Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]#[N:12].Cl.Cl[CH2:23][CH2:24][N:25]([CH:33]([CH3:35])[CH3:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.CCCCCCC.O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH2:23][CH2:24][N:25]([CH:33]([CH3:34])[CH3:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]#[N:12]
Reactant: CC(C)N(CCCl)Cc1ccccc1
Reactant: N#CC(CCN1CCCCC1)c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCCCCC
Solvent: O
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)Cc1ccccc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a reaction vessel under a nitrogen atmosphere was charged 35.0 kg of pulverized potassium hydroxide (90%) and 34.0 L of dimethyl sulfoxide. A solution of 29.5 kg of α-(2-chlorophenyl)-1-piperidinebutanenitrile (product of Example 3) in 23 L of dimethyl sulfoxide was added while maintaining the temperature below 25° C. A solution of 30.7 kg of N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in 112 L of dimethyl sulfoxide was added while maintaining the temperature below 20° C. The mixture was stirred at 25° C. until the reaction was complete as indicated by gas chromatographic analysis (GC Method C). The mixture was cooled and diluted with 122 L of heptane and 200 L of water. The layers were separated, and the organic phase was filtered through a layer of diatomaceous earth. The filter cake was washed with 40 L of heptane. The combined organic phase was washed twice with 70 L of water and dried by azeotropic distillation. The solvent was removed by distillation under reduced pressure to give 49.4 kg (100.0%) of the title product α-(2-chlorophenyl)-α-[2-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanenitrile as an oil. Analysis calcd for C27H36ClN3 : C,74.03; H,8.28; Cl,8.09; N,9.59. Found: C,73.35; H,8.36; Cl,7.27; N,9.15. The crude product (oil) was carried forward to the next step without purification. The purity of the title compound was estimated to be >85% based on GC Method C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,5-Diaminobenzenesulfonamide (Example 17c, 11.16 g, 59.61 mmol) was dissolved in acetonitrile (300 mL) and pyridine (7.07 g, 89.41 mmol) was added. Methanesulfonyl chloride (7.17 g, 62.59 mmol) was added dropwise over a period of 10 min and the reaction mixture was stirred for 16 h at 25° C. after which time a precipitate had formed. Most of the acetonitrile was removed in vacuo and water (200 mL) was added to afford a clear solution. The product slowly started to precipitate and the mixture was placed in an ice bath for 3 h. The precipitate was collected by vacuum filtration and dried under high vacuum to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (also made in Examples 3d and 3d′) (11.1 g, 41.84 mmol, 70.2% yield) as a brown solid. 1H NMR (400 MHz, CD3OD) δ: 2.89 (3H, s), 6.82 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.58 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C7H11N3O4S2 265.02, found 266.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]C(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][Br:35]
Reactant: COc1cccc2c1CCCC2CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc2c1CCCC2CCBr
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethanol (0.20 g) and triphenylphosphine (0.42 g) in dichloromethane (10 ml) was added tetrabromomethane (0.90 g) at 5° C. The solution was stirred at 5° C. for 1.5 hours and evaporated in vacuo. To the residue, ethyl acetate was added and the insoluble material was filtered off. The ethyl acetate solution was evaporated in vacuo. The residue was chromatographed (n-hexane) over silica gel to afford 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl bromide (0.18 g) as a colorless oil.
Reaction SMILES: N1C=CN=C1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.[CH2:17]([O:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=O)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:36][C@@H:37]([CH2:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:38]([C:40]1[O:41][CH:42]=[CH:43][CH:44]=1)[OH:39]>ClCCl.O1CCCC1.CN(C)C=O>[CH2:17]([O:24][C:25]([NH:27][C@H:28]([C:33]([NH:36][C@@H:37]([CH2:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:38]([C:40]1[O:41][CH:42]=[CH:43][CH:44]=1)[OH:39])=[O:35])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)c1ccco1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1ccco1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of 1.4 g of imidazole in 18 ml of dichloromethane is added 0.90 ml of phenyl dichlorophosphate in 6 ml of dichloromethane. The mixture is stirred for 20 minutes, cooled to 0° C. and a solution of 0.60 g of imidazole, 2.4 ml of N,N-dimethylformamide and 1.6 g of Nα -[(benzyloxy)carbonyl]-L-leucine in 6 ml of tetrahydrofuran added. The mixture is stirred at 0°C. for 40 minutes and then 1.30 g of (S)-2-amino-3-cyclohexyl-(R)-1-(2-furanyl)propan-1-ol added. The mixture is stirred at 0° C. to 25° C. (ice bath allowed to melt) overnight and the solvent removed. The residue is dissolved in 20 ml of ethyl acetate and washed with water, 2N citric acid, sodium bicarbonate solution and dried (MgSO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with several volumes of ethyl acetate. The filtrate is concentrated under vacuum to give 2.3 g of N-[N-(benzyloxy)carbonyl-L-leucyl]-(S)-2-amino-3-cyclohexyl-(R)-1-(2-furanyl)propan-1-ol as an oil. The preceding compound (1.85 g) and 1.0 g of ammonium formate in 24 ml of methanol under nitrogen is warmed on a steam bath and then the solution is chilled to 0° C. To the mixture (without stirring) is added (by pipette) 0.96 g of 10% palladium on carbon suspended in 5 ml of ethanol. The mixture is stirred at 0° C. for one hour, diatomaceous earth added and the mixture filtered. The filter pad is washed with methanol and the filtrate evaporated to dryness. The residue is partitioned between ammonium hydroxide and dichloromethane. The organic layer is separated, dried (MgSO4) and the solvent removed to give 1.24 g of a gum. Crystallization from 5 ml of diisopropyl ether gives 0.74 g of N-(L-leucyl)-(S)-2-amino-3-cyclohexyl-(R)-1-(2-furanyl)propan-1-ol as colorless crystals, mp 83°-84° C. [α]D26 -17°±1 (c, 1.031, CH3OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:24]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: CCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.70 g (3.39 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.59 g (3.69 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under an inert atmosphere. To the thickened reaction mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-hexanimidamide (compound of Example 38; 0.9 g, 6.9 mmol) diluted with 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mass was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After the completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:15][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH3:15])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(Cl)cc2)s1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 2-(4-Chloro-phenyl)-thiazole-5-carbaldehyde (4.95 g, 22.14 mmol) in THF (65 ml) at 0° C. under an atmosphere of nitrogen was added methyl magnesium chloride (3M in THF; 8.11 ml, 24.35 mmol) dropwise over a period of 5 minutes. The reaction was then allowed to warm to room temperature and stirred for a further 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 ml) and stirred for 5 minutes, before the methanol is removed under reduced pressure. The resulting heterogeneous mixture was then extracted with ethyl acetate (2×100 ml), the combined organics dried over magnesium sulphate and the solvent removed under reduced pressure to give 1-[2-(4-Chloro-phenyl)-thiazol-5-yl]-ethanol (4.71 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:26]3)[CH:9]=2)[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CN2CCOCC2)C1

Procedure:
A solution of 50 mg (0.09 mmol) of trans-toluene-4-sulfonic acid 3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester in 1 ml of morpholine (Fluka, Buchs, Switzerland) is stirred at RT for 72 h. The solvent is evaporated to dryness and the residue is purified by flash-chromatography (ethylacetate:methanol:NH4OHaqu.=95:5:1) to provide trans-5-(3-benzyloxy-phenyl)-7-(3-morpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=9.29 min (Grad 1); ES-MS: m/eo=470.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[NH:13][N:12]=[C:11]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:3])=[O:2].Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[N:13]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:12]=[C:11]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:3])=[O:2]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)C1=NNC(C)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Product: CCOC(=O)C1=NN(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]

Procedure:
This compound is prepared using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-nitrophenyl)-6-methyl-3,5-pyridazine dicarboxylate and N-(2-chloroethyl)morpholine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][N:31]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:36][C:33]4[CH:34]=[N:35][N:31]([CH3:30])[CH:32]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1cc(C=O)cn1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (388 mg) and 1-methylpyrazole-4-carboxyaldehyde (540 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (519 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:3) to give methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (321 mg) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:18][Li].O>O1CCCC1>[CH3:18][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:6]=1
Reactant: [Li]C
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
The title compound of Step A (9.0 g, 38 mmol) was dissolved in 50 mL of tetrahydrofuran and treated with methyl lithium (1.4 M in ether, 34 mL, 47 mmol) at a temperature of −70° C. The reaction mixture exothermed to −35° C. The mixture was stirred at −30° C. for 1.5 h and then treated with 1 mL of water and dichlorodicyanoquinone (9.44 g, 42 mmol). The mixture was stirred at 25° C. for 30 minutes and then partitioned twice between 100 mL of water and 100 mL of dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The residue after evaporation was subjected to silica gel chromatography using hexanes/ethyl acetate (95:5) as eluent to give 9.02 g of the title compound of Step B as a white solid melting at 128-131° C. 1H NMR (CDCl3): δ2.31 (s, 3H), 2.56 (s, 3H), 7.71 (d, 2H), 8.49 (d, 2H), 8.53 (s, 1H).
Reaction SMILES: C(Cl)Cl.C(OC(=O)/C=C/[C@H:10]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[N:11]1[C:24](=[O:28])[CH2:25][CH:26]=[CH2:27])C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(N(CC)CC)C>[F:21][C:19]1[CH:20]=[C:15]([C@H:12]2[N:11]3[C@@H:10]([CH:27]=[CH:26][CH2:25][C:24]3=[O:28])[CH2:14][CH2:13]2)[CH:16]=[C:17]([F:23])[C:18]=1[F:22]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OCC)CC[C@H]1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC=C[C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A methylene chloride solution (60 mL) of (E)-3-[(2R,5S)-1-(3-butenoyl)-5-(3,4,5-trifluorophenyl)pyrrolidin-2-yl]acrylic acid ethyl ester (1.33 g) and Grubbs catalyst second generation (153 mg) was heated under reflux for 2 hr. The reaction solution was allowed to cool to room temperature, and then triethylamine (0.5 mL) was added thereto. The resulting mixture was stirred for 1 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1 to 0:1) to give 680 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:19]Br)=[O:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:19][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH:8]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (501 mg) and 2-bromo-4-methylacetophenone (638 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one and three quarter hours, then cooled and the solid filtered off. The filtrate was evaporated, the residue was diluted with water (100 ml) and the product was extracted with ethyl acetate (3×50 ml). This was combined with the solid and crystallised from acetone: yield 306 mg, m.p. 214°-217° dec: λmaxEtOH 253 nm (ε 19760), 332 nm (ε 2620), λinf 232 nm (ε 11040).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[O:2]1.[BrH:12]>O>[Br:12][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([OH:2])=[O:11]
Reactant: O=C1Cc2ccccc2CO1
Reactant: Br
Solvent: O
Product: O=C(O)Cc1ccccc1CBr
Reaction time: 0.17 h

Procedure:
3-Isochromanone (30 g), Mann, F. G. and Stewart, F. H., Journal of the Chemical Society 2819 (1954) is added with swirling to 150 ml of hydrobromic acid (48%) at 80° C. The resulting mixture is then heated on a steam bath with occasional swirling for 10 min and thereafter poured into a mixture of crushed ice and water (750 g). The resulting mixture is then extracted with ethyl acetate and the ethyl acetate extracts washed with a mixture of water and brine (1:1) and dried over magnesium sulfate. Concentration under reduced pressure yields a residue of crude o-(bromomethyl)phenylacetic acid. (Crystallization of the crude product from methylene chloride yields a product with melting point 130°-131° C. and a C:H ration of 46.90:4.09). The crude o-(bromomethyl)phenylacetic acid, 400 ml of benzene and 38 g of triphenylphospine is stirred at 80° C. for 5 hr and cooled and filtered to yield 57 g of title product, melting point 248°-249° C. The C:H:Br:P ratio is 66.22:4.94:16.16:6.49.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+]([O-])=O)=[CH:10][CH:11]=2)[NH:6][C:5](=[O:16])[C:4]1=[O:17])[CH3:2].C[N:19](C)C=O>[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]2[C:7]([NH:6][C:5](=[O:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:8][CH:9]=1
Reactant: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)C=O
Agent: [Pd]
Product: CCn1c(=O)c(=O)[nH]c2ccc(N)cc21
Yield: 81 %

Procedure:
8.3 g (35 mmol) of 1-ethyl-6-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of dimethylformamide and, after addition of 2 g of palladium/carbon (10%), were hydrogenated. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 5.9 g (81%) of the product.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[Cl:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: Clc1ccc2c(c1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(Cl)cc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 63 mg (0.37 mmol) 6-chloro-2,3-dihydro-1H-indole, 0.15 mL (0.87 mmol) DIPEA and 130.00 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and suction filtered. The precipitate was dried under HV.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)=O.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:38]([CH3:40])[CH3:37])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 60 °C

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (20 mg, 0.04 mmol) in THF and AcOH (4.8 mg, 0.08 mmol) was added acetone (2.0 mL, 0.2 mmol) and sodium triacetoxy borohydride (85.0 mg, 0.4 mmol). The mixture was heated at 60° C. for one hour. Saturated sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over sodium sulfate. Then the mixture was, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-isopropylpiperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=495)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:25]=4[CH:24]=3)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O.CCOC(C)=O>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:25]=4[CH:24]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(N2CCNCC2)nc1)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.16 mmol) in 15 mL of dichloromethane and 5 mL of TFA was stirred at room temperature for 2 hr. The reaction mixture was taken up in 100 mL of EtOAc and washed with 100 mL of 1N NaOH, brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was triturated with diethyl ether and hexanes (1:1 ratio), followed by filtration, to afford the product 4-chloro-benzo[b]thiophene-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide, (50 mg, 85% yield) as an off white solid. LCMS for C18H17ClN4OS calcd. (m/e) 372, observed 373 (M+H).