Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.C(N(CC)CC)C.[ClH:27].[Cl:28][CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>>[ClH:28].[ClH:27].[CH:36]12[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]1)[CH2:32][N:31]([CH2:30][CH2:29][N:14]1[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:37]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 34 %

Procedure:
Prepared by the method described in Example 9 from 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.2 g, 0.020 moles), triethylamine (4.9 g, 0.048 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (5.4 g, 0.024 moles). Recrystallization from methanol yielded the final product (3.3 g) as the dihydrochloride, mp 229°-234° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:38]#[N:39].[K+].C(Cl)(Cl)Cl.CO.[NH4+].[OH-]>CS(C)=O.CCOC(C)=O.OS([O-])(=O)=O.[Na+]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:38]#[N:39])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1cc(CBr)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: [C-]#N
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1cc(CC#N)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: -78 °C

Procedure:
To a solution of the crude product of Step A dissolved in 1.5 mL of methyl sulfoxide was added 0.050 g (0.762 mmol) of potassium cyanide at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h when TLC analysis (80:15:1 CHCl3 -MeOH-NH4OH) indicated that the reaction was complete. The reaction mixture was diluted with EtOAc and 10% aqueous NaHSO4 solution. The aqueous phase was separated and the EtOAc portion was washed with brine (2×10 mL). The EtOAc portion was then dried over MgSO4, filtered, evaporated to a residue, and purified. Purification was done by reversed phase HPLC (Waters Millipore Delta Prep 4000 with Delta-Pak C18 15 μm 100 A column cartridge) with a solvent system of 30:70 water-acetonitrile and 0.1% TFA buffer. The purified fractions collected were combined in a round bottom flask, frozen in a -78° C. dry ice-acetone bath, and lyophilized. The resulting lyophilized powder afforded 0.071 g (35% 2-step yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Li][CH2:20]CCC.CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([CH3:20])[C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
N-(4-chloro-3-(trifluoromethyl)phenyl)pivalamide (3b) (3 g, 10.7 mmol) was dissolved in dry THF (30 mL), cooled to 0° C., and n-BuLi (15.6 mL, 25.7 mmol) was added. After 3 h, a solution of MeI (0.66 mL, 10.56 mmol) in THF (7 mL) was added to the reaction mixture maintaining the temperature at 0° C. and stirred for further 3 h. and quenched with aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was purified by column chromatography to afford N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3c) (2.0 g, 64%) as off white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:26]=[CH:27][CH:28]=1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[C:25]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCCOc1cccc(C2=NNC(=O)CC2)c1
Product: O=C1CCC(c2cccc(OCCNCC(O)COc3ccc(CCOCC4CC4)cc3)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=1.O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:15][CH:16]=1
Reactant: OC1CCOCC1
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
tetrahydro-2H-pyran-4-ol (850 mg, 8.32 mmol) was dissolved in DMF (10 mL), cooled to 0° C., NaH (500 mg, 10.4 mmol) was added and stirred for 45 minutes at room temperature, then 5-bromo-2-chloropyridine (2 g, 10.4 mmol) was added and the mixture was stirred overnight at 60° C. The mixture was poured into water, extracted by EA, the organic layer was washed by brine, dried over Na2SO4, concentrated and purified by flash chromatography, gave 1.7 g white solid. MS: (m/z): 258 (M−H)+, 260 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O.CC(C)=O>[CH2:24]([O:17][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[CH:5]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=c1c2ccccc2oc2cc(OCc3ccccc3)cc(O)c12
Temperature: 60 °C
Yield: 42.6 %

Procedure:
The compound (1.77 g, 7.75 mmol) synthesized in Step 1 of Example 2 and K2CO3 (2.76 g, 0.02 mol) were charged to a dry round-bottom flask, and anhydrous acetone (200 mL) was added thereto. To the reaction mixture was added benzyl bromide (1.38 mL, 11.63 mmol), followed by stirring under reflux at 60° C. for one day. After the reaction was completed, the reaction liquid was cooled to room temperature, and 200 mL of water was added thereto. The reaction liquid was acidified with 3M-HCl and extracted twice with ethyl acetate. The organic layer was combined, successively washed with water and brine, and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: CH2Cl2) to give the title compound (1.05 g, 42.6%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][S-:16].[Na+]>CS(C)=O.CN(C=O)C.O>[CH3:15][S:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1ccnc(Oc2ccccc2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccnc(Oc2ccccc2)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-phenoxypyrimidine (2.00 g, 9.68 mmol) in dry DMSO (15 ml) and DMF (10 ml) at 10° C. under nitrogen was added dropwise a solution/ suspension of sodium methanethiolate (0.77 g, 9.68 mmol) in dry DMSO (15 ml) and DMF (5 ml). After approximately one hour below 15° C., the reaction mixture was diluted with water and then extracted (x3) with ether. The combined ether extracts were washed with brine and then dried. Evaporation of the solvent gave 4-methylthio-2-phenoxypyrimidine as a thick, pale yellow oil (2.00 g,87% pure by GC) which was used in the next stage without further purification.
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.Br[CH:24]1[CH2:29][CH2:28][O:27][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C.ClCCl>[O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:24]2[CH2:29][CH2:28][O:27][CH:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:14])([F:15])[F:13])[CH:7]=1
Reactant: BrC1CCOC(c2ccccc2)C1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCOC(c3ccccc3)C2)C1
Temperature: 60 °C

Procedure:
To a solution of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (100 mg, 0.32 mmol), 4-bromo-2-phenyltetrahydro-2H-pyran (92 mg, 0.38 mmol, prepared according to Org. Let. 2003, 1979-1982) in DMF (3 mL) was added cesium carbonate (156 mg, 0.48 mmol) and the mixture was heated to 60° C. overnight. The mixture was cooled to room temperature, and NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL) were added. The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to preparative HPLC to afford, as a mixture of diastereomers, N-(2-oxo-2-{[(3R)-1-(2-phenyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide as a white solid. 1H-NMR (CDCl3) δ: 1.42-1.71 (m, 2H), 1.93-1.99 (m, 2H), 2.15-2.20 (m, 2H), 2.15-2.20 (m, 1H), 2.59-2.72 (m, 1H), 3.53-3.61 (m, 2H), 3.87-3.99 (m, 2H), 4.09-4.19 (m, 3H), 4.29-4.32 (m, 2H), 7.28-7.33 (m, 5H), 7.55-7.58 (m, 1H), 7.73-7.75 (m, 1H), 8.00-8.03 (m, 1H), 8.08-8.11 (m, 1H). MS m/z: 476 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[CH:14][O:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[CH3:23])[N:4]=[N:3]1.[C:24]1([N:30]2[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[CH:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:33]3[CH:32]=[N:31][N:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:34]=3)=[CH:18][C:17]=2[CH3:23])[N:4]=[N:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(-c2ccccc2)c1
Reactant: Cc1cc(I)ccc1OC=C1C=CC=CC1n1nnn(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cnn(-c3ccccc3)c2)ccc1OC=C1C=CC=CC1n1nnn(C)c1=O
Yield: 15.7 %

Procedure:
A solution of 1.48 g (3.5 mmol) of the tetrazolone from Example 5, 1.51 g of (1-phenylpyrazol-4-yl)tributylstannane and 0.2 g of tetrakis(triphenylphosphine)palladium(0) in 20 ml of anhydrous toluene was stirred at 70° C. for 2 hours and then refluxed for 2 hours. The solvent was distilled off and the residue was chromatographed over silica gel (cyclohexane:methyl tert-butyl ether mixture 1:1), giving 0.24 g of the title compound of m.p. 152-153° C.
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].[OH:7][C:8]1[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=1)[C:12](O)=[O:13]>CC(O)=O>[OH:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:15][CH:16]=1)[C:12](=[O:13])[NH:5][C:17]2=[O:19]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: O=C1NC(=O)c2cc(O)ccc21
Temperature: 120 °C

Procedure:
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated tot approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].C(OC(N[C@@H:41]1[C@H:46]([CH2:47][CH:48]=O)[CH2:45][C@H:44]2[CH2:50][C@H:42]1[C:43]2([CH3:52])[CH3:51])=O)(C)(C)C.O>O1CCCC1>[C:2]([CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:48]\[CH2:47][CH:46]1[CH2:41][CH:42]2[CH2:50][CH:44]([C:43]2([CH3:51])[CH3:52])[CH2:45]1)#[N:3]
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@H](CC=O)C[C@H]2C[C@H]1C2(C)C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C2CC(C/C=C\CCCC#N)CC1C2
Yield: 41.8 %

Procedure:
To a suspension of 30.3 g of (4-cyanobutyl)triphenylphosphonium bromide in 140 ml of tetrahydrofuran is added 8.07 g of potassium-tert-butoxide under stirring in an nitrogen atmosphere and the mixture is stirred at room temperature for 1.5 hours. A solution of the above prepared crude aldehyde 3c in 50 ml of tetrahydrofuran is dropwise added at 0° C. and the resulting mixture is stirred at the same temperature for 1 hour. Water is added to the reaction mixture, then which is extracted with ether. The organic layer is washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue is purified by flash chromatography on 200 g of silica gel (hexane:ethyl acetate=6:1) to give 6.9 g of the titled compound 7a in 41.8% yield.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]([C:15]#[N:16])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][CH2:4][O:3]1.COCCO[AlH2-]OCCOC.[Na+].O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH3:1][CH:2]1[O:7][C:6]([CH2:15][NH2:16])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][CH2:4][O:3]1
Reactant: CC1OCCC(C#N)(c2ccccc2Cl)O1
Agent: COCCO[AlH2-]OCCOC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC1OCCC(CN)(c2ccccc2Cl)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Thirty-two g (0.135 mole) of 2-methyl-4-(cyano)-4-(2-chlorophenyl)-1,3-dioxane was dissolved in 100 ml of toluene. To this solution was added 60 g (0.21 mole) of red-al in benzene (Aldrich Chemical Company). The reaction exothermed to 40° C. The reaction was allowed to stir 1 hour at room temperature and was then heated at 90° C. for 5 hours. The reaction was stirred overnight at room temperature. The reaction was quenced by the cautious addition of H2O. One hundred ml of saturated NH4Cl was added and the slurry was filtered. The layers were separated and the organic layer was dried and stripped to yield 25.6 g of 2-methyl-4-(aminomethyl)-4-(2-chlorophenyl)-1,3-dioxane. Structure as confirmed by infrared, nuclear magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][CH:25]([C:16]3[CH:17]=[N:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=3)[CH2:30][CH2:29]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2nc(C3CCN(CCCCn4nnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Yield: 63 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl)piperidine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.3 g compound (I-123) with a yield of 62.7%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C=CN=C1.S(Cl)(Cl)=O.[CH2:24]([C:26]1[N:27]=[C:28]([C@@H:31]([NH2:42])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)[S:29][CH:30]=1)[CH3:25]>C(Cl)Cl>[CH2:24]([C:26]1[N:27]=[C:28]([C@@H:31]([NH:42][C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)[S:29][CH:30]=1)[CH3:25]
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)CCC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Benzoylpropionic acid (0.250 g) is dissolved in CH2Cl2 (5 mL), N-methyl imidazole (0.333 mL) is added and the resulting solution is cooled to 0° C. after which a solution of thionyl chloride (0.320 g) in CH2Cl2 (2 mL) is added dropwise. After 0.5 hours (S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) is added. The reaction is stirred forl 8 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed with 1N HCl and brine. The solution is dried over Na2SO4, filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:8][C:7]1[C:6]([CH3:11])=[CH:5][C:4]([CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:3][C:2]=1[OH:1]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CC(=O)OC(C)(C)C)cc(O)c1N
Yield: 91.1 %

Procedure:
A solution of t-butyl 3-hydroxy-5-methyl-4-nitrophenylacetate (0.47 g, Reference Example 11) in ethanol (25 mL) was treated with palladium on charcoal (approximately 0.08 g, 10%) and stirred under a hydrogen atmosphere. After 4 hours the mixture was filtered through a pad of celite and the filtrate was evaporated to give the title compound (0.38 g) as a green oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]2[N:21]([CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH2:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=4)[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1ccc(CN2CCOc3cc(N)ccc32)cc1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccc(C(=O)OC)cc2)nc1Cl
Yield: 70.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (2 mL), methyl 4-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101b) (0.28 g, 0.97 mmol) and pyridine (5 mL). The resulting solid was washed with dichloromethane/hexane=1/1 to obtain 0.31 g of the title compound as a light yellow solid (70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:28][O:29][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:9]3=[O:27].[C:30]([N:37]1[CH2:41][CH2:40][C@@H:39]([NH2:42])[CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:27]=[C:9]1[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([NH:42][C@@H:39]4[CH2:40][CH2:41][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:38]4)=[CH:3][C:4]=3[O:29][CH2:28]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc(Br)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc3c(c2)OCC32C(=O)N(Cc3ccc(C(F)(F)F)o3)c3ccccc32)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 47.7 %

Procedure:
To a stirred solution of 6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.80 g, 1.73 mmol), (R)-1-Boc-3-aminopyrrolidine (0.48 g, 2.59 mmol) and (2-biphenyl)di-tert-butylphosphine (0.08 g, 0.28 mmol) in toluene (15 mL) was added palladium(II) acetate (0.09 g, 0.14 mmol) followed by the addition of sodium tert-butoxide (0.42 g, 4.3 mmol). The mixture was stirred at 100° C. for 18 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane; 1/2) to afford tert-butyl (3R)-3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)amino]pyrrolidine-1-carboxylate (0.47 g, 48%): 1H NMR (300 MHz, CDCl3) δ7.32-7.24 (m, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.05 (dd, J=7.4 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.76-6.69 (m, 1H), 6.45 (d, J=8.2 Hz, 1H), 6.36 (d, J=3.2 Hz, 1H), 6.19 (d, J=2.0 Hz, 1H), 6.02 (dd, J=8.2, 2.0 Hz, 1H), 5.05 (d, J=16.2 Hz, 1H), 4.95-4.81 (m, 2H), 4.65 (d, J=9.0 Hz, 1H), 4.00-3.90 (m, 1H), 3.88-3.76 (m, 1H), 3.73-3.57 (m, 1H), 3.52-3.34 (m, 2H), 3.30-3.11 (m, 1H), 2.23-2.06 (m, 1H), 1.96-1.77 (m, 1H), 1.45 (s, 9H); MS (ES+) m/z 570.2 (M+1).