Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1OC2C(C(=O)CC3C=CC=CC=3)(C(=O)N2C(=C(C)C)C(OC)=O)N1)(O)=O.S(Cl)(Cl)=O.[N+](=[CH:35][C:36]([CH:38]1[O:44][CH:43]2[C:40]([C:54](=[O:62])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:41](=[O:53])[N:42]2[C:45](=[C:50]([CH3:52])[CH3:51])[C:46]([O:48][CH3:49])=[O:47])[NH:39]1)=[O:37])=[N-].[ClH:63]>C(Cl)Cl>[Cl:63][CH2:35][C:36]([CH:38]1[O:44][CH:43]2[C:40]([C:54](=[O:62])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:41](=[O:53])[N:42]2[C:45](=[C:50]([CH3:52])[CH3:51])[C:46]([O:48][CH3:49])=[O:47])[NH:39]1)=[O:37]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Reactant: Cl
Agent: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1.45 g of methyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 7 ml of methylene chloride is added 1.2 ml of thionyl chloride, and the mixture refluxed under heating for 2 hours and concentrated under reduced pressure. The resulting residue [methyl α-(3ξ-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate] is dissolved in 20 ml of tetrahydrofuran and mixed with 15 ml of ether solution of diazomethane which has been prepared from 1.5 g of nitrosomethylurea, and the mixture is kept at room temperature for 30 minutes. Into the resulting solution of methyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is introduced hydrogen chloride gas under ice-cooling until the spot of diazo ketone disappears. The mixture is concentrated under reduced pressure, and the residue is purified by chromatography on 17 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.19 g of methyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 75.3% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])O.[Na+:38].O.[H][H]>C1COCC1.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)[CH3:2].[Na+:38]
Reactant: CCOc1ccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 3 h
Yield: 42 %

Procedure:
4-Nitrobenzyl (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.39 g) prepared in accordance to the method described in Tetrahedron Letters, 34, 3211-3214 (1993)] was dissolved in THF (28 mL), and thereto were added under ice cooling sodium hydrogencarbonate in ion-exchange water (28 mL), and 10% palladium-carbon [50% water] (0.14 g). Then the atmosphere was changed with a hydrogen gas, and the mixture was stirred at the same temperature for 3 hours. After filtration of the insoluble materials with Celite, to the filtrate was added chloroform (80 mL). The organic layer was separated, and extracted with ion-exchange water (20 mL). The organic solvent in the aqueous solution separated and extracted was removed over one hour period in vacuo, purified with C18 reverse column chromatography (Wakosil C18 reverse column, mobile phase; ion-exchange water/THF) and lyophilized to give sodium (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.44 g, yield 42%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[N+:29]([C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O.CCO.[Pd]>[NH2:29][C:32]1[CH:33]=[N:34][N:35]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:36]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Pd]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Diisopropyl azodicarboxylate (3.60 mL, 18.3 mmol) was added dropwise to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (2.45 g, 12.2 mmol), 4-nitro-1H-pyrazole (1.38 g, 12.2 mmol) and PPh3 (4.79 g, 18.3 mmol) in THF (25 mL) at 0° C. The resulting mixture was maintained at this temperature for 10 minutes and then warmed to room temperature at which it was stirred for 6 days. The mixture was diluted with hexanes (80 mL) and EtOAc (20 mL) and stirred for 5 hours at room temperature before filtering, washing the filter cake with hexanes (50 mL) and concentrating the filtrate in vacuo. The resulting oil was purified by silica gel column chromatography (Biotage Isolera, 2×40 g SiO2 cartridges, 0-50% EtOAc in cyclohexane) to give a residue that was dissolved in EtOH (200 mL). 10% Pd/C (53% water; 0.500 g) was added and the resulting suspension stirred under an atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered through Celite, washing with EtOAc (ca. 100 mL) and then the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in EtOAc (200 mL) and washed with water (2×100 mL) and then aqueous 2 M HCl (100 mL). The acidic layer was basified with aqueous 2 M NaOH to pH 13 and extracted with EtOAc (2×100 mL). The combined organic layers from the basified extraction were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A124 as a purple oil (1.39 g, 34%); 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=0.9 Hz, 1H), 7.02 (d, J=0.9 Hz, 1H), 4.20 (s, 2H), 4.11 (m, 1H), 2.95-2.76 (m, 4H), 2.11-2.02 (m, 2H), 1.83 (qd, J=12.3, 4.5 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:11]([CH:24]2[C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:3]=[CH:2]1.S(Cl)(Cl)=O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:11]([CH:24]2[C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1cccc2cc[nH]c12)C1CCCc2cccnc21
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NCCCCN(Cc1cccc2cc[nH]c12)C1CCCc2cccnc21
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of tert-butyl 4-(((1H-indol-7-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)butylcarbamate, 6, (0.27 g, 0.60 mmol) in methanol (5 mL) was treated with thionyl chloride (1 mL) at room temperature. The resulting mixture was stirred for 30 min. The reaction mixture was then concentrated and dried under reduced pressure to afford 0.26 g (87% yield) of the desired product, B: 1H NMR (400 MHz, d6-DMSO) δ 11.97 (bs, 1H), 8.44 (d, J=4.8 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.48-7.40 (m, 1H), 7.35-7.20 (m, 2H), 6.98 (t, J=6.8 Hz, 1H), 6.44 (bs, 1H), 4.90-4.78 (m, 2H), 3.60-3.53 (m, 2H), 3.10-3.00 (m, 2H), 2.80-2.60 (m, 4H), 2.50-2.39 (m, 1H), 2.30-1.40 (m, 7H); ESI+ MS: m/z (rel intensity) 349.2 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1c2c(=O)n(C)c(=O)n(CC3CCC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and (bromomethyl)cyclobutane using potassium carbonate as a base in DMF at 80° C. Mass: 478.16 (M+H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[F:15][C:16]1[CH:17]=[C:18]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1>C(O)C>[F:15][C:16]1[CH:17]=[C:18]([C:22](=[O:24])[CH2:23][C:6](=[O:8])[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cccc(F)c1
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To a solution of sodium ethoxide (123 g, 362 mmol) in ethanol (300 mL) at 0° C. was added a solution of diethyl oxalate (49.4 mL, 362 mmol) in ethanol (25 mL) and the resulting solution was stirred for 10 min. 1-(3-Fluorophenyl)ethanone (50 g, 362 mmol) in ethanol (25 mL) was added and the reaction mixture was stirred at room temperature for 16 h. Ethanol was distilled off under reduced pressure and the residue obtained was quenched with ice cold water and the brown product was filtered. This crude product was purified by ISCO using 220 g silica gel column and 20% ethyl acetate in hexane as eluent. The combined fractions were concentrated to afford Intermediate 4A (62.5 g, 73%). MS(ES): m/z=239 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 15.13 (bs, 1H), 7.77-7.83 (m, 1H), 7.67-7.73 (m, 1H), 7.51 (td, J=8.03, 5.48 Hz, 1H), 7.29-7.37 (m, 1H), 7.28 (s, 1H), 4.43 (q, J=7.18 Hz, 2H), 1.40-1.47 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CCCCC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=467.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:3]=1.[Cl:26]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:26][C:3]1[C:4]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[N:5][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]=1[CH3:1]
Reactant: Cc1cc(NCC(=O)N(C)c2ccccc2)nc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)nc(NCC(=O)N(C)c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 2-(6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (1.0 g) obtained in Example 88, N-chlorosuccinimide (0.44 g) and acetic acid (15 ml) is heated with stirring at 90° C. for three hours, and the reaction mixture is concentrated under reduced pressure. To the residue is added ice-water (30 ml) with stirring, and the precipitates are collected by filtration, washed with water, and recrystallized from isopropanol to give the desired compound (1.1 g), m.p. 154-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([S:30]([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][S:30]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)(=[O:32])=[O:31])[CH:35]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Reactant: Nc1cccc(CS(=O)(=O)C2CCCCC2)c1
Product: O=S(=O)(Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1)C1CCCCC1

Procedure:
Example 6 was prepared under similar conditions as described in the preparation of Example 3 using 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and 3-[(cyclohexylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The batch was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH:16]([N:21]=[C:22]=[S:23])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH:16]([NH:21][C:22]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[S:23])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)NC(N=C=S)C(F)(F)F)cc1
Reactant: Nc1cccnc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC(NC(=S)Nc2cccnc2)C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 3-aminopyridine (145 mg, 1.54 mmol) in benzene (8 mL) at ambient temperature was treated with a solution of Example 1C (500 mg, 1.54 mmol) in benzene (1.5 mL). The reaction mixture was stirred for 1.5 hours, then concentrated to a nominal volume. The white solids which precipitated from solution were collected by filtration and were washed with diethyl ether. Recrystallization from 25% ethyl acetate/hexanes provided the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:6][NH:5][N:4]=1)[CH3:2].[H-].[Na+].[CH2:23]([S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)C>CN(C=O)C>[CH2:1]([C:3]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:5]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][CH3:23])=[CH:27][CH:28]=2)[N:4]=1)[CH3:2]
Reactant: CCSc1ccc(CCl)cc1
Reactant: CCc1n[nH]cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(SC)cc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 3-ethyl-4-(N-t-butoxycarbonylpiperid-4-yl)-1H-pyrazole (0.83 g, 2.97 mmol, from Step B) in 4 mL DMF was cooled to 0° C. and sodium hydride (155 mg, 3.87 mmol, 60% dispersion in mineral oil) was added cautiously. The mixture was warmed to rt and 4-(ethylthio)benzyl chloride (crude material from Step C) in 6 mL DMF was added. The mixture was stirred for 14 h. The mixture was concentrated and the residue was taken up in methylene chloride. The solution was washed with water and sat'd sodium chloride then dried over magnesium sulfate and concentrated. Flash chromatography (40 g silica, 4/1 hexane/EtOAc) afforded the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:20](=[O:24])[CH2:21][CH2:22]Cl)([CH3:18])[CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@@:8]2([CH3:18])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:20](=[O:24])[CH2:21][CH2:22][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN(C(=O)CCCl)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CCOC[C@@]2(C)c2cc(Br)ccc2F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-[(R)-1-(5-Bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-chloro-N-(4-methoxy-benzyl)-propionamide (2.08 g, 3.63 mmol) was dissolved in tetrahydrofurane (45 ml) and the solution cooled to 0° C. A solution of tetrabutylammonium fluoride (1 N in tetrahydrofuran, 7.25 ml) was added and the reaction mixture left to warm to room temperature. After 16 hours, the solvent was evaporated at reduced pressure, the residue dissolved in ethyl acetate (25 ml) and water (25 ml) and the mixture stirred for 15 minutes at room temperature. The aqueous layer was separated and extracted with ethyl acetate (50 ml). The organic layers were washed with brine (25 ml), combined, dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent, (R)-3-(5-bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-3-methyl-[1,4]oxazepan-5-one (intermediate C10A) was obtained as a white foam (1.34 g, 88% of theory). MS (ISP): m/z=422.1, 424.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[C:27]([O-])(=[O:31])[C@@H:28]([CH3:30])[OH:29].[Na+].[OH-].[Na+]>CN(C=O)C.O1CCOCC1.CCOC(C)=O.O>[OH:29][C@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1)=[O:31]
Reactant: C[C@@H](O)C(=O)[O-]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(C(=O)[C@@H](C)O)C3)cc1-2
Reaction time: 2 h
Yield: 36 %

Procedure:
Following the procedure for 318, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and sodium D-lactate in DMF were reacted. After purification by flash chromatography a lactate-ester by-product of the title compound was present. The mixture (0.11 g, 0.2 mmol) was dissolved in 1,4-dioxan (2 mL) and treated with 1M aqueous sodium hydroxide solution (0.2 mL, 0.2 mmol). The reaction mixture was stirred for 2 hours then diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (×2) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Further drying under vacuum gave 398 (90 mg, 36%). LCMS: RT=10.71 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.37 (1H, s), 7.90 (1H, s), 7.20-7.12 (1H, m), 7.06 (1H, dd, J=8.28, 5.28 Hz), 5.85-5.76 (1H, m), 4.64-4.30 (4H, m), 4.25-4.10 (3H, m), 3.98-3.87 (1H, m), 3.45-3.35 (2H, m), 1.62 (6H, d, J=6.65 Hz), 1.33 (3H, dd, J=11.04, 6.67 Hz). 1 Exchangeable not observed
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([C:46](Cl)=[O:47])=[N:40]2)=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:46]([C:41]2[C:42]([O:44][CH3:45])=[CH:43][N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=2)=[O:47])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cn(-c2ccc(F)cc2)nc1C(=O)Cl
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)cc4OC)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q7 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and E3 following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.01 (m, 2H), 2.51 (m, 6H), 3.61 (m, 4H), 3.86 (s, 3H), 3.94 (s, 3H), 4.20 (t, J=6.2 Hz, 2H), 6.46 (d, J=5.3 Hz, 1H), 7.43 (m, 4H), 7.53 (s, 1H), 7.72 (t, J=9.1 Hz, 1H), 8.01 (m, 3H), 8.47 (d, J=5.3 Hz, 1H), 8.49 (s, 1H), 10.19 (s, 1H). MS (ES) C34H33F2N6O6 requires: 645. Found: 646 (M+H)+.
Reaction SMILES: [SH:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[C:20]1[N:19]=[C:18]([S:1][CH:2]([CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH3:3])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(S)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(Sc1cccc(C(F)(F)F)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C
Yield: 94.2 %

Procedure:
To a 16 ml vial was added tert-butyl 4-(1-mercaptoethyl)piperidine-1-carboxylate (500 mg, 2.04 mmol), 2-bromo-6-(trifluoromethyl)pyridine (460 mg, 2.04 mmol), Pd(dppf)Cl2 (42 mg, 0.051 mmol) and Cs2CO3 (996 mg, 3.06 mmol) and 4 ml toluene. The vial was flushed with nitrogen, sealed and heated at 75° C. for 36 hours. After cooling to room temperature, the reaction mixture was diluted with 30 ml ether, and washed with 30 ml water. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:9 to 1:4 ethyl acetate/hexane to give 750 mg desired product was light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:18][C:13]3[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: ClCc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(Br)cccc1N1Cc2ccccc2C1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
A mixture of 3-bromo-2-methylaniline (372 mg, 2.00 mmol), 1,2-bis(chloromethyl)benzene (385 mg, 2.20 mmol), and potassium carbonate (304 mg, 2.20 mmol) in water (2 mL) was heated via microwave irradiation in a sealed tube at 120° C. for 25 min. The mixture was extracted with EtOAc and the organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 30:70 EtOAc-hexane) to provide 2-(3-bromo-2-methylphenyl)isoindoline as a light yellow oil (360 mg, 63%). Mass spectrum m/z 288, 290 (M+H)+.