Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[CH:14](=[O:16])[CH3:15]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH:14]([OH:16])[CH3:15])=[N:10][CH:9]=[N:8]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Cn2cncn2)cc1
Reactant: CC=O
Product: Cc1ccc(Cn2ncnc2C(C)O)cc1
Yield: 86 %

Procedure:
1-[1-(4-Methylbenzyl)-1H-1,2,4-triazol-5-yl]ethanol was synthesized in a manner similar to that of the procedure in Example 21B but using 1-(4-methylbenzyl)-1H-1,2,4-triazole and acetaldehyde as the starting materials. The product was isolated as a white solid in 86% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, 3H, J=6.9 Hz), 2.22 (s, 3H), 3.27 (s, 1H), 4.88-4.94 (m, 1H), 5.66 (d, 2H, J=5.91 Hz), 7.09 (s, 4H), 7.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32]>ClCCl>[CH2:34]([O:33][C:31](=[O:32])/[CH:30]=[CH:29]/[C:28]1[CH:36]=[CH:37][CH:38]=[C:26]([NH:25][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=1)[CH3:35]
Reactant: CCOC(=O)/C=C/c1cccc(N)c1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 500 mg (1.85 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 369 mg (1.93 mmol) of ethyl 3-amino-trans-cinnamate to 150° C. for 1.5 h. After cooling, add dichloromethane and purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 20:1). 539.5 mg (73.9% of theory) of the target product are obtained as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Br:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Br)CC1
Reaction time: 14 h
Yield: 36 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) under an atmosphere of nitrogen was added 2-bromoaniline (0.474 g, 0.00276 mole), acetic acid (0.18 g, 0.00301 mole) and sodium triacetoxyborohydride (0.638 g, 0.00301 mole). Stirring was continued at ambient temperature for 14 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.320 g (35%) of desired 4-(2-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.44-7.38 (m, 1H), 7.2-7.12 (m, 1H), 6.84-6.78 (m, 1H), 6.58-6.48 (m, 1H), 4.65 (d, 1H), 3.9 (m, 2H), 3.5 (m, 1H), 3.0-2.8 (m, 2H), 2.0-1.8 (m, 2H), 1.4 (s, 9H). To a cooled solution (0° C.) of 4-(2-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 0.00087 mole) in dioxane (0.5 mL) was added dioxane.HCl (2.5 mL). The mixture was stirred at the same temperature for 10 minutes, then gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure to afford a residue which was washed with dry ether to afford 0.106 g (42%) of 2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride.
Reaction SMILES: [CH:1]1([CH:6]([OH:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:7])[CH3:16]
Reactant: CC(O)C1CCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC(C)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of 1-cyclopentylethan-1-ol (1.14 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.03 mmol). The reaction mixture is stirred at rt for 0.5 h. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue is purified by chromatography on silica gel; elution with EtOAc:heptane (1:9) gives 0.81 g of the product 452. 1H NMR (CDCl3) δ 4.30-4.15 (m, 2 H), 4.09 (d, 2 H), 3.25-3.15 (m, 1 H), 2.00-1.78 (m, 2 H), 1.75-1.35 (m, 6 H), 1.29 (t, 3 H), 1.15 (d, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CN1CCN(c2ccc(Br)cc2C#N)CC1
Temperature: 140 °C
Yield: 92.8 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (0.20 g, 1.0 mmol), 1-methylpiperizine (0.15 g, 1.5 mmol) and triethylamine (0.20 g, 2.0 mmol) in 1-butanol (3.0 mL) was heated at 140° C. for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with water, brine, dried over Na2SO4, filtered and concentrated to provide the desired product (0.26 g, 92%). LCMS calculated for C12H15BrN3(M+H)+: m/z=280.0. Found 280.0.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]1[N:27]([CH2:34][C@:35]2([CH3:38])[CH2:37][O:36]2)[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[N:30]=1>CN(C=O)C>[CH3:37][C@@:35]1([CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]3)=[O:7])=[CH:21][CH:22]=2)[O:36][C:26]2=[N:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][N:27]2[CH2:34]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
Tert-butyl 4-(4-hydroxybenzoyl)piperazine-1-carboxylate (6.6 g, 21.5 mmol) was dissolved in DMF (50 ml). To the solution, sodium hydride (991 mg, 24.8 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (5.16 mg, 23.7 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water, dissolved in methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-diisopropyl ether to afford tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)benzoyl]piperazine-1-carboxylate (7.35 g, yield 70%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:17])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Yield: 28.1 %

Procedure:
A solution of 9.4g (45 mmol) of 3-chloro-2,4,5-trifluorobenzoic acid, oxalyl chloride (7.6 g, 60 mmol), 3 drops of dimethylformamide, and 100 ml of dichloro-methane was stirred at room temperature for three hours. The solvent and excess oxalyl chloride were evaporated on the steam bath, and the residue was distilled at 121°-123° C. at 30 mm Hg to give 2.9 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:29][O:30][CH3:31])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: COCCl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide (12.0 g, 35.0 mmol) and K2CO3 (24.0 g, 170 mmol) in 80 mL anhydrous THF was added chloromethyl methyl ether (4.0 mL, 52.7 mmol). The resultant heterogeneous solution was stirred for 60 minutes at ambient temperature and the solids were subsequently removed via filtration. The filtrate was then removed in vacuo and the residue was dissolved in EtOAc. The organics were washed with saturated Na2CO3, dried over MgSO4, and evaporated in vacuo to generate a brownish oil. The oil was finally triturated with hexanes and the resultant solid filtered to produce the desired product as a light yellowish solid (11.5 g, 86% yield): MS (ES) M+H expected 447.0, found 447.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N[C@H:7]([C:15]([OH:17])=[O:16])CCCNC(=N)N.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)C(C)C.N[C@H](C(O)=O)CS.N[C@H](C(O)=O)CCCCN>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:7][C:15](=[O:16])[OH:17]
Reactant: NCC(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
1.1 (1), Glx:3.2 (3), Ser:0.9 (1), Gly:3.1 (3), Arg:2.2(2), Thr:2.2 (2), Pro:1.1 (1), Tyr:1.3 (2), Val:1.6 (2), Cys:-(2), Lys:5.9 (6)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:16][CH2:17][CH3:18])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:28][CH:29]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1oc(-c2ccccc2Br)nc1C(=O)O
Product: CCCc1oc(-c2ccccc2Br)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25BrN4O3 (m/e) 473, obsd 474 (M+H).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[N:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=O)=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=O)[CH:23]=1.CN(C)CCN>CN(C=O)C>[CH3:25][N:24]([CH3:27])[CH2:23][CH2:22][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(O)c1cccc2nc3ccc4cnccc4c3nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cnccc4c3nc12
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of pyrido[4,3-α]phenazine-11-carboxylic acid (II.3) (0.11 g, 0.38 mmol) and CDI (0.12 g, 0.76 mmol) in DMF (5 mL) was heated and stirred at 50-60° C. for 2 h. N,N-Dimethylethylenediamine (0.5 mL, excess) was then added, and the mixture was stirred at room temperature for 2 h. The DMF was removed under reduced pressure, and the residue was diluted with water. The resulting precipitate was collected and crystallized from CH2Cl2/hexane to give pyrido[4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (0.11 g, 84%): mp 213-215° C.; 1H NMR [CDCl3] δ 2.48 [s, 6 H, N(CH3)2], 2.75 [t, J=5.7 Hz, 2 H, CH2N(CH3)2], 3.89 (q, J=5.5 Hz, 2 H, CH2NH), 8.03-8.14 (m, 3 H, 3xArH), 8.42 (dd, J=8.4, 1.5 Hz, 1 H, ArH), 9.00 (d, J=5.5 Hz, 1 H, H-1 or H-2), 9.07 (dd, J=7.2, 1.5 Hz, 1 H, H-10), 9.34 (s, 1 H, H-4), 9.36 (d, J=5.5 Hz, 1 H, H-1 or H-2), 10.66 (br, 1 H, CONH).
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:5]1[F:7]>CN(C)C(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[F:7][CH:5]1[CH2:6][CH:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1(Cl)CC1F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1CC1F
Yield: 96 %

Procedure:
Sodium borohydride (170 mg, 4.50 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of ethyl 1-chloro-2-fluoro-cyclopropane-1-carboxylate (hereinafter the compound will be referred to as “compound (1b)”) (cis/trans=95/5) (500 mg, 3.00 mmol). Cobalt chloride hexahydrate (3.6 mg, 0.015 mmol) was added to the resultant solution at the same temperature. After completion of addition, the resultant mixture was stirred at 40° C. for one hour. After completion of reaction, the whole reaction mixture was diluted with an HPLC mobile phase to 50 mL, to thereby yield a solution containing 381.3 mg (yield: 96%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][N:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[NH2:2].[ClH:15]>CO.[Pt](=O)=O>[ClH:15].[C:1]([CH:4]1[CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][CH2:13][NH:14]1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccnc(C(N)=O)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1CCNC(C(N)=O)C1
Reaction time: 3 h
Yield: 90 %

Procedure:
Ethyl 2-carbamoylisonicotinate (4.24 g, 21.83 mmol) was slurried in MeOH (50 mL) and HCl in MeOH (17.47 mL, 21.83 mmol) and platinum(IV) oxide (0.248 g, 1.09 mmol) were added. The mixture was hydrogenated at 5 bar in a Büchi hydrogenation apparatus. After 3 h there were still starting material left. platinum(IV) oxide (0.14 g, 0.62 mmol) was added and the reaction continued for 2 h when platinum(IV) oxide (0.387 g, 1.70 mmol) was added and the reaction was stirred overnight. The reaction mixture was filtered and evaporated to give ethyl 2-carbamoylpiperidine-4-carboxylate hydrochloride (3.93 g, 90%). 1H NMR (400 MHz, dmso) δ 1.16 (t, 3H), 1.31-1.63 (m, 2H), 1.86 (d, 1H), 2.26 (d, 1H), 2.54-2.66 (m, 1H), 2.74-2.88 (m, 1H), 3.10-3.19 (m, 1H), 3.47-3.56 (m, 1H), 4.06 (q, 2H), 7.38 (s, 1H), 7.71 (s, 1H). MS m/z 201 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][C:15](=[O:25])[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:19]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccc(Cl)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1COc2ccc(Cl)cc2N1C1CCNCC1
Yield: 137.7 %

Procedure:
4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (7.2 g, 19.6 mmol) was set stirring and a 1:1 TFA/CH2Cl2 solvent mixture was added. After 1 h the mixture was evaporated under reduced pressure and the resulting red oil brought up in Et2O. A solid formed and was filtered and air dried to give 7.2 g (96%) of a light beige solid. MS (electrospray): exact mass calculated for C13H15ClN2O2, 266.08. m/z found, 267.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.52 (s, 1H), 7.20-7.00 (m, 2H), 4.60 (s, 2H), 4.50-4.40 (m, 1H), 3.65-3.55 (m, 2H), 3.28 (t, J=13.1 Hz, 2H), 3.10-3.00 (m, 2H), 2.15 (d, J=13.9 Hz, 2H).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:14]2[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[CH:16][O:17][C:13]=2[C:12]([Cl:34])=[CH:11][N:10]=1)=O)(C)C.ClC1C2OC=C(C3C=C4C(=CC=3)N(C(OC(C)(C)C)=O)CC4)C=2C(NC(OC(C)(C)C)=O)=NC=1.Cl>C(Cl)Cl>[Cl:34][C:12]1[C:13]2[O:17][CH:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21]4)[C:14]=2[C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(Cl)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c34)ccc21
Agent: CC(C)(C)OC(=O)Nc1ncc(Cl)c2occ(-c3ccc4c(c3)CCN4C(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: ClCCl
Product: Nc1ncc(Cl)c2occ(-c3ccc4c(c3)CCN4)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.5 %

Procedure:
The products 1,1-dimethylethyl 5-[4-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-7-chlorofuro[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (81 mg, 0.138 mmol), and 1,1-dimethylethyl 5-[7-chloro-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)furo[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (33 mg, 0.068 mmol) (0.206 mmol total) were combined in DCM and concentrated to a pale yellow oil. To this oil was added 1,4-Dioxane (0.5 mL) and to the resulting solution was added HCl (4 M, dioxane) (2 mL, 8.00 mmol), and the reaction stirred overnight at room temperature. The reaction mixture was concentrated to afford crude 7-chloro-3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (81.5 mg, 0.227 mmol, 164% yield) as a beige solid. LC-MS (ES) m/z=286 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (t, J=7.83 Hz, 2H), 3.09-3.19 (m, 2H), 6.83 (s, 2H), 6.90 (s, 1H), 7.32 (s, 1H), 7.46 (s, 1H). Note, NHs are not observed.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:18][CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:54][C:55]1([C:61]2[CH:68]=[CH:67][C:64]([C:65]#[N:66])=[CH:63][CH:62]=2)[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C)C=O>[C:65]([C:64]1[CH:67]=[CH:68][C:61]([C:55]2([F:54])[CH2:60][CH2:59][N:58]([C:9]([C:8]3[C:7]([CH2:18][CH3:19])=[CH:6][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH2:57][CH2:56]2)=[CH:62][CH:63]=1)#[N:66]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 70.0 mg, 0.270 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). HBTU (210 mg, 0.550 mmol, 2.07 equiv), DIEA (150 mg, 1.16 mmol, 4.35 equiv) were added to the reaction mixture at 0° C., and stirred for 30 min. This was followed by the addition of 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 HCl salt, 80.0 mg, 0.330 mmol, 1.20 equiv). The resulting solution was stiffed for 15 h at 25° C., and then quenched with 20 mL of ice-water. The mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 100 mg (84%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][CH2:41][OH:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH2:40][CH2:41][OH:42])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OCCCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CC[C@@H](Cc2nn(CCO)c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.3 eq) and 2-chloroethanol (24 mg, 0.299 mmol, 2.3 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had gone to completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (41 mg, 67%). MS(ES)+ m/e 473.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([O:32]CC2C=CC=CC=2)=[O:31])[CH2:29][CH2:28]1)=[O:26].CO.[H][H].[CH2:44]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH3:45]>O1CCCC1.[Pd]>[CH2:44]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH3:45].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH:20]([OH:22])[CH2:21]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC(O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
Benzyl 1-[({2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (84.2 mg) was dissolved in tetrahydrofuran and methanol (1:1) (2 ml) under a nitrogen atmosphere. 10% palladium on carbon (33.2 mg) was added and the air in the reaction vessel was replaced by hydrogen, and the mixture was stirred at room temperature for 20 hours. The air in the reaction vessel was replaced by nitrogen, and triethylamine (0.0435 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was removed by filtration, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (75.3 mg, 88%) as a white solid.