Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:10]2>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:10]2
Reactant: O=S(Cl)Cl
Reactant: O=C(NC1CCc2cc(CO)ccc21)OCc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CCc2cc(CCl)ccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Thionyl chloride (2.0 g, 16.8 mmol) was added to a suspension of benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ylcarbamate (2.53 g, 8.5 mmol) in DCM (35 mL). The solution was stirred at rt for 1 h before the reaction mixture was evaporated to dryness in vacuo and the material was co-evaporated with diethyl ether (2×100 mL) to afford the title compound as a white solid (2.63 g, 98%). MS (ESI): m/z [M+NH4]+ 333.2
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:39])[NH:24][C:25]4[CH:31]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])[CH:29]=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:21]([C:17]3[CH:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:22][C:23](=[O:39])[NH:24][C:25]=2[CH:31]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)cc1

Procedure:
) The title compound was prepared from the above described 3′-[7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-biphenyl-4-sulfonic acid tert-butylamide (310 mg, 0.573 mmol, 45% purity) and TFA (5 mL) according to the general procedure I step 2. Obtained as an off-white solid (20 mg, 13%, 80% purity). MS (ISP) 486.0 [(M+H)+]; mp 240-250° C. (dec).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:23])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of p-acetoxyphenylacetic acid was dissolved in 5 ml of methylene chloride. To the solution were added, with ice cooling, a catalytic amount of N,N-dimethylformamide and 0.12 ml of oxalyl chloride. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain p-acetoxyphenylacetyl chloride. This compound was dissolved in 5 ml of methylene chloride. To the solution was added 260 mg of a sulfur trioxide-dioxane complex with ice cooling. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure to obtain DL-2-(p-acetoxyphenyl)-2-sulfoacetyl chloride. This compound was dissolved in 5 ml of anhydrous tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(N)c1[N+](=O)[O-]
Yield: 86.6 %

Procedure:
3-methyl-2-nitroaniline (6.2 g, 41 mmol) was dissolved in 150 mL acetic acid, stirred and treated in portions with N-bromosuccinimide (7.3 g, 41 mmol). After 1 h the mixture was poured into 400 mL water with stirring. The precipitated product was collected by filtration, washed well with water, and then taken up in 200 mL ethyl acetate. This solution was washed with 50 mL water, 50 mL saturated NaHCO3, 50 mL saturated NaCl, dried (Na2SO4) and evaporated under vacuum to give the title compound as a bright orange solid (8.2 g, 87%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.33 (d, J=8.8 Hz, 1H), 6.62-6.49 (d, J=8.8 Hz, 1H), 4.75 (s, 2H), 2.41 (s, 3H); EIMS m/z 230.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(N2CCC3(CC2)OCCO3)ncn1

Procedure:
A solution of 1,4-dioxa-8-azaspiro[4.5]decane (3.04 g, 2.72 mL, 21.2 mmol), 4-chloro-6-methylpyrimidine (3.00 g, 23.4 mmol) and N,N-diisopropylethylamine (4.12 g, 5.56 mL, 31.8 mmol) in dioxane (50 mL) was heated to 140° C. in the microwave for 40 minutes. The reaction mixture was concentrated, then directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as orange oil (4.64 g, 93%).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CN1C(=O)CCC1.CCOC(C)=O>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:14]=1
Reactant: NCc1ccncc1
Reactant: N#Cc1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cccnc1NCc1ccncc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 15.5 %

Procedure:
To a stirred solution of 2-chloro-nicotinonitrile (Aldrich, 10.4 g, 75.06 mmol) in dry NMP (40 ml) was added 4-(aminomethyl)pyridin (15.2 ml, 150.26 mmol). The reaction mixture was heated to 130° C., and stirred at this temperature for 20 hours. The mixture was cooled to room temperature and diluted with EtOAc (500 ml) and washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The remaining red-brown solid material was recrystallised from ethanol affording the title compound (7.73 g) as an off-white solid. The filtrate was evaporated under reduced pressure, redissolved in 2% methanol/EtOAc (v/v) and filtrated through a pad of silica gel. The filtrate was evaporated under reduced pressure and the residue was recrystallised from ethanol and gave an additional amount of the title compound (2.44 g).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][C:32](O)=[O:33]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][C@@H:27]5[CH2:28][CH2:29][CH2:30][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C[C@@H]1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (40 mg, 72.9%), MS (ISP) m/z=443.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.124 mmol) and (S)-2-(tetrahydrofuran-2-yl)acetic acid
Reaction SMILES: [CH3:1][NH2:2].CO.CO.[C:7]([O:11][C:12]([N:14]([CH:16]([C:22]([O:24]CC)=O)[C:17]([O:19][CH2:20]C)=[O:18])[CH3:15])=[O:13])([CH3:10])([CH3:9])[CH3:8].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[C:7]([O:11][C:12]([N:14]([CH3:15])[C@H:16]([C:22]([NH:2][CH3:1])=[O:24])[C:17](=[O:18])[O:19][CH3:20])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 34 %

Procedure:
A 40% methylamine-methanol solution (67 mL) was added to a methanol (2.1 L) solution of diethyl [(t-butoxycarbonyl)(methyl)amino]propanedioate (Intermediate 3-1, 0.21 kg), and the mixture was stirred for 19 hours at room temperature. Further, a 40% methylamine-methanol solution (23 mL) was added, and the mixture was stirred for 4 days at the same temperature. Then, ethyl acetate (0.30 L) was added, and citric acid monohydrate (81 g) was slowly added under ice cooling, followed by stirring the mixture for 30 minutes under ice cooling. The precipitated solid was filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=75/25→15/85) to obtain N2-(t-butoxycarbonyl)-N,N2,O-trimethyl-3-oxoserinamide (Intermediate 4-2, yellow oil) (63 g, 34%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-trifluoromethyl-pyridine following a procedure analogous to that described in Example 19. LC (method 5): tR=2.18 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [CH2:1]([S:6](Cl)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1>N1C=CC=CC=1.ClCCl>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)=[O:24]
Reactant: CCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
1-Pentanesulfonyl chloride (0.034 g, 0.30 mmol) was added slowly to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone in pyridine (2 mL) at 0° C. The mixture was stirred at 25° C. for 16 hours and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the product was purified by column chromatography to afford the title compound in 4% yield (2.7 mg). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.87, 7.74, 7.61, 7.36, 6.94, 4.47, 4.11, 3.87, 3.68, 3.60, 3.42, 2.99, 1.77, 1.32, 0.88. MS (ES+) m/z 485.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:17])=[C:7]2[C:12](Cl)=[C:11]([C:14]#[N:15])[CH:10]=[N:9][N:8]2[CH:16]=1)=[O:4].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:17])=[C:7]2[C:12]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[C:11]([C:14]#[N:15])[CH:10]=[N:9][N:8]2[CH:16]=1)=[O:4]
Reactant: COC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: COC(=O)c1cn2ncc(C#N)c(NC3CCN(Cc4ccccc4)CC3)c2c1C

Procedure:
The title compound was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester (prepared using the procedure of Example 1D) (65.0 mg, 0.246 mmol) and 4-amino-1-benzylpiperidine (52.6 μl, 0.258 mmol) by a route analogous to that used for the preparation of compound 388D. It (100 mg, 97%) was a white crystalline solid. LCMS Found: (M+H)+=418.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][N:13]=[CH:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])=[C:4]([F:21])[CH:3]=1.[C:22]([CH2:24][C:25](OCC)=[O:26])#[N:23].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:25](=[O:26])[C:24]([C:22]#[N:23])=[C:15]([C:16]([F:19])([F:18])[F:17])[CH:14]=[N:13]2)=[C:4]([F:21])[CH:3]=1
Reactant: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2ncc(C(F)(F)F)c(C#N)c2=O)c(F)cc1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
After 4.345 g of 3, 3, 3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone) was dissolved in 20 mL of pyridine, 2.1 mL of ethyl cyanoacetate was added to the pyridine solution, which was followed by stirring for 4 hours at 120° C. After cooling to room temperature, the reaction solution was poured into 3N-hydrochloric acid and extracted with diethyl ether. After the organic layer was washed with aqueous saturated sodium bicarbonate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane=2/8) to afford 2.858 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCCCNC(=O)OC(C)(C)C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of (3-Amino-propyl)-carbamic acid tert-butyl ester and 2-acetylpyridine with NaBH(OAc)3 in CH2Cl2 gave [3-(1-pyridin-2-yl-ethylamino)-propyl]-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)[CH3:10])[CH:6]=[CH:5][N:4]=1.[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH2:40])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH:40][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=3)[CH3:10])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzoic acid (Step B, 800 mg, 2.94 mmol) in CH2Cl2 (40 mL) was added 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (812 mg, 2.94 mmol), TBTU (1.0 g, 3.23 mmol), and DIEA (1.5 mL, 8.81 mmol). The reaction was stirred at RT under N2 for 20 h. The reaction was quenched with sat. NH4Cl, washed with water, brine, dried over MgSO4, and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with Hexanes:acetone mixture (80:20) gave final compound. MS m/z: 531.2 (M+H). Calc'd. for C30H37N6O3-531.66.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])(=[O:27])=[O:26]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])(=[O:27])=[O:26])=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1
Reactant: C[C@@H](O)CNS(=O)(=O)c1ccccc1Br
Reactant: Nc1ncc(-c2ncc(B(O)O)cc2F)cn1
Product: C[C@@H](O)CNS(=O)(=O)c1ccccc1-c1cnc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H18FN5O3S, 403.11; m/z found, 404.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.02 (d, J=0.8, 2H), 8.52-8.47 (m, 1H), 8.09 (dd, J=7.9, 1.4, 1H), 7.81 (dd, J=11.9, 1.8, 1H), 7.72 (m, 1H), 7.66 (m, 1H), 7.46 (dd, J=7.5, 1.4, 1H), 3.74-3.59 (m, 1H), 2.84-2.66 (m, 2H), 1.06 (d, J=6.3, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:14]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7](=[O:12])[C:8]1=[O:11])[CH3:15]
Reactant: CCI
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(=O)c2cccc(F)c21

Procedure:
7-Fluoro-1H-indole-2,3-dione (prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325 (4.00 g, 24.2 mmol), iodoethane (3.87 ml, 48.5 mmol) and potassium carbonate (6.61 g, 48.5 mmol) in DMF (20 ml) are stirred at room temperature for 20 hours. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as an orange solid. HPLC r.t. 4.48 min; MS for C10H8FNO2 m/z 193.9 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[Cl-].[NH4+].O[N:49]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:40]([CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)(=[O:41])[NH2:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole (32 mg) in N,N-dimethyl-formamide (1 mL) were added ammonium chloride (8 mg), 1-hydroxybenzotriazole (9 mg), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimidehydrochloride (15 mg) and triethylamine (21 mg), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, 5 mol/L aqueous sodium hydroxide solution (0.5 mL) was added to the filtrate, and the resulting mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/90) to give the title compound (7 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: O=C1CN(CCc2ccccn2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 56.4 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (280 mg, 0.761 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (156 mg, 0.760 mmol) were reacted according to Example 2 (step f) to provide the title compound (210 mg, 56%) as a yellow oil: ESI MS m/z 490 [M+H]+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH:4]=[N:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[K].[O-]CCCC.Cl>CN1C(=O)CCC1.O>[I:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[N:5]=[CH:4]2
Reactant: O=C(O)c1cccc(NN=Cc2cc(I)ccc2F)c1
Agent: CCCC[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc(-n2ncc3cc(I)ccc32)c1
Yield: 107.4 %

Procedure:
3-(2-(2-Fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (I1b, 3.47 g, 9 mmol) and potassium tert, butoxide (2.3 g, 20.5 mmol) was stirred under argon atmosphere in NMP (45 mL) at 150° C. for 30 minutes. After cooling, the mixture was diluted with water (100 mL), acidified with aqueous HCl (1.7 M) and extracted trice with EtOAc. The combined organic phases were washed twice with water and then with brine. Evaporation of the organic phase afforded crude title compound (3.52 g, quant.) as a light brown, amorphous, gummy solid.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br.[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1>>[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[CH:24]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Agent: Br
Product: CCCCCCCCc1noc(-c2ccc(CNCc3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,1′-biphenyl-3-ylmethylamine hydrobromide gave the title compound as an oil. M+(LC/MS(ESI)): 454.6 HPLC (Condition A), Rt: 4.52 min (HPLC purity: 81%).