[BH3:26].[O:7]1[CH2:8][CH2:9][CH2:5][CH2:6]1
Reactant: [BH4-]
Agent: CS(=O)(=O)O
Agent: FB(F)F
Agent: [Al+3]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: B
Reaction time: 5 h

Procedure:
Step E comprises reduction of the amide carbonyl of compound VI by slowly adding a Lewis acid such as boron trifluoride etherate or aluminum chloride or an anhydrous strong acid such as methanesulfonic acid or trifluoroacetic acid to a stirred slurry of VI and sodium borohydride in dry THF at about -5° C. to about +5° C. followed by stirring about 4 to 6 hours at about -5° to +5° C. followed by 12 to 18 hours at about 25°-40° C. On completion, the reaction mixture is slowly added to cooled dilute acid followed by isolation by standard procedures if desired. As one skilled in the art would appreciate, the above reaction with sodium borohydride in dry THF and an acid such as boron trifluoride etherate or methanesulfonic acid produces borane-tetrahydrofuran in the process of forming compound VII. Alternatively, compound VII can be formed by reducing compound VI with borane-tetrahydrofuran or borane-dimethyl sulfide, without use of the acid.