Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][NH:26]C(=O)OCC5C=CC=CC=5)[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCCNC(=O)OCc4ccccc4)C3)cc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCCN)C3)cc12

Procedure:
To a solution of Example 127 (100 mg, 0.194 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 20% palladium hydroxide on carbon (wet, 20 mg, 0.015 mmol). The mixture was heated under 50 psi hydrogen at 45° C. for 3 hours and cooled. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by reverse phase HPLC, and was eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 383.23 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.74 (m, 3H) 1.82-1.93 (m, 1H) 1.95-2.07 (m, 2H) 2.18 (d, 1H) 2.81-2.97 (m, 4H) 3.14-3.23 (m, 2H) 3.48 (t, 2H) 3.74 (s, 3H) 6.10 (s, 1H) 7.08 (d, 1H) 7.17-7.23 (m, 2H) 7.25-7.34 (m, 1H) 8.22 (d, 1H) 10.17 (s, 1H) 11.88 (s, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[CH:28]=[CH2:29])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(Cl)Cl.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[C@@H:28]1[O:6][CH2:29]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]([C@H]1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
1.360 g (6.19 mmole) of 3-chloroperoxybenzoic acid of 80% purity) were added at 0° C. to a solution of 960 mg (3.44 mmole) of (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-penten-2-ol (which was synthesized following the procedure disclosed in Japanese Patent Provisional Publication No. Sho 60-36468) in 30 ml of methylene chloride. Five minutes after the addition, the reaction mixture was stirred, and this stirring was continued overnight at room temperature. The reaction mixture was then diluted with ethyl acetate, after which it was washed, in turn, with an aqueous solution of sodium sulfite, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride. After it had been dried, the mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:2 by volume mixture of ethyl actate and hexane as the eluent, to afford 320 mg of stereoisomer A of the title compound (having the lower polarity), melting at 160°-180° C. and 206 mg of the desired stereoisomer B of the title compound (having the higher polarity) as an oil.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:14])[CH2:12][CH3:13]>CO>[Br:1][CH:12]([CH3:13])[C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])=[O:14]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)cc1Cl
Solvent: CO
Product: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Yield: 97.1 %

Procedure:
51.4 g (0.322 mol) of bromine was added dropwise to a solution of 63.2 g (0.311 mol) of 2′,4′-dichloropropiophenone in 140 g of methanol at a reaction temperature of 50 to 55° C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (150 ml×3 times). Thereafter, the toluene was distilled off under reduced pressure, giving 85.2 g (0.302 mol) of crude brown oily 2-bromo-2′,4′-dichloropropiophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(c1ccc(C#N)cc1)[Si](C)(C)C
Yield: 95.2 %

Procedure:
About 5.09 g of 4-aminobenzonitrile, 10.03 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 22.02 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 40 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 4-[bis(trimethylsilyl)amino]benzonitrile (4-BTMSABZN) as a brown oil (10.77 g, 95% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 6.93 (doublet, 2H, aromatic protons), 6.43 (doublet, 2H, aromatic protons), −0.07 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=O)([O-:19])=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C.O>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][CH:24]2[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:9])[C:2]1=[O:1])([O-:19])=[O:18]
Reactant: O=C(Nc1ccncc1)c1ccc[nH]c1=O
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c2cccc3[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (8.0 g, 1.0 eq) in dry DMF (30 mL) was added 4-nitro-2,3-dihydro-1H-inden-1-one (1.2 eq) and PPh3 (3.0 eq), then added DIAD (3.0 eq) under N2 atmosphere. Then the mixture was stirred at room temperature overnight. At the end of reaction, water was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, filtrated and evaporated to give the crude product, which was purified by Flash Column (PE:EtOAc=1:2), concentrated the crude product, and recrystallized by EtOAc to give 1-(4-nitro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (3.5 g, 21%). MS (ESI) 377.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.22 (s, 1H), 8.62 (m, 1H), 8.53 (m, 2H), 8.24 (m, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 6.75 (m, 1H), 6.50 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 2.97 (m, 1H), 2.21 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 57 %

Procedure:
A stirred solution of 1-benzylpiperazine (8.81 g, 50.0 mmol), 4-fluoronitrobenzene (5.31 mL, 50.0 mmol), and K2CO3 (6.90 g, 50.0 mmol) in ethanol is heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water, and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo to give a solid residue. The solid is triturated with 20:80 ethyl acetate:hexanes and filtered. The filtercake is air-dried to afford the title compound as orange crystals, 8.45 g (57% yield), mp 218-219° C., characterized by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]#[CH:23])=[N:11][CH:10]=1.[N+:35]([CH2:38][CH3:39])([O-])=[O:36].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(#N)C.C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]2[O:36][N:35]=[C:38]([CH3:39])[CH:23]=2)=[N:11][CH:10]=1
Reactant: CC[N+](=O)[O-]
Reactant: C#Cc1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.8 %

Procedure:
To a solution of 55 mg (0.12 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-ethynyl-N-methyl-4-o-tolyl-nicotinamide (Example 63), 0.026 ml (0.35 mmol) nitroethane and 1 mg (0.01 mmol) 4-N,N-dimethylaminopyridine in 0.5 ml acetonitrile a solution of 77 mg (0.35 mmol) di-tert-butyl dicarbonate in 0.1 ml toluene was added, and the mixture was stirred at room temperature over night. Another portion of 0.026 ml (0.35 mmol) nitroethane and 77 mg (0.35 mmol) di-tert-butyl dicarbonate were added, and stirring was continued for 24 h. Quenching with water was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 21 mg (34%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:21]2=[N:22][N:23]([CH3:25])[N:24]=[C:20]2[CH:19]=1>>[CH3:25][N:23]1[N:22]=[C:21]2[CH:26]=[CH:27][C:18]([CH2:17][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)=[CH:19][C:20]2=[N:24]1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: Cn1nc2ccc(CCl)cc2n1
Product: Cn1nc2ccc(CN(c3ccc([N+](=O)[O-])cc3)n3cnnc3)cc2n1

Procedure:
Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 5-chloromethyl-2-methyl-2H-benzotriazole
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>O1CCCC1.O>[C:21]([O:20][C:18]([NH:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)CC(C)(N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred solution of 2-amino-2,4-dimethylpentanoic acid (1 g, 6.89 mmol) in tetrahydrofuran (15 mL) and water (15 mL) was added K2CO3 (3.81 g, 27.5 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the resultant mixture (BOC)2O (3.20 mL, 13.77 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate (3×15 mL) and acidified with a saturated aqueous solution of citric acid (25 mL) then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentanoic acid (1.6 g, 6.89 mmol, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.36 (bs, 1H), 2.10 (m, 1H), 1.77 (m, 2H), 1.74-1.65 (m, 3H), 1.59 (s, 9H), 0.89 (m, 3H), 0.94 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCC(CCCCN)CCCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C

Procedure:
To a solution of 2200 g or crude ethyl 8-amino-4-[3-(3-pyridyl)propyl]-octanoate in 28.8 l of dichloromethane is added 1377 g of triethylamine. The solution is cooled to 0° and a solution of 1435 g of p-chlorophenylsulfonyl chloride in 14.3 l of dichloromethane is added over a period of 45 min maintaining the temperature below 5°. The reaction mixture is allowed to slowly warm up to room temperature overnight. The reaction mixture is washed 3 times with 15 l of aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated to dryness to yield ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate (compound of example 4b) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.[OH-].[K+].O>CS(C)=O>[Cl:17][C:16]1[C:11]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: COc1ccc(O)cn1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2ncc(Cl)cc2Cl)cn1
Yield: 88.2 %

Procedure:
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2,3,5-trichloropyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 1.5 hours. The solution was poured slowly into water (200 mL). The precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.39 g, 88% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>C(#N)C>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([NH2:21])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: C[C@@H](N)c1ccccn1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 400 mg,) and (R)-1-(pyridin-2-yl)ethanamine (293 mg) in acetonitrile (30 ml) was heated at 60° C. for 2 h. The reaction mixture was extracted with DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2SO4, filtered and concentrated to dryness. The resulting compound was taken-up in ether, filtered and dried in vacuo. The residue was dissolved in ethanol (20 ml) and HCl (3.8 ml). Tin (II) chloride dihydrate (0.89 g) was then added in four portions and the reaction mixture was stirred for 1 h at 40° C. The reaction mixture was hydrolysed using a solution of sodium hydroxide (1N). The mixture was extracted with DCM, the organic dried over Na2SO4, filtered over Celite and concentrated to dryness. The crude product was purified via flash column chromatography on silica gel eluting with DCM/MeOH (95/5) and the obtained product was taken-up in diisopropylether to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-[(1R)-1-(2-pyridinyl)ethyl]-3,4-quinolinediamine (250 mg) as a brown powder. LC/MS: Rt 2.62 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[N:16]=[CH:17][O:18][C:19]=2[C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[O:14])[CH:9]=[N:8]1.Cl[C:28]1[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:37][O:36][C:30]1[CH:31]=[C:32]([O:34][CH3:35])[N:33]=[C:28]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][O:18][C:19]=3[C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:14])[CH:9]=[N:8]2)[N:29]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(OC)nc(N2CCCC2Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)n1
Yield: 55.2 %

Procedure:
To a microwave tube was added rac-N-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (40 mg, 0.11 mmol), 2-chloro-4,6-dimethoxypyrimidine (18 mg, 0.10 mmol) and Cs2CO3 (175 mg, 0.228 mmol) in MeCN (0.8 mL). The reaction mixture was irradiated at 180° C. for 30 min in the microwave, then the reaction mixture was diluted with DCM (30 mL). The organic layer was separated and washed with H2O (5 mL) and brine (5 mL). The combined organic layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (hex/EtOAc 3:7) Rf=0.4) yielded the title compound (27 mg) as a yellowish solid. LC-MS conditions D: tR=1.16 min, [M+H]+=490.3.
Reaction SMILES: C(OC([N:8]([CH:27]1[CH2:29][CH2:28]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:26])[O:24][CH3:25])[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:27]1([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:26])[O:24][CH3:25])[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=2)[CH3:10])[CH2:29][CH2:28]1
Reactant: CCc1ncc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc1CCCNC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ncc(C(C)NC2CC2)cc1CCCNC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-ethylpyridin-3-yl)propyl]carbamate (204 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice-cooled aqueous saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: chloroform→chloroform/methanol=21/1) to give methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-ethylpyridin-3-yl}propyl)carbamate [REx(113-8)] (142 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[C:9]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)#[N:10]>C(OC(=O)C)(=O)C>[CH3:8][C:4]1[N:3]=[C:2]([CH:1]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(C)n1
Reactant: N#Cc1ccccc1C=O
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2ccccc2C#N)n1

Procedure:
A solution of 2,6-dimethyl pyridine (5.8 ml, and 50 mMol), and 2-cyanobenzaldehyde (6.81 g, and 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 400 g). The column is first eluted with toluene (400 ml) and then with toluene/ethyl acetate 95:5. The fractions containing the desired compound are combined, evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and white crystals are isolated. (melting point: 113-114°).
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([O:9][C:10](=O)[C:11]=1[Cl:12])=[O:8].Cl.[CH3:15][NH2:16].O>C(O)(=O)C>[Cl:5][C:6]1[C:7]([N:16]([CH3:15])[C:10](=[O:9])[C:11]=1[Cl:12])=[O:8]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (3.56 g, 50 mmol) was added to a solution containing 2,3-dichloromaleic anhydride (5.56 g, 33.3 mmol) and methylamine hydrochloride (3.50 g, 55.0 mmol) in 40 mL of acetic acid. The mixture was stirred under a CaCl2 drying tube at 25° C. for 16 hours and then refluxed for 4 hours. The cooled mixture was poured into water (350 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 100 mL portions of saturated aqueous NaHCO3, water and brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 3.82 g (64%) of 2,3-dichloro N-methylmaleimide as white crystals. Concentration of the mother liquor and chromatography of the residue by radial preparative layer chromatography (Chromatotron, Harrison Research), gave an additional 0.81 g of 2,3-dichloro N-methylmaleimide, raising the yield to 77%.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9]C)=O)[CH2:2][CH3:3].C(O)C.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:14]1([NH:17][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:16][CH2:15]1
Reactant: CCC[C@H]1O[C@@H]1C(=O)OC
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.8 %

Procedure:
Methyl (2S,3R)-3-propyl-2-oxiranecarboxylate (0.26 g, 1.8 mmol), ethanol (1 ml) and cyclopropylamine (1.03 g, 18 mmol) were mixed, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with 1 N HCl (5 ml) and water (5 ml). The solvent was evaporated away under reduced pressure to obtain the title compound as a pale yellow solid (0.17 g, yield: 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: ClCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccnc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (48 mg, 0.101 mmol), 3-(chloromethyl)pyridine (18.3 mg, 0.11 mmol, 1.05 equiv), and cesium carbonate (99.0 mg, 0.303 mmol) were combined in dimethylformamide (1.5 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 51.0 mg (92%). Mass spec.: 563.3 (MH)+.