Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])=[CH2:2].[Cl:10]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1ccccn1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
A mixture of 4.0 g of 2-isopropenylpyridine, 4.5 g of N-chlorosuccinimide and 8 ml of carbon tetrachloride was stirred at 150° to 160° C. for 20 minutes. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1) to obtain 1.0 g of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16]Br)[CH:9]=[N:10]2.[CH3:19][NH:20][CH3:21].C(O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:20]([CH3:21])[CH3:19])[CH:9]=[N:10]2
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(CBr)cc12
Reactant: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (3-bromomethyl-6-chloro-quinolin-5-yl)-acetic acid methyl ester (500 mg, 1.52 mmol) in DMF (10 mL) was added a 33% solution of dimethylamine in ethanol (547 μL, 3.04 mmol). The reaction mixture was stirred for 16 h at room temperature, followed by removal of the solvents in vacuo. The residue was purified by flash column chromatography (silica gel, gradient of CH2Cl2/MeOH 100:0 to 90:10) to afford the title compound as a violet solid (424 mg, 1.45 mmol, 95%). %). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=8.89 (d, J=2.0 Hz, 1H), 8.38 (bs, 1H), 8.00 (d, J=9.1 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 4.36 (s, 2H), 3.69 (bs, 2H), 3.63 (s, 3H), 2.24 (bs, 6H). MS (ES+): 293 (M(C15H1735ClN2O2)+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].O=[C:12]1[CH2:16][CH2:15][S:14][CH:13]1[C:17](OC)=[O:18].C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:17]([OH:18])[C:13]3[S:14][CH2:15][CH2:16][C:12]=3[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C1SCCC1=O
Reactant: N=C(N)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2
Temperature: 85 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a solution of 3-chlorobenzimidamide (4.8 g, 31.2 mmol) in ethanol (150 mL) was added methyl 3-oxotetrahydrothiophene-2-carboxylate (5.0 g, 31.2 mmol) and sodium methoxide (1.7 g, 31.2 mmol). The mixture was stirred at 85° C. for 16 h. The mixture was concentrated after which ethanol (10 mL) was added and the suspension was chilled to 0° C. HCl (2 M, 50 mL) was added and the suspension was filtered and washed with water. The solid was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (1.9 g, 23%) as a brown solid. MW=264.73. 1H NMR (DMSO-d6, 500 MHz) δ 12.85 (s, 1H), 8.13 (s, 1H), 8.07-8.01 (m, 1H), 7.63-7.59 (m, 1H), 7.56-7.51 (m, 1H), 3.41-3.24 (m, 4H); APCI MS m/z 265 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-tert-butoxycarbonyl-5-hydroxyindan-2-amine (0.42 g), potassium carbonate (0.34 g), ethyl bromoacetate (0.24 ml), and N,N-dimethylformamide (4.2 ml) was stirred at ambient temperature for 20 hours. An additional portion of ethyl bromoacetate (0.12 ml) and potassium carbonate (0.17 g) was added to the mixture, and stirring was continued for an additional 12 hours. The mixture was diluted with ethyl acetate and the precipitates were filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (eluent; 5:1 n-hexane-ethyl acetate) to give N-tert-butoxycarbonyl-5-ethoxycarbonylmethoxyindan-2-amine (0.44 g).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][S:25]([CH:28]=[C:29]3[CH2:32][N:31]([CH:33]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:30]3)(=[O:27])=[O:26])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])C)(C)(C)C>C(O)=O>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH:33]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[N:31]2[CH2:30][C:29](=[CH:28][S:25]([CH2:24][C:20]3[CH:19]=[C:18]([N:15]4[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][NH:7][CH3:6])[CH2:17][CH2:16]4)[CH:23]=[CH:22][CH:21]=3)(=[O:27])=[O:26])[CH2:32]2)=[CH:39][CH:38]=1
Reactant: CN(CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1)C(=O)OC(C)(C)C
Solvent: O=CO
Product: CNCC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Yield: 83.3 %

Procedure:
A solution of 81 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl }-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester in 2.5 cm3 of formic acid is stirred for 1 hour at a temperature close to 45° C. The reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30° C., taken up in 10 cm3 of ethyl acetate and alkalinized with 10 cm3 of a saturated aqueous sodium bicarbonate solution. After separating after settling out, the organic phase is washed with 10 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 58 mg of 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone are thus obtained in the form of a beige lacquer [1H NMR spectrum (300 MHz, CDCl3), δ in ppm): from 1.95 to 2.15 (broad unresolved complex, 1H), 2.51 (broad s, 3H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), 3.49 (broad s, 2H), 3.58 (mt, 2H), from 3.75 to 3.90 (mt, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2 Hz, 1H), 7.00 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[C:22]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C>[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N[C@@H]1CCNC1)c1cccc2ccccc12
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc(N2CC[C@@H](N[C@H](C)c3cccc4ccccc34)C2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 157 mg of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 120 mg of methyl 6-chloro-4-(trifluoromethyl)-nicotinate in 5 ml of dioxane was added 346 mg of potassium carbonate, and the reaction solution was stirred at 100° C. for 1 day. Further, to the reaction mixture was irradiated at 140° C. for 1 hour by using a Microwave reaction system, and then, the reaction mixture was cooled to room temperature. To the mixture were added water and ethyl acetate, and the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50), and then, purified by NH thin layer silica gel column chromatography (hexane:ethyl acetate=67:33) to obtain methyl 6-[(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-4-trifluoromethylnicotinate (the following Table, Example, 12.001).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:13]=2)[CH:3]=1.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1.C(N(CC)CC)C.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[N:5]=[C:6]([NH:36][C@H:33]2[CH2:34][CH2:35][C@H:30]([NH2:37])[CH2:31][CH2:32]2)[N:7]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3c[nH]c4ncccc34)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 42b (160 mg, 0.356 mmol), trans-cyclohexane-1,4-diamine (81 mg, 0.713 mmol), triethylamine (0.10 mL, 0.713 mmol) and dioxane (4 ml) was heated at 60° C. for 2 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was taken into methanol (3 mL), treated with dropwise addition of NaOH solution (1.0 mL, 1.0 mmol), stirred at room temperature for 1 hour, neutralized with dilute hydrochloric acid, and purified by reverse-phase HPLC (same condition as described in Example 7b) to afford the title product (28 mg, 23% yield). MS (ESI+) m/z 343 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ppm 1.33-1.63 (m, 4H) 1.98-2.20 (m, 4H) 2.99-3.15 (m, 1H) 3.73-3.87 (m, 1H) 7.11 (s, 1H) 7.17 (dd, J=7.93, 4.58 Hz, 1H) 7.73 (s, 2H) 8.30 (dd, J=4.58, 1.53 Hz, 1H) 8.36 (s, 1H) 8.78 (d, J=7.93 Hz, 1H) 12.05 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[CH:9]1([NH:8][C:5]2[N:4]=[CH:3][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:7][N:6]=2)[CH2:11][CH2:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc(NC2CC2)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc(NC2CC2)nc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
5-Bromo-N-cyclopropylpyrimidin-2-amine (1.06 g, 5 mmol), trimethylsilylacetylene (2.5 g, 25 mmol), Pd(PPh3)4 (289 mg, 0.25 mmol) and CuI (71 mg, 0.375 mmol) were placed in a two neck flask with a rubber plug. The mixture underwent 3 cycles of vacuum and filling with Ar2, a solution of DIPEA (968 mg, 0.45 mmol) and DMF (10 mL) was injected to the flask. The mixture was stirred at 80° C. for 15 hrs, and then was poured into 50 mL water, extracted with EtOAc (30 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc 82:18 to 64:36) to give 1.1 g N-cyclopropyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine. This compound was dissolved in 20 mL CH2Cl2, a solution of TBAF (1.3 g, 5 mmol) in 10 mL CH2Cl2 was added into the above solution. The mixture was stirred at rt for 1 h, evaporated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc 82:18 to 64:36) to give 0.55 g product as a pale yellow solid (72.8%). 1H NMR (300 MHz, CDCl3) δ: 8.43 (2H, s), 5.77 (1H, brs), 3.18 (1H, s), 2.76-2.81 (1H, m), 0.82-0.87 (2H, m), 0.54-0.59 (2H, m). LCMS: m/z [M+H]+ 160.0863.
Reaction SMILES: [OH-].[Na+].O.NN.[C:6]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)CO>[C:7]1([CH2:6][C:14]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccc(O)c2ncccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Oc1ccc(Cc2ccccc2)c2cccnc12
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 2.88 g (72 mmol, 5.5 eq.) of powdered sodium hydroxide and 6.55 ml (135 mmol, 10.3 eq.) of hydrazine monohydrate in 40 ml of ethylene glycol was added 3.08 g (13.1 mmol) of 5-benzoyl-8-quinolinol and the resultant mixture was heated at 120° C. for one hour. The reflux condenser was removed and heating was continued until the pot temperature had reached 195° C. The condenser was replaced and refluxing continued for an additional three hours. The solution was cooled, diluted with 120 ml of water and brought to pH 7 with 1M hydrochloric acid. After the addition of 100 ml of pH 6.5 lM phosphate buffer and 500 ml of ethyl acetate, the layers were separated. The organic phase was washed with 100 ml of pH 6.5 1M phosphate buffer, two 100 ml portions of water and 100 ml of brine, dried over sodium sulfate and evaporated to yield 3.64 g of a dark brown, viscous oil. Purification required flash chromatography on 200 g of silica, eluted with 5:95 methanol:dichloromethane followed by recrystallization from heptane to provide 2.14 g of yellow crystals:melting point 112°-113° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][CH3:40])(=[O:38])[CH2:34][C:35]([CH3:37])=O>CS(C)=O.C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:11]2[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C@H:5]2[CH2:4][N:1]2[C:35]([CH3:37])=[C:34]([C:33]([O:39][CH3:40])=[O:38])[N:3]=[N:2]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN=[N+]=[N-])C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1nnn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6S,7R)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMSO (2 mL) were added potassium carbonate (276 mg) and methyl acetoacetate (0.08 mL) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (149 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:17]=3[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.CN1C(=O)CCC1>[CH3:30][S:31]([NH:34][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:17]=3[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: N#Cc1cc(C(=O)NCc2ccc(Br)nc2)c2ccn(-c3ccc(F)cc3)c2c1
Reactant: CS(N)(=O)=O
Agent: [Cu+2]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)c2cc(C#N)cc3c2ccn3-c2ccc(F)cc2)cn1
Temperature: 125 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 6-cyano-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (75 mg, 0.17 mmol), methanesulfonamide (81 mg, 0.85 mmol), copper (II) trifluoromethanesulfonate (105 mg, 0.290 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (55.2 μL, 0.35 mmol) and potassium carbonate (247 mg, 1.79 mmol) in a sealed tube is added NMP (2.5 mL). The solution is degassed with argon for 3 minutes. The reaction is warmed at 125° C. in a microwave reactor. After 40 minutes, the reaction is diluted with saturated aqueous potassium carbonate (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers are washed with brine (2×15 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is purified by preparative reversed phase HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].[CH3:31][O:32][C:33]1[C:34](=O)[C:35](=[O:39])[C:36]=1[O:37]C.CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:34]2[C:35](=[O:39])[C:36](=[O:37])[C:33]=2[O:32][CH3:31])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 71.5 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.40 g, 0.942 mmol, Example #8 Step M) in MeOH (3 mL) was added 3,4-dimethoxycyclobut-3-ene-1,2-dione (0.14 g, 0.98 mmol) and DIEA (0.18 mL, 1.0 mmol). The reaction was stirred at rt for about 16.5 h. Then the solid from the reaction mixture was collected via vacuum filtration, while washing with cold MeOH (about 4° C., 10 mL), and dried in a vacuum oven at about 60° C. to give crude 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.36 g, 73%, 90% purity): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 535 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]2[C:14]([OH:30])=[CH:15][C:16]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH3:19])=[CH:17][C:4]=2[O:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:30][C:14]1[C:5]2[C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)=[CH:7][C:2]([CH3:1])([CH3:31])[O:3][C:4]=2[CH:17]=[C:16]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:19])[CH:15]=1)(=[O:34])[CH3:33]
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C=C2c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)CCCc2ccc(F)cc2)cc2c1C(c1ccncc1)=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.17 g. (0.01 mole) of the hydroxy compound of Example 3 was dissolved in 8 ml. of dry pyridine to which was added 1.22 g. (0.012 mole) of acetic anhydride. The reaction was stirred at room temperature overnight, evaporated, treated with benzene and evaporated again. The residue was taken up in ether, washed with water, dried over magnesium sulfate and evaporated. The compound was then purified on a Florosil activated aluminum magnesium silicate column using methanolbenzene as an eluting solvent to obtain a glass residue. IR and Raman spectra confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=3)[C:12]=2[NH:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][C:30]2=[O:35])=[O:10])=[N:6][CH:7]=1.[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20]([N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH3:42])=[O:22])=[CH:16][CH:17]=3)[C:12]=2[NH:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][C:30]2=[O:35])=[O:10])=[N:6][CH:7]=1
Reactant: CNCCOC
Reactant: O=C(CCCCN1CCOCC1=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccc(C(=O)O)nc12
Product: COCCN(C)C(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)CCCCN3CCOCC3=O)c2n1
Yield: 75 %

Procedure:
2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-{[5-(3-oxomorpholin-4-yl)pentanoyl]amino}furo[3,2-b]pyridine-5-carboxylic acid (82 mg) obtained in Example 139 and N-(2-methoxyethyl)methylamine (28 mg) are treated in a similar manner to Example 85 to give the title compound (70 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)[CH:14]=1)[O:11][C:10]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:9][C:8]2=[O:26])=[O:4].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:35][C:31]1[CH:30]=[C:29]([N:16]2[CH2:17][CH2:18][CH2:19][CH:15]2[C:13]2[CH:14]=[C:5]([C:3]([N:2]([CH3:27])[CH3:1])=[O:4])[CH:6]=[C:7]3[C:12]=2[O:11][C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:9][C:8]3=[O:26])[CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: Fc1cccc(Br)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc(C2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
Diacetoxypalladium (3.9 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), 1-bromo-3-fluorobenzene (0.049 ml, 0.44 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 mL). The resulting suspension was degassed with argon and stirred at 100° C. for 16 h then cooled to room temperature, filtered and concentrated. The crude product was dissolved in DMA (2 mL) and purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (67 mg, 41%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[SH:10])[C:5]#[N:6].[CH2:11]([OH:13])[CH3:12]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[O:13][CH2:11][CH3:12])[CH:7]=[CH:8][C:9]=1[SH:10]
Reactant: N#Cc1ccc(S)c(Br)c1
Reactant: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(S)c(Br)c1
Reaction time: 0.5 h

Procedure:
3-Bromo-4-mercaptobenzonitrile (10 g) was dissolved in toluene (50 ml) and chloroform (80 ml), followed by adding thereto ethanol (3.0 ml), and the resulting mixture was cooled to −10° C. Hydrochloric acid gas was bubbled into the mixture through a bubbler for 10 minutes and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was allowed to stand in a refrigerator for 60 hours and then the completion of the reaction was confirmed by HPLC(ODS-A212). Dry nitrogen was bubbled into the reaction solution through a bubbler for 20 minutes and the hydrochloric acid gas was distilled off. The precipitate was collected by filtration, washed with toluene/chloroform and then dried to obtain ethyl 3-bromo-4-mercaptobenzene-carboximidate (13.6 g) as a light-yellow solid.