Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2.CC(=C(C)C)C.O.P([O-])(O)(O)=[O:31].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([N:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][C:2]([OH:31])=[O:1])[CH:5]=2)[CH2:9]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: O=P([O-])(O)O
Agent: CC(C)=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.33 h

Procedure:
To a solution of benzyl 5-(2-oxoethyl)isoindoline-2-carboxylate (290 mg, 1 mmol) in tert-butanol (10 mL) was added 2,3-dimethyl-but-2-ene (1.1 mL). To this mixture was added a solution comprising sodium dihydrogenphosphate hydrate (1.08 g, 8 mmol) and sodium chlorite (1.08 g, 9.5 mmol tech grade). This mixture was stirred for 20 min diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 3-20% methanol in dichloromethane) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:22][C:21]2=[O:35])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:36][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[O:22][C:21]2=[O:35])=[O:8])=[CH:5][CH:4]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 4-(chloromethyl)benzoyl chloride (2.24 g, 11.9 mmol) in methylene chloride (25 mL) was added to a cold (0° C.) stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (4.0 g, 10.8 mmol) and pyridine (0.96 mL, 11.9 mmol) in methylene chloride (25 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1 N HCl and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with sat'd NaHCO3, water, brine and then dried (MgSO4). Evaporation of the solvent gave the crude product which was recrystallized from methylene chloride/hexanes to afford the title compound as white crystals (4.8 g, 85%): mp 142-144° C.; MS m/e: 523 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8](O)[CH2:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]2[CH:8]=[CH:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCCC(O)c2c(Br)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CCC=Cc2c(Br)cccc21
Temperature: 25 °C

Procedure:
A solution of 4-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (4.402 g, 16.35 mmol) and p-toluenesulfonic acid monohydrate (0.31 g, 1.64 mmol) in toluene (80 ml) was heated under reflux in a reaction vessel equipped with a Dean-Stark trap under dehydrating conditions for 0.5 hr. After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane) to give the objective substance.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:28])[C:7](=[C:14]([NH:16][C@@H:17]1[C@@H:23]([OH:24])[C@H:22]([OH:25])[C@@H:21]([CH2:26][OH:27])[O:20][CH:18]1[OH:19])[CH3:15])[C:8]2=[O:13])([O-:3])=[O:2].C(O[C:33](=[O:35])[CH3:34])(=O)C>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:28])[C:7](=[C:14]([NH:16][C@@H:17]1[C@@H:23]([O:24][C:8](=[O:13])[CH3:7])[C@H:22]([O:25][C:18](=[O:19])[CH3:17])[C@@H:21]([CH2:26][O:27][C:33](=[O:35])[CH3:34])[O:20][C@@H:18]1[OH:19])[CH3:15])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=C2C(=O)c3cccc([N+](=O)[O-])c3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4-nitro-1,3-dioxoindan-2-ylidene)ethylamino]-D-glucopyranose (100 mg, 0.23 mmol), pyridine (2 ml) and acetic anhydride (3 ml) stirred at room temperature overnight. The reaction mixture was evaporated, and the residue was purified by chromatography using CHCl3/EtOAc 10:4 as the mobile phase to give 2-Deoxy-2-[1-(4-nitro-1,3-dioxoindan-2-ylidene)-ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranose (23) (165 mg, 79%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([N:32]1[CH:36]=[C:35]([CH:37]=[O:38])[N:34]=[CH:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+].[C:41]([O:44][CH2:45][CH3:46])(=[O:43])[CH3:42]>C1COCC1.CCCCCC.O>[OH:38][CH:37]([C:35]1[N:34]=[CH:33][N:32]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([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)[CH:36]=1)[CH2:42][C:41]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -70 °C

Procedure:
Diisopropylamine (33.8 ml) was dissolved in dry THF (445 ml) under an argon atmosphere. A solution (1.6 M; 150 ml) of n-butyl lithium in hexane was added at not more than 0° C. with stirring under ice-cooling (ice-salt), and the mixture was stirred for 30 min. The mixture was then cooled to −70° C. in a dry ice-acetone bath and ethyl acetate (23.5 ml)/dry THF (60 ml) solution was added at not more than −65° C. The mixture was stood with stirring for 1 h 20 min. The reaction mixture was added to a solution (1185 ml) cooled to −70° C. of 1-trityl-4-formyl-1H-imidazole (67.7 g) in dry THF at not more than −60° C., and the mixture was stirred for 1 h. A 20% aqueous ammonium chloride solution (445 ml) was added to stop the reaction and the mixture was allowed to warm to room temperature over 1 h. An equivalent amount of water was added and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was combined and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated, and the precipitated crystals were finely divided with hexane, collected by filtration and dried to give the title compound (77.26 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([C:5]1[N:6]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:29](=[O:31])(=[O:30])[NH:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:39][CH:40]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:21])([F:22])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)[nH]1
Product: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 88 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-[4-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]-methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5.0% MeOH in CH2Cl2) gave an 88% yield of the title compound as an orange solid, mp >78° C. (gradual), homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 632 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:29])[NH:21][CH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:29][C:20]([NH:21][CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: NC(=C[N+](=O)[O-])NC1CCCCCC1
Reactant: CSCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NC2CCCCCC2)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethyl sulphide are reacted with 40 grams of 2-nitro-N-cycloheptyl-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. The product melts at 91°-94° C. Spectrophotometric analyses confirm its structure.
Reaction SMILES: Br[C:2]1[C:3]([F:31])=[C:4]([C:18]([CH3:30])=[C:19]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10](=[O:17])[C:9]=1[CH2:8][NH:7][C:5]([C:4]1[C:3]([F:31])=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:20]=[C:19]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:18]=1[CH3:30])=[O:6]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)c(F)c(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)c(F)c(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a solution of 3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide (112 mg, 0.23 mmol) in 1,4-Dioxane (2 ml) and Water (1 ml) was added 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (103 mg, 0.34 mmol) followed by Na2CO3 (84.04 mg, 0.79 mmol). The solution was purged with nitrogen for 5 minutes before the addition of palladium-triphenylphosphine (1:4) (26 mg, 0.02 mmol). The yellow mixture was then purged with nitrogen for 5 minutes before being heated to 100° C. After 4 hours LCMS indicated no unreacted starting material was present. The darken reaction mixture was diluted with deionized water (5 ml) and extracted with 10% MeOH in DCM (5×5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 99:1 DCM:MeOH to 95:5 DCM:MeOH) to give 69 mg (52%) of the title compound as an off-white solid. LC-MS 97%, 2.70 min (7 minute LC-MS method), m/z=591.2, 1H NMR (500 MHz, Chloroform-d) δ ppm 12.10 (br s, 1H), 7.53-7.30 (m, 4H), 7.13 (d, J=7.4 Hz, 1H), 7.07 (br s, 1H), 5.88 (s, 1H), 4.55 (br s, 2H), 3.93 (d, J=11.2 Hz, 2H), 3.73-3.69 (m, 4H), 3.52 (s, 2H), 3.30 (t, J=10.8 Hz, 2H), 3.02 (q, J=6.9 Hz, 2H), 2.92 (ddd, J=14.6, 10.7, 3.7 Hz, 1H), 2.46 (s, 4H), 2.35 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H), 1.79-1.43 (m, 4H), 0.86 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[C:17]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][N:2]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7])[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCCNC(=O)OC(C)(C)C)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C

Procedure:
To a mixture comprising 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (2-methylamino-ethyl)-amide (Intermediate E) (0.5 g, 2.0 mmol) and 4-(Boc-amino)butyl bromide (0.8 g, 3.1 mmol) in DMF (5 mL) is added sodium carbonate (0.4 g, 4.0 mmol). The resulting mixture is heated at reflux for 3 h and then allowed to cool to RT, filtered and concentrated in vacuo. The crude product is dissolved in DCM and filtered to remove any undissolved impurities. The filtrate is concentrated in vacuo to yield the title compound which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:13]=1B(O)O>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].C(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2cccc(C(=O)O)n2)c1
Yield: 20 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2-fluoro-5-propoxyphenyl)picolinic acid in 20% yield. LC/MS=276.0 (M+H), Rt=0.87 min.
Reaction SMILES: [Br:1][C@@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11].CO>C1COCC1>[Br:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@H:8]1[OH:7]
Reactant: N
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1

Procedure:
(1R,4S,5R)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (351a) (2.13 g, 10.4 mmol) was taken up in THF (20 mL) and treated with 0.880 ammonia (5.3 mL) at 20° C. for 24 h with stirring. The solvent was then removed in vacuo to give a white solid in quantitative yield; [α]D=+40.6° (c=1, MeOH).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:44][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:43][CH:42]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(CN4CCN(C)CC4)cc3)nn12
Yield: 24.7 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.3789 mL, 0.002175 mol) and 4-(4-Methyl-piperazin-1-ylmethyl)-phenylamine (0.179 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (0.500 mL, 0.00512 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 46.12 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine as a lyophilized powder. (M+H)=429.07. 1H NMR (400 MHz, DMSO, d6) δ 9.55 (s, 1H), 8.97 (s, 1H), 7.79 (dd, 1H, J=1.64, 5.97 Hz), 7.73 (d, 2H, J=8.36 Hz), 7.48 (m, 1H), 7.22 (d, 3H, J=7.96 Hz), 7.12 (t, 1H, J=7.45 Hz), 6.95 (m, 2H), 3.85 (s, 3H), 3.72 (m, 6H), 3.40 (m, 4H), 2.76 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[NH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28]([N:30](CC)[CH2:31]C)C.Cl.CNC>CC#N>[Cl:1][C:2]1[CH:11]=[C:10]([N:30]([CH3:31])[CH3:28])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[NH:7]2
Reactant: CCN(CC)CC
Reactant: CC1(c2ccccc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)c1cc(Cl)c2c(c1)NC(=O)C(C)(c1ccccc1)C2=O
Yield: 65.3 %

Procedure:
To a solution of 5,7-dichloro-3-methyl-3-phenyl-1H-quinoline-2,4-dione (1.00 g, 3.12 mmol) in MeCN (10 mL) were added K2CO3 (0.65 g, 4.68 mmol), triethylamine (0.65 mL, 4.68 mmol), and dimethylamine hydrochloride (0.35 g, 7.80 mmol) at room temperature. The reaction mixture was then heated for 10 hours at reflux temperature. After the reaction completed, the solvent was removed. The residue was diluted with 1N HCl solution and extracted with ethyl acetate (100 mL×2). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude was purified by a column chromatography on silica gel to give the objective compound (0.67 g, 65%): 1H NMR (200 MHz, CDCl3) δ 1.89 (s, 3H, CH3), 2.64 (s, 6H, 2NCH3), 6.29 (d, J=2.03 Hz, 1H, ArH), 6.49 (d, J=2.03 Hz, 1H, ArH), 7.23-7.33 (m, 5H, ArH), 9.13 (br s, 1H, NH); m.p. 224-226° C.; MS(EI) m/e 328 [M+], 313, 196, 132; HRMS m/e cacld. for C18H17N2O2Cl 328.0979, found 328.0979.
Reaction SMILES: [OH:1][C@H:2]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:34]([O:1][C@H:2]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@H](O)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl([(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37, Method A, 6.35 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol) and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 24 hours. The reaction mixture was then poured into a saturated NaHCO3 solution (50 mL). The mixture was extracted with ether (100 mL×2). The ether layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a near white syrup which was purified by column chromatography (silica gel, hexanes/ethyl acetate (5/1, v/v)) giving the desired compound as a colorless oil. LC-MS m/z 625.0 (MH+), RT=4.09 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl[C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:23]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:23])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COC(=O)CCC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 96.8 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added methyl 3-(chlorocarbonyl)propanoate (0.63 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.75 g (97%) of product as an off-white solid: mp 224-226° C.; 1H NMR (DMSO-d6) δ 11.18 (s, 1H), 9.79 (s, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.62 (d, J=7.3 Hz, 1H), 5.16 (dd, J=5.2 and 12.6 Hz, 1H), 3.61 (s, 3H), 2.99-2.48 (m, 7H), 2.11-2.06 (m, 1H); 3C NMR (DMSO-d6) δ 172.84, 172.66, 170.94, 169.75, 167.61, 166.70, 136.39, 136.15, 131.52, 126.39, 118.43, 117.04, 51.51, 48.95, 31.22, 30.96, 28.39, 22.03; Anal. Calcd. For C18H17N3O7: C, 55.82; H, 4.42; N, 10.85. Found: C, 55.68; H, 4.41; N, 10.61.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 82.4 %

Procedure:
Prepared according to the procedure described for Example 121 using 3-nitrobenzenesulfonyl chloride (2.44 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p. 208-210° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]1[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[C:13]([O:14]C)[C:8]=2[CH2:7][CH:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O:5]1.Br>C(O)(=O)C>[ClH:1].[NH2:2][CH2:3][CH:4]1[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[C:13]([OH:14])[C:8]=2[CH2:7][CH:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O:5]1
Reactant: COc1ccc(C)c2c1CC(C1CCCCC1)OC2CN
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(O)c2c1C(CN)OC(C1CCCCC1)C2

Procedure:
A suspension of 294 mg (0.9 mmol) of 1-aminomethyl-3-cyclohexyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benzopyran hydrochloride, from Step 3, in 8 mL of glacial acetic acid and 8 mL of 48% aqueous hydrobromic acid was stirred at reflux temperature for 2 h. The reaction mixture was concentrated in vacuo to remove most of the hydrobromic acid. The aqueous concentrate was adjusted to pH 8.0 with 50% aqueous sodium hydroxide solution and saturated aqueous sodium bicarbonate solution. The resultant aqueous solution was extracted with 2×100 mL of methylene chloride and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 5% methanol in methylene chloride to give the free amine. The amine was treated with diethyl ether saturated with anhydrous hydrogen chloride and the resultant precipitate was crystallized from methanol/ether to afford 152 mg (55% yield) of the title compound, m.p.>280° C.(dec); MS DCI-NH3M/Z: 276 (M+H)+. Analysis calculated for C17H26CINO2 +0.2H2O: C, 64.73; H, 8.42; N, 4.47. Found: C, 64.78; H, 8.33; N, 4.26.