Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][C:18]=1[F:19].C(N(CC)CC)C>C(OC)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:12][C:13]1[CH:14]=[C:15]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Fc1ccc(I)cc1F
Reactant: C#Cc1ccc(OCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCOc1ccc(C#Cc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-ethoxyphenylacetylene, 0.02 m of 3,4-difluoroiodobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with 100 ml of methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4-difluoro-4'-ethoxytolan, K 67 I, Δε=11.18.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20]Cl.F[B-](F)(F)F.C[O+](C)C>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:20])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(=O)[nH]ccc2n1Cc1ccccc1
Reactant: ClCCl
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COc1nccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
To a mixture of 1-benzyl-2-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (1) (3.48 g, 16.62 mmole) in dichloromethane (160 mL) trimethyloxonium tetrafluoroborate (4.52 g, 29.24 mmole) was added. The mixture was stirred at room temperature for 18 h. Additional trimethyloxonium tetrafluoroborate (2.25 g, 14.55 mmole) was added and stirred for 18 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (20:1 CH2Cl2:MeOH) to afford intermediate (2) Yield: 1.31 g, 35%.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])/[C:6](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7]/[C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[NH2:40][CH2:41][C:42]1[CH:53]=[CH:52][C:45]([CH:46]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>O>[CH:1]1([NH:4][C:5](=[O:24])/[C:6](/[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:7]/[C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([CH:46]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)/C(=C/c1ccc(C(=O)O)cc1)c1ccc(F)cc1
Reactant: COC(=O)C=Cc1ccc(CN)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(CNC(=O)c2ccc(/C=C(/C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
To a suspension of 4-((1E)-3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)benzoic acid (0.3 g, 0.9 mmol, prepared according to the procedure described in Example 99, step-III) in DMF (5 mL) EDCl (0.35 g, 1.8 mmol), HOBt (0.12 g, 0.9 mmol), methyl 4-aminomethylcinnamate (0.237 g, 1.1 mmol), were added followed by triethylamine (0.4 mL, 3 mmol). The reaction mixture was stirred for 8 hours after which the mixture was poured to cold water (100 mL), the white precipitate formed was filtered, washed with water (1×150 mL), dried under vacuum to afford the title compound as a yellow solid (0.4 g, 87% yield).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:8][C:7]1[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2nccnc2Cl)cn1
Temperature: 90 °C
Yield: 53.3 %

Procedure:
To 2,3-dichloropyrazine (1.12 g, 7.52 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.56 g, 7.52 mmol), bis(triphenylphosphine)palladium(II) dichloride (270 mg, 0.38 mmol), and Na2CO3 (2.4 g, 22.56 mmol) in a pressure tube were added 1,2-dimethoxyethane (15 mL) and water (2 mL). The flask was evacuated and flushed with argon (3×) and then sealed and heated at 90° C. overnight. The mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (780 mg, 53%). LCMS (ESI) m/z 195 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[F:27][C:28]([F:38])([F:39])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:32][CH:31]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccc(OC(F)(F)F)cc2)CO3)N1
Temperature: 90 °C
Yield: 46 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.7 mmole) and 4-trifluoromethoxybenzylamine (2.0 g, 11 mmole) were combined in 30 ml of dry DMSO and heated to 90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with 400 ml of 1:1 ethyl acetate/hexane and washed with 400 ml of saturated sodium bicarbonate solution, with two 250 ml portions of water and with saturated brine. The mixture was dried over sodium sulfate, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 1% methanol/CHCl3 as eluant. The free base of the title compound (0.49 g) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.29 g of the (S) enantiomer of the title compound as a white solid fumarate, m.p. 201°-202° C.
Reaction SMILES: Cl.C([NH:4][C@H:5]([C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:6][C:7](=[O:9])[OH:8])=O.[CH2:24](N(CC)CC)C>CO>[CH3:24][O:8][C:7](=[O:9])[CH2:6][CH:5]1[C:10](=[O:11])[NH:12][CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21](=[O:23])[NH:4]1
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution having 9.6 g of hydrogen chloride dissolved in 400 ml of methanol was fed 61.6 g of N-formyl-α-L-aspartyl-L-phenylalanine and the resulting mixture was reacted at 50°-60° C. for 6 hours. The resulting reaction solution was cooled to room temperature, added dropwise with 30.4 g of triethylamine, and then subjected to further reaction under reflux for 8 hours. The reaction mixture was cooled to room temperature and the crystal thereby deposited was filtered and washed with methanol to obtain 40.2 g of 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester having a melting point of 216°-218° C.
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[C:16]1(=[O:26])[N:20]([CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:6])[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12
Reactant: COc1ccc(C(=O)CCC(C)Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCC(C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Yield: 80.9 %

Procedure:
To a solution of 4-chloro-4′-methoxyvalerophenone (Rieke Metals) (2.26 g, 10.0 mmol) in DMF (10 mL) was added potassium phthalimide (1.85 g, 10 mmol mmol). The solution was heated under N2 (g) at 70° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (70 mL) and water (50 mL). The organic layer was washed with another portion of water (50 mL), followed by saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to give a tan solid (2.73 g, 81% yield). MS m/e 220; HPLC retention time 3.52 min (Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:12]([CH2:14][O:15][S:32]([CH3:31])(=[O:34])=[O:33])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CO)c(COC3CCCCO3)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc(COS(C)(=O)=O)c(COC3CCCCO3)o2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.44 g [2-(4-Methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazol-4-yl]-methanol were dissolved in 30 ml dichloromethane and cooled in an ice bath. 0.29 ml triethylamine were added, followed by the addition of 0.13 ml methanesulfonylchloride. The reaction mixture was stirred at 0° C. for one hour then the ice bath was removed and the resulting mixture stirred at room temperature for an additional hour. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 0.55 mg of methanesulfonic acid 2-(4-methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazol-4-ylmethyl ester as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Br:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[N:10][CH:11]=1.C(N(CC)CC)C>C(O)C>[Br:5][C:6]1[CH:7]=[N:8][C:9]([NH:3][CH2:2][CH2:1][NH2:4])=[N:10][CH:11]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCCNc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethane-1,2-diamine (200 mg) was added to a solution of 5-bromo-2-chloro-pyrimidine (500 mg) and triethylamine (1 mL) in ethanol (10 mL) at 0° C. The reaction mixture was stirred under nitrogen at room temperature overnight. The formed mixture was concentrated to give crude N1-(5-bromopyrimidin-2-yl)ethane-1,2-diamine. Yield: 687 mg (100% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:9]=CC(C=O)=[CH:4][CH:3]=1.C[Mg][Br:12].[NH4+].[Cl-].[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[Br:12][C:15]1[CH:19]=[CH:4][C:3]([CH:2]([Br:1])[CH3:9])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(Br)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a 50 mL round-bottomed flask containing polystyrene resin (5 Scheme 18, 200 mg, 0.30 mequiv/g) in dry THF (15 mL) at −78° C. was added methylmagnesium bromide (10 equiv). The reaction slurry was stirred for 1 h at −78° C., then warmed slowly to room temperature and further stirred for 2 h. After cooling the flask to −20° C., saturated NH4Cl (0.5 mL) was added, and the mixture was stirred for 20 min at room temperature. The resin was filtered and washed with 1:1 THF/water (twice), water (twice), methanol (twice), CH2Cl2 (twice), then dried under reduced pressure. To a slurry of resin in CH2Cl2 (8 mL) was added Br2 (100 μL). After agitation for 20 min, the cleavage solution was removed, and the resin was rinsed with CH2Cl2 (5 mL). Concentration of the combined filtrates gave 4-bromo-α-methyl benzyl bromide (7 Scheme 18) as a colorless oil (12 mg, 75%); 1H NMR (300 MHz, CDCl3) δ 2.03 (d, J=6.97 Hz, 3 H), 5.17 (q, J=6.97 Hz, 1 H), 7.32 (d, J=8.49, 2 H), 7.49 (d, J=8.49, 2 H); 13C NMR (75 MHz, CDCl3) 27.0, 48.5, 122.4, 128.8 (2C), 132.1 (2C), 142.5.
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:24])[N:15]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:25]>CO>[C:18]1([C@H:16]([N:15]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]([NH2:25])[C:12]=3[N:13]=[C:14]2[NH2:24])[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N
Reactant: C[C@H](c1ccccc1)n1c(N)nc2c(Cl)nc3ccccc3c21
Agent: Br
Solvent: CO
Product: C[C@H](c1ccccc1)n1c(N)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide (4.2 g, 13 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.4:7.6:92). The chromatographed product was washed with diethyl ether to provide 362 mg of 1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline-2,4-diamine as brown needles, mp 156-160° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](Cl)=[O:21])=[CH:15][N:14]=1>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](=[O:21])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:15][N:14]=1
Reactant: CC(C)N
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of isopropylamine (1.28 ml, 15.0 mmol) and triethylamine (2.10 ml, 15.1 mmol) in dry THF (5 ml) was added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (obtained as described in J. Med. Chem., 1972, 15, 200; 3.18 g, 15.0 mmol) in dry THF (8 ml) at −10° C. The solution was stirred 0° C. for 2 hours, filtered and evaporated to dryness to yield the product (0.93 g), which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][NH:39][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)[CH:42]=1
Reactant: NCc1cccnc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cncc(CNCCCOc2cccc(-c3noc4ccsc34)c2)c1
Yield: 77 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-(aminomethyl)pyridine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.28 g, 77% Yield) as and oil. Purity by LC/MS (APCI)=98% area, [M+H]+=366 m/e.
Reaction SMILES: CO.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:4][CH2:5][CH3:6].Cl[C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C[O-].[Na+]>O>[Cl:14][C:12]1[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:13]=1[S:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCOc1cc([N+](=O)[O-])c(OCCCC)c(Sc2ccccc2)c1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 110 parts of methanol was added 51 parts of 2,5-dibutoxy-4-chloronitrobenzene. The mixture was heated to 50° C. A methanol (50 parts) solution of 25 parts of p-chlorobenzenethiol and 9.8 parts of sodium methylate was added dropwise thereto over a period of about one hour to carry out a reaction. After completion of the dropwise addition, the reaction was further continued under reflux for 5 hours. After completion of the reaction, 85 parts of water were added to the reaction mixture to precipitate a crystal. The resulting crystal was recovered by filtration and recrystallized from methanol to obtain 59 parts of 4-chlorophenylthio-2,5-dibutoxynitrobenzene having a m.p. of 74° to 75° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:4]2([CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5]2)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:25]=[C:26]([C:28]1[CH:29]=[CH:30][C:31]([CH3:46])=[C:32]([NH:34][C:35]([C:37]2[N:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][CH:38]=2)=[O:36])[CH:33]=1)[NH2:27]>CN1C(=O)CCC1>[CH3:46][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[N:25]=[C:8]([CH:6]3[CH2:5][C:4]4([CH2:3][C:2](=[O:1])[CH2:11]4)[CH2:7]3)[O:10][N:27]=2)=[CH:33][C:32]=1[NH:34][C:35]([C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][CH:38]=1)=[O:36]
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C1CC2(C1)CC(C(=O)O)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC4(CC(=O)C4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of 6-oxospiro[3.3]heptane-2-carboxylic acid (50 mg, 0.32 mmol) in anhydrous NMP (1 mL) was added 1,1′-carbonyldiimidazole (CDI) (52.3 mg, 0.32 mmol). The reaction was stirred for 3 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (100 mg, 0.32 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120° C. for 15 minutes. The crude reaction was purified by reverse phase preparative HPLC to give N-(2-methyl-5-(5-(6-oxospiro[3.3]heptan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F75). MS m/z 428.2 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[O:50]1[CH2:54][CH2:53]OC1=O.O>CN(C=O)C>[OH:50][CH2:54][CH2:53][O:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.416 g, 0.686 mmol) obtained in Step 2 in DMF (6 mL) was added with potassium carbonate (1.42 g, 10.3 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with 1,3-dioxolan-2-one (0.725 g, 8.23 mmol), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and then added with water (60 mL), and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-{[6-(2-hydroxyethoxy)-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.331 g, 74%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:27]1(/[CH:26]=[CH:25]/[CH2:24][C@H:15]([C@H:14]([OH:13])[CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC[C@@H](O)CC(=O)OCC
Reactant: BrCC=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](O)[C@@H](C/C=C/c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of diisopropylamine (2.28 g, 20.63 mmol) in THF (20 mL) cooled to 0° C. is added n-butyllithium (20.63 mmol, 2.5 M in hexanes) and the resulting solution is stirred at 0° C. or 0.5 h. The reaction mixture is cooled to −50° C. followed by slow addition of ethyl (3R)-3-hydroxyhexanoate (1.5 g, 9.38 mmol). After 0.5 h a solution of cinnamyl bromide (2.67 g, 14.06 mmol) in HMPA (2 mL) is added and the reaction mixture is allowed to warm to −20° C. and stirred for 16 h. The reaction mixture is quenched by addition 3 mL of saturated aqueous ammonium chloride solution, is poured into 20 mL of 1 N hydrochloric acid, and is extracted with two 50-mL portions of EtOAc. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% EtOAc-hexanes) to afford ethyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxyhexanoate as a yellow oil (1.82 g, 70% yield).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH:2]=[CH2:3].[Br:8][CH2:9]/[CH:10]=[C:11](\[CH3:15])/[C:12]([OH:14])=[O:13]>>[Br-:8].[CH2:1]([NH+:4]=[C:5]([NH2:7])[S:6][CH2:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCNC(N)=S
Reactant: C/C(=C\CBr)C(=O)O
Product: C=CC[NH+]=C(N)SCC=C(C)C(=O)O
Product: [Br-]
Yield: 70 %

Procedure:
Example 1 was repeated with N-allylthiourea and 4-bromo-2-methylcrotonic acid, affording the title compound in a yield of 70%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([CH3:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)=[O:33])[CH:7]=3)[C:9](=[O:21])[N:10]2[CH2:19][CH3:20])=[CH:15][N:14]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2C)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.1 %

Procedure:
A solution of Example A6 (0.200 g, 0.603 mmol) and TEA (0.126 mL, 0.904 mmol) in THF (6 mL) was treated with 3-fluorophenyl isocyanate (0.083 ml, 0.723 mmol) and stirred at RT for 4 h. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was treated with DCM and the solid collected via filtration. The filtrate was concentrated to dryness, re-purified via silica gel chromatography (MeOH/DCM) and combined with the isolated solid to afford 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (88 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.77 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.46 (dt, J=12.0, 2.3 Hz, 1H), 7.28 (m, 1H), 7.18 (d, J=12.2 Hz, 1H), 7.05 (ddd, J=8.2, 2.0, 0.9 Hz, 1H), 6.77 (td, J=8.3, 2.5 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 469.1 [M+H]+.