Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:26])[C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[CH2:22][CH:23](O)[CH3:24])[CH:17]=[CH:18][CH:19]=1.[CH2:27]([N:29](CC)CC)C>ClCCl>[CH3:27][NH:29][CH:23]([CH2:22]/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:13]([CH3:26])[CH3:12])[CH:15]=1)[CH3:24]
Reactant: CCN(CC)CC
Reactant: CC(O)C/C=C/c1cccc(N(C)C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNC(C)C/C=C/c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
p-Toluenesulfonyl chloride (782 mg, 4.10 mmol) was added, in one portion, to a stirred solution of (4E)-5-(3-(dimethylamino)phenyl)-4-penten-2-ol (648 mg, 3.16 mmol) in triethylamine (2 mL) and dichloromethane (5 mL) at 10° C. under nitrogen. The cooling bath was removed, and the mixture was stirred at 25° C. for 18 h. Saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture was vigorously stirred for 2 h. The layers were separated and the aqueous layer was extracted once with dichloromethane (10 mL). The combined organic layers were dried (Na2SO4) and evaporated, and the residue was combined with DMF (1 mL) and 40% aqueous methylamine (3 mL). This mixture, also biphasic, was vigorously stirred at 25° C. for 18 h, poured into a mixture of 30% aqueous NaOH (1 mL) and saturated aqueous NaCl (25 mL), and extracted with ether (3×20 mL). The ether extracts were dried (Na2SO4) and evaporated, and the residue was chromatographed on 30 g of Merck silica gel 60 (70-230 mesh) with 5% (v/v) methanol, 5% triethylamine (v/v) in benzene. This gave 206 mg (29.9% yield) of yellow oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH3:30])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CN.O1CC[CH2:38][CH2:37]1>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:30][CH2:37][CH3:38])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC)cc4)cc23)CC1
Agent: CN
Product: CCCNCCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Yield: 27.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1H-indole-7-carboxamide, substituting 2 M propylamine in tetrahydrofuran (0.4 mL) for methylamine to afford 15 mg of the title compound (27.5%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].C([O-])(O)=O.[Na+]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]3)[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.155 g (0.368 mmol) of trans-(4-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester was solved in dichloromethane (2 mL) and trifluoroacetic acid was added at 0° C. (0.230 mL, 3 mmol) and the mixture was stirred at room temperature overnight. NaHCO3 was slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 0.160 g (0.368 mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 321.4 (M+H+).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl>ClC1C=CC=CC=1>[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:6]1[CH:14]=[CH:13][C:12]([Cl:2])=[CH:11][CH:7]=1)=[O:9]
Reactant: [Cl-]
Reactant: Cc1cccc(C(=O)Cl)c1O
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Temperature: 100 °C

Procedure:
Chlorobenzene (78.79 g, 71.6 ml; 0.7 mole) and AlCl3 (14 g, 0.105 mole) were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12 g, 0.07 mole) in chlorobenzene (20 ml). The mixture was stirred and heated at 100° C. overnight. The cooled mixture was added to conc. HCl (10 ml) and ice, extracted with ether, and ether washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and the filtrate distilled, to give (after removal of the ether), a main fraction 2-hydroxy-3-methyl-4'-chlorobenzophenone, b.p. 148°-152° C./0.5 mm (8.18 g), which solidified to yellow microplates, m.p. 55°-58° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12]Br.[CH2:14]([O:21][C:22](=[O:26])[NH:23][CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:14]([O:21][C:22](=[O:26])[N:23]([CH2:12][C:3]1[CH:4]=[C:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(O)c1ccc(Br)c(CBr)c1
Reactant: CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(C(C)(C)O)ccc1Br)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To 2-(4-bromo-3-bromomethyl-phenyl)-propan-2-ol (0.255 g, 0.83 mmol) and ethyl-carbamic benzyl ester (0.446 g, 2.49 mmol) in DMF (15 mL) was added sodium hydride (60% in mineral oil; 0.103 g, 2.57 mmol), and the reaction was stirred for 30 minutes. The mixture was quenched with H2O and worked-up. The residue was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]([CH2:8][OH:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[H]1[BH2][H][BH2]1.CO>C1COCC1>[OH:9][CH2:8][CH:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN1C(=O)C(CO)C[C@H]1COc1cccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CN1CC(CO)C[C@H]1COc1cccnc1

Procedure:
A 401 mg (2 mmol) sample of 3-(1-methyl4-hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine, from step 48a above, was dissolved in 6 mL of THF and 6 mL of 1M B2H6 was added. The reaction mixture was heated at reflux for 2 hours, then stirred at room temperature for 15 minutes after methanol was added. The solvent was removed under pressure, and the residue was dissolved in 4 mL of ethanol. The this solution was added 251 mg of CsF, and the reaction mixture was heated at reflux for 16 hours. The solvent was removed, and the residue was purified on a column of silica gel, eluting with 100:5 to 10:1 chloroform:methanol 78 mg of a mixture of cis and trans product. cis compound: MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (m, 1H), 8.23 (t, 1H, J=3 Hz), 7.21 (m, 1H), 4.16-3.94 (m, 2H), 3.77-3.54 (m, 2H), 3.09-3.01 (m, 1H), 2.88-2.64 (m, 1H), 2.58-2.47 (m, 1H), 2.46 (m, 1H), 2.46 (s, 1H), 2.38-2.29 (m, 1H), 1.98-1.81 (m, 1H). trans compound: MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) d: 8.33 (m, 1H), 8.23 (m, 1H), 7.23 (m, 1H), 4.20-3.96 (m, 2H), 3.74-3.59 (m, 2H), 3.42-3.26 (m, 1H), 2.97-2.83 (m, 1H), 2.54 (s, 1H), 2.48-2.23 (m, 1H), 2.04-1.80 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[C:5]([NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH:15]=2)[N:10](C(OC(C)(C)C)=O)[N:9]=1)=[O:6].Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[C:5]([NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH:15]=2)[NH:10][N:9]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)c2cccc(Cl)c2)c2cc(NC(=O)NCc3cc(F)ccc3F)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1cc(F)ccc1F)Nc1ccc2[nH]nc(NC(=O)c3cccc(Cl)c3)c2c1
Yield: 31 %

Procedure:
7.2 90 mg of tert-butyl 3-(3-chlorobenzoylamino)-5-[3-(2,5-difluorobenzyl)ureido]indazole-1-carboxylate are stirred for 16 hours with 3 ml of HCl/dioxane (4 M). The batch is evaporated and dried well. Purification of the residue by column chromatography on silica gel (eluent:heptane/EA 9:1) gives 23 mg of 1-[3-(3-chlorobenzoylamino)-1H-indazol-5-yl]-3-(2,5-difluorobenzyl)urea (“A21”) as a colourless powder (31%), MS-FAB (M+H+)=456;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]1=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:16])[N:9]1[N:8]=[CH:7]2.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]#[N:8])[C:11]=1[C:10]1[NH:9][C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][C:12]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3cccc(Cl)c3c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cccc(Cl)c1-c1[nH]c(=O)c(-c2ccccc2)cc1C(=O)O
Yield: 99.4 %

Procedure:
A.a) A mixture of 72.9 g of methyl 11-chloro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxylate, 112 g of potassium hydroxide and 1200 ml of methanol was heated to boiling under reflux for 46 hours under argon. The mixture was then concentrated to about 200 ml, the yellow suspension was diluted with 1000 ml of water, filtered and the aqueous phase was extracted three times with 200 ml of methylene chloride each time. The aqueous phase was acidified with 25 percent hydrochloric acid and the separated crystals were filtered off, washed with water and dried in a vacuum. There was obtained 69.7 g of 2-[2-chloro-6-cyanophenyl]-1,6-dihydro-6-oxo-5-phenylnicotinic acid as yellowish crystals with a m.p. of 279°-281° (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:35]#[N:36])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51].O>CN(C)C=O>[C:35]([C:34]1[CH:33]=[C:32]([CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=1)[CH2:31][N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:5]1[N:6]=[CH:7][C:2]([O:1][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:3][CH:4]=1)#[N:36]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(OCCCC(=O)OC(C)(C)C)cn1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
3-{[(5-Hydroxy-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (150 mg) is dissolved in N,N-dimethylformamide (2.5 ml), and thereto is added 60% sodium hydride (12 mg) under ice-cooling and the mixture is stirred for 30 minutes and thereto is added tert-butyl 4-bromobutyrate (85 mg), and the mixture is stirred at room temperature for 6 hours. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (169 mg). MS (m/z): 742 [M+H]+
Reaction SMILES: [N:1]1([C:10]2([CH2:15][C:16]([NH2:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.N1C(Cl)=NC(Cl)=NC=1Cl.C(OCC)(=O)C.O>CN(C)C=O.CCCCCC>[N:1]1([C:10]2([CH2:15][C:16]#[N:18])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: NC(=O)CC1(n2ccc3cccnc32)CCCC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#CCC1(n2ccc3cccnc32)CCCC1
Yield: 58.1 %

Procedure:
To a stirred solution of 2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamide (398) (1.6 g, 6.58 mmol) in dimethylformamide (25 mL) was added cyanuric chloride (728 mg, 3.95 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature (TLC, 30% ethyl acetate in hexane, Rf=0.8). Cold water was added and the mixture was extracted with ethyl acetate (2×50 mL) and washed with water (2×50 mL) and brine (50 mL). The organic phase was thereafter dried and concentrated to get a crude product. The crude product was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to get (1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetonitrile (399) (861 mg, 58%) as a light yellow thick oil.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:32])[C:7]([C:30]#[N:31])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[N:19]=2)=[C:12]([Cl:29])[CH:11]=1)C.C([O-])(=O)C.[K+].C(O)(=O)C.O>CN(C)C(=O)C.C(#N)C>[Cl:29][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:32])[C:7]([C:30]#[N:31])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[O:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Oc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A solution of (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (68) (6.5 g, 13.12 mmol) and potassium acetate (1.42 g, 14.43 mmol) in N,N-dimethylacetamide was heated to 120° C. for 2 h. At this time, the reaction was cooled to room temperature and was treated with glacial acetic acid (1.5 mL) and water (65 mL). The mixture was stirred at room temperature for 15 min. The solids which resulted were collected by filtration, washed with water (65 mL) and dried under vacuum to give an orange solid. The solid was suspended in acetonitrile (36 mL), heated to reflux for 3 h and then cooled to room temperature. The resulting solids were then collected by filtration, washed with acetonitrile (12 mL) and methyl tert-butyl ether (24 mL) and dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (69) (5.06 g, 85.8%) as an orange solid; ES(+)-HRMS m/e calcd for C18H14Cl2N6O4 (M+H)+ 449.0527, found 449.0527. Exact Mass=448.0454; Molecular Weight=449.26.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]([NH2:13])=[CH:8][CH:9]=[C:10]([F:12])[CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:23](=[O:24])[NH:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[NH:5][CH:1]1[CH2:2][CH2:3][CH2:4]1)[CH3:26])([CH3:15])([CH3:16])[CH3:17]
Reactant: Nc1ccc(F)cc1NC1CCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
A mixture of N2-cyclobutyl-4-fluorobenzene-1,2-diamine (0.63 g, 3.5 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.73 g, 3.9 mmol), HOAt (0.53 g, 3.9 mmol), 4-methylmorpholine (0.85 mL, 7.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.75 g, 3.9 mmol) in DCM (12 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclobutylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (853 mg, 69%). LCMS (Method J): RT 3.54 min [M+H]+ 352.2.
Reaction SMILES: O=[C:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[Cl:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:25]=1[NH2:26]>C1C=CC=CC=1>[Cl:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:25]=1[NH:26][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)C(=O)C(=O)OCc1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC(C)[C@H](Nc1c(Cl)cc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of m-phenoxybenzyl 2-oxo-3-methylbutanoate, 0.39 g of 2,4,6-trichloroaniline, 0.02 g of p-toluenesulfanylacetate and 10 ml of benzene is heated to reflux for about 5.5 hr. A Dean-Stark trap is used to remove water. The reaction is worked by pouring into ether/sodium bicarbonate solution. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated. To the reaction product (0.79 g) is added 3 ml of methanol, 1 ml of THF and 0.19 g of NaCNBH3. The reaction mixture is stirred at RT and then adjusted to pH 3 to 4 with concentrated sulfuric acid. Stirring at RT is continued overnight. The reaction is worked up as before using ether/sodium bicarbonate solution and subjected to prep. TLC eluting with 20% ether/hexane to yield the m-phenoxybenzyl ester of N-(2,4,6-trichlorophenyl)valine, MS m/e 477 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3-fluorobenzoyl chloride (0.45 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-benzamide as a white solid (0.7 g, 77%): mp, 215-217° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.2 min. (99%); 1H NMR (DMSO-d6): δ 2.07-2.12 (m, 1H), 2.54-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.39-7.84 (m, 7H), 9.26 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.40, 48.86, 114.29, 118.49, 121.92, 123.50, 127.15, 130.62, 131.52, 133.09, 134.82, 136.31, 138.97, 163.69, 165.31, 166.94, 167.51, 169.83, 172.74. Anal Calcd for C21H16FN3O5: C, 61.61; H, 3.94; N, 10.26; F, 4.64. Found: C, 61.36; H, 3.84; N, 10.00; F, 4.74.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:4]([CH2:5][CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:3][N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[Cl:22][C:14]1[C:8]2[NH:7][CH2:6][CH2:5][C@@H:4]3[CH2:3][N:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:1][C@H:10]3[C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCNc3ccccc3[C@@H]2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CCNc3c(Cl)cccc3[C@@H]2C1
Temperature: 50 °C

Procedure:
To a solution of Example 389B (172 mg, 0.60 mmol) in N,N-dimethylformamide (1 mL) was added N-chlorosuccinimide (80 mg, 0.60 mmol). The mixture was heated at 50° C. for 2 hours and purified by reversed phase HPLC (0.1% trifluoroacetic acid(aq):acetonitrile) to afford the title compound with a longer retention time than that of Example 391A.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Cl-].[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH:51]([CH3:62])[CH2:52][O:53][C:54](N1C=C[N+](C)=C1)=[O:55])([O-:44])=[O:43]>ClCCl>[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH:51]([CH3:62])[CH2:52][O:53][C:54]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)=[O:55])([O-:44])=[O:43]
Reactant: CC(COC(=O)n1cc[n+](C)c1)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](OC(=O)OCC(C)c3ccccc3[N+](=O)[O-])[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A solution of 2 g 5′-O-(4,4′-dimethoxytrityl)thymidine (3) (3.67 mmol) in 20 ml dichloromethane is added dropwise at 0° C. to 1.2 equiv N3-[2-(2-nitrophenyl)propoxycarbonyl]-N-methylimidazolium chloride (2) (4.4 mmol) in 30 ml dichloromethane through a molecular sieve 4 Å within 10 minutes. The reaction mixture was stirred at 0° C. overnight, then extracted using 0.5% HCl (100 ml), dried via Na2SO4 and evaporated. 10% trichloroacetic acid (70 ml) in dichloromethane is added to the organic phase and stirred for 2 minutes. Thereafter, the deep-red solution is extracted twice using saturated NaHCO3 (100 ml), dried via Na2SO4 and evaporated. Purification via flash chromatography (0-10% methanol in toluene/ethyl acetate (5:4)) yielded 1.53 g (93%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH:31]([NH:34][C@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]([CH:31]([CH3:33])[CH3:32])[C@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)N[C@H](C)COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@H](C)COC(=O)c3ccc([N+](=O)[O-])cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoyl chloride and 4-nitro-benzoic acid (R)-2-isopropylamino-propyl ester hydrochloride as described for example 9.