Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C=C.[CH3:5][N:6]([CH3:16])[C:7]1[CH:15]=[CH:14][C:10]([CH:11]=[N:12]O)=[CH:9][CH:8]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:5][N:6]([CH3:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: CN(C)c1ccc(C=NO)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: C=CC#N
Product: CN(C)c1ccc(C#N)cc1
Temperature: 135 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A solution of 53 g of acrylonitrile and 1.0 g of copper(II) acetate in 100 g of o-xylene was heated to the boil (85° C.), after which a solution of 82 g of p-dimethylaminobenzaldoxime in 110 g of o-xylene was added dropwise by heating further. During the addition, the boiling point of the reaction mixture increased to 135° C. The mixture was stirred under reflux for a further 30 minutes and was then left to cool. The precipitated acrylamide was filtered off under suction, and the mother liquor was extracted by shaking with a little water. The organic phase was evaporated down and the residue was taken up in 400 ml of petroleum ether. After the mixture had been left to stand overnight at 0° C., 66 g (90%) of p-dimethylaminobenzonitrile were obtained in the form of yellow crystals of melting point 75°-76° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([Br:9])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[CH:41]([C:43]([CH3:45])=[O:44])=[CH2:42]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([Br:9])[N:5]=[CH:6][C:7]=1/[CH:42]=[CH:41]/[C:43](=[O:44])[CH3:45]
Reactant: C=CC(C)=O
Reactant: Nc1cc(Br)ncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)/C=C/c1cnc(Br)cc1N
Temperature: 80 °C
Yield: 78.8 %

Procedure:
4-Amino-2-bromo-5-iodopyridine (4.49 g 15 mmol), tri-o-tolylphosphine (363 mg 1.2 mmol) and palladium acetate (135 mg 0.60 mmol) were dissolved in DMF (45 mL) and di-isopropylethylamine (3.76 mL, 21.6 mmol) and methyl vinyl ketone (2.45 mL, 30 mmol) were added. The reaction was placed under nitrogen and heated at 80° C. for 70 minutes. The reaction was cooled and concentrated in vacuo. Ethyl acetate (150 mL) was added and the solution was washed with water (80 mL). The organic layer was collected, washed with water (2×60 mL) brine, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ether (2×10 mL) to afford the title compound (2.85 g, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7]2[N:8]=[CH:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:3]1[CH2:4][CH2:5][C:6]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:8][C:7]=2[C:2]1([CH3:17])[CH3:1])=[O:22]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: CC1(C)NCCc2c1ncn2-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)c2ncn(-c3ccccc3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of the product of Example 53, Step B (59 mg, 0.26 mmol) in DCM (2 mL) was added Intermediate 12 (63 mg, 0.26 mmol) and K2CO3 (89 mg, 0.65 mmol). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was filtered and concentrated and then purified on 12 g SiO2 column with 0-4% NH3/MeOH CH2Cl2 to give the desired compound (55 mg, 48%). MS (ESI): mass calcd. for C22H19ClF3N3O, 433.1. m/z found, 434.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J=7.8, 1.4 Hz, 1H), 7.67 (s, 1H), 7.54-7.37 (m, 5H), 7.30 (dd, J=5.3, 3.3 Hz, 2H), 3.53-3.38 (m, 2H), 2.72-2.54 (m, 2H), 2.01 (d, J=6.3 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[CH:37]([NH2:39])=[O:38].C1(C)C(C)=CC=CC=1.OS(O)(=O)=O>O.CC#N>[CH3:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])=[CH:6][C:5]=1[C:3]1[N:39]=[CH:37][O:38][CH:2]=1
Reactant: NC=O
Reactant: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2cocn2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A mixture of 5-(bromoacetyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 50 (c), 100 mg, 0.17 mmol), formamide (135 μl, 3.4 mmol), xylene (300 μl) and conc. H2SO4 (10 μl) was heated with stirring for 2 h. The reaction was diluted with water and CH3CN and purified on preparative HPLC, affording the title compound (23 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 94.8 %

Procedure:
4.5 g of 4-(5-nitro-2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (12.8 mmol) was dissolved in 40 mL of methanol, 1.36 g of 10% Pd/C was added and the mixture was hydrogenated under hydrogen gas for 4 h at 40° C. The reaction mixture was filtered over Celite and the filtrate evaporated to dryness in vacuo to yield 3.9 g of the title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][NH:14][C:13]1=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[P:29](=O)([O-:33])[O:30][CH2:31][CH3:32].[Cl-].[Na+]>O1CCCC1>[CH2:31]([O:30][P:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:23]=1)([N:14]1[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:16])=[O:33])[CH3:32]
Reactant: CCOP(=O)([O-])c1ccccc1Cl
Reactant: O=C(NC1CNC1=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(c1ccccc1)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a solution of 3-benzyloxycarbonylamino-2-azetidinone (5.0 g) in dry tetrahydrofuran (125 ml), cooled to -78° C., was added sec-butyl lithium (18.5 ml) and the mixture was stirred for 5 minutes. Ethyl chlorophenylphosphonate (4.71 g) was added and the mixture was stirred for 1 hour at -78° C. followed by the addition of 125 ml of saturated sodium chloride solution. The mixture was then extracted twice with 125 ml portions of ethyl acetate and the extracts were combined, dried over anhydrous sodium sulfate and the solvent removed in vacuo yielding the crude product as a foam. The crude product was purified by chromatography on silica gel (750 g), eluting with dichloromethane:ethyl acetate (1:1) followed by ethyl acetate. The ethyl acetate fractions were stripped and the residue triturated with ether to yield 4.94 g of product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4CCNCC4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][C:35]([OH:37])=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:6][CH2:7][N:8]([C:35](=[O:37])[CH2:34][O:33][CH3:32])[CH2:9][CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: COCC(=O)O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Product: COCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 243.5 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 188 mg; 0.43 mmol) and 2-methoxyacetic acid (41 mg; 0.46 mmol), 260 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][NH:17]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccnc(CCc2ccc(F)cc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(CCc2ccc(F)cc2)C1
Reaction time: 5 h
Yield: 100 %

Procedure:
Methyl 2-(4-fluorophenethyl)isonicotinate (3.8 g, 14.66 mmol) dissolved in acetic acid (150 mL) and platinum(IV) oxide (0.25 g, 1.10 mmol) was added. The mixture was hydrogenated in a Büchi hydrogenation apparatus at 5 bar and room temperature for 5 h. The catalyst was removed by filtration and the solvent was evaporated. The residue was taken up in DCM and washed with satd NaHCO3. The organic phase was filtered through a phase separator and evaporated. Methyl 2-(4-fluorophenethyl)piperidine-4-carboxylate (3.89 g, quant.) was isolated. MS m/z 266 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:36]=[CH:37][N:38]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:36]=[CH:37][N:38]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
A mixture of methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoate (100 mg, 0.19 mmol) and sodium hydroxide (100 mg) in 1,4-dioxane (5 mL) and water (5 mL) was stirred at 40° C. for 2 h. The residue was concentrated to ˜5 mL in vacuo and adjusted pH=2 with 1M HCl. The crude mixture was concentrated and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (9.5 mg, 10%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.29 (s, 1H), 8.80 (d, 1H, J=5.4 Hz), 8.13 (s, 1H), 8.00-7.92 (m, 5H), 7.51-7.40 (m, 2H), 6.98-6.92 (m, 2H), 4.58 (brs, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 2.28-1.98 (m, 5H). LC-MS: [M+H]+, 504, tR=1.236 min, HPLC: 98.3% at 214 nm, 98.4% at 254 nm, tR=4.52 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH:12]2[O:13][C:14](=[O:21])[CH:15]3[CH:16]([C:17]([O:19][CH3:20])=[O:18])[CH:9]1[CH2:10][CH:11]23)=[O:6].CN(C)C=O.[C:27]([O-:32])(=[O:31])[C:28]([CH3:30])=[CH2:29].[Na+].[I-].[Na+]>O>[C:27]([O:32][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH:12]2[O:13][C:14](=[O:21])[CH:15]3[CH:16]([C:17]([O:19][CH3:20])=[O:18])[CH:9]1[CH2:10][CH:11]23)=[O:6])(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: C=C(C)C(=O)[O-]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 10.0 g of the 4-chlorobutyrate obtained in Example 1-1-1 and 30 g of dimethylformamide was added dropwise to a mixture of 4.69 g of sodium methacrylate, 0.71 g of sodium iodide and 20 g of dimethylformamide at 60-70° C. The mixture was stirred at the temperature for 8 hours. 100 ml of water was added below 30° C. This was followed by ordinary work-up and silica gel chromatography purification, obtaining 8.12 g of the target compound (yield 70%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]1
Reactant: COc1ccccc1N1N=C(C)CC1=O
Agent: Br
Solvent: CC(=O)O
Product: CC1=NN(c2ccccc2O)C(=O)C1
Reaction time: 6.5 h
Yield: 71 %

Procedure:
An amount of 1.80 g of 1-(2-methoxyphenyl)-3-methyl-2-pyrazolin-5-one was added into a mixture of 18 ml of 47% hydrobromic acid and 18 ml of acetic acid, and the mixture were refluxed under stirring for 6.5 hours. After evaporation of the solvent, an aqueous NaHCO3 solution was added to the residue to adjust to pH 4 and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, followed by recrystallization of the residue from ethanol to give 1.19 g of 1-(2-hydroxyphenyl)-3-methyl-2-pyrazolin-5-one (Compound No. 44) as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:24]([NH2:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>ClCCl>[C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:34][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCN
Reactant: CSCCC(OC(C)=O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)C(CCSC)OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetoxy-4-(methylthio)butanoic acid (17.1 g, 89 mmol) in dichloromethane (350 mL) at 0° C. was added thionyl chloride (32.4 mL, 445 mmol) dropwise over 1 hr. The reaction was stirred at 0° C. for 1.5 hrs then the cooling bath was removed and the reaction was warmed to room temperature with stirring for 3 hrs. The solvent was evaporated and the resulting oil was dried under high vacuum for 1 hr to give an orange oil. A solution of the resulting oil in dichloromethane (˜30 mL) was added to a solution of triethylamine (24.8 mL, 178 mmol) and decylamine (17.8 mL, 89 mmol) in dichloromethane (150 mL) at 0° C. and the reaction was allowed to warm to room temperature with stirring overnight. The reaction was evaporated, redissolved in EtOAc (300 mL) and washed with 1N HCl (3×150 mL), saturated sodium bicarbonate (3×150 mL), and brine(1×150 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography with 0-40% EtOAc/heptane to give a yellow oil. (21.1 g, 71%). m/z 332 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added benzenesulfonyl chloride (230 μL, 1.8 mmol) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 418.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-])=O.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1cccc(N)c1)OCC

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with diethyl 3-aminobenzylphosphonate to generate the title compound. The diethyl 3-aminobenzylphosphonate was prepared by sequential treatment of commercial 3-nitrobenzyl bromide with triethyl phosphite at 125° C. for 6 hours followed by reduction with Na2S2 O4 in THF/H2O at 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: Nc1ccncc1Cl
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4Cl)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-chloro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 120. 1H NMR (500 MHz, CDCl3) δ ppm 1.24 (d, J=6.60 Hz, 6 H) 1.59-1.64 (m, 2 H) 1.66-1.74 (m, 2 H) 2.85-2.93 (m, 2 H) 3.44-3.47 (m, 2 H) 4.25-4.29 (m, 4 H) 4.80-4.87 (m, 1 H) 4.87-4.94 (m, 1 H) 7.60 (s, 1 H) 8.09 (s, 1 H) 8.31 (d, J=6.05 Hz, 1 H) 8.44 (s, 1 H) 8.75 (d, J=5.50 Hz, 1 H). LRMS (ESI): 433.3/435.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]1)[C:8](=[O:53])[NH:7]2)=[O:5])C.O.CO.[OH-].[Li+]>O1CCCC1>[C:29]([O:28][C:26]([NH:25][N:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]2)[C:8](=[O:53])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Compound 17 (39 mg, 0.054 mmol) was dissolved in tetrahydrofuran (3.5 ml), water (1.75 ml) and methanol (1.75 ml). Lithium hydroxide (430 μl, 1 M in water) was then added and the reaction was stirred at room temperature for 24 h. The volume was reduced to half and water (10 ml) was added. Acidification (pH=5) followed by extraction with chloroform gave the pure title compound (34 mg, 90%). MS (M+H+) 700.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:30][CH2:31]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(c3ccccn3)CC2)c2nccc(C)c2c1
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
A mixture of 3.3 g (0.009 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.8 g (0.01 mole) of 1-(2-pyridinyl)piperazine in 10 ml of toluene was heated in an oil bath at 120° for 2.5 hr. After 1.5 hr, excess triethylamine was added slowly with stirring. After cooling, the reaction mixture was taken up in dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness in vacuo. Recrystallization from 2-propanol afforded 3.4 g (85%) of the desired product, mp 120°-121°.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5](OC2CCN(C(OC(C)(C)C)=O)CC2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:31][CH:30]([C:32]([NH:34][C:35]3[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=3)=[O:33])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[C:2]1([NH:1][C:39]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:32]([CH:30]3[CH2:29][N:28]([C:24]4[N:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH2:31]3)=[O:33])=[CH:43][CH:42]=2)=[O:40])[CH:21]=[CH:20][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: O=C(Nc1ccccc1)c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting aniline for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 4-(1-(pyridazin-3-yl)azetidine-3-carboxamido)benzoic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6/D2O) δ ppm 8.53 (dd, J=4.4, 1.3 Hz, 1H), 7.98-7.92 (m, 2H), 7.77-7.65 (m, 5 H), 7.38-7.24 (m, 3 H), 7.15-7.07 (m, 1H), 4.49 (t, J=9.0 Hz, 2H), 4.46-4.38 (m, 2H), 4.00-3.81 (m, 1H); MS (ESI(+)) m/e 374 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=2[S:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.CN(C)C=O.[N+:32](=[CH2:34])=[N-:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([CH:34]=[N+:32]=[N-:33])=[O:16])=[CH:10][C:9]=2[S:17][CH3:18])=[O:7])=[CH:19][CH:20]=1
Reactant: CSc1cc(C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1cc(C(=O)C=[N+]=[N-])n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of the crude 5-(p-chlorobenzoyl)-2-hydroxycarbonyl-4-methylthio-1-methylpyrrole in 3 ml of methylene chloride is added 100 μl of (COCl)2 followed by the addition of 0.5 μl of dimethylformamide (DMF). The resulting reaction mixture is stirred for about an hour and then concentrated to give a yellow solid. Subsequently freshly prepared diazomethane is added dropwise to a stirred solution of the yellow solid in 1 ml of methylene chloride at 0°. The reaction is allowed to warm up to room temperature over a period of one hour. After the excess amount of diazomethane is removed by bubbling nitrogen through the reaction mixture, the solvents are removed by evaporation under reduced pressure and a bright yellow solid is collected. This crude product, i.e., 5-(p-chlorobenzoyl)-2-diazomethylcarbonyl-4-methylthio-1-methylpyrrole, is used directly in the next step without further purification.