Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7]C)=[O:6].[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.N.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>[CH3:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:11]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2cc(C(=O)O)cc(N(C)S(C)(=O)=O)c2)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
A mixture of methyl 3-bromo-5-[methyl(methylsulfonyl)amino]benzoate obtained in Reference Example 15 38 mg (0.12 mmol), 3-methyl-phenylboronic acid 33 mg (0.24 mmol), cesium carbonate 3.7 mg (0.012 mmol), palladium(II) acetate 1.4 mg (0.0060 mmol), triethylamine 0.056 mL (0.40 mmol) and N,N-dimethylformamide (0.5 mL) was stirred at 100° C. under argon atmosphere for 7 hours. The mixture was diluted with a mixed solvent of ethyl acetate/toluene=1:1 and wished successively with 10% aqueous ammonia and 1N hydrochloric acid. After drying of the mixture on magnesium sulfate, the mixture was concentrated and the residue was purified by a column chromatography on silica gel (eluted with hexane/ethyl acetate=5:13:1). The resulting solid was dissolved in a mixture of 2N aqueous sodium hydroxide solution (0.5 mL), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) and the mixture was stirred at room temperature for 15 hours. The solvent was concentrated and the residue was adjusted by adding 1N hydrochloric acid to pH=3, and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 28 mg (0.355 mmol) of the title compound (yield: 75%).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F)([O-:10])=[O:9].[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=1>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:23]1[CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=[C:22]1[CH3:21])([O-:10])=[O:9]
Reactant: CCOC(=O)c1c[nH]c(C)n1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(C)n1

Procedure:
16 ml of triethylamine was added to 14.5 g (0.078 mol) of 2,4-dinitrofluorobenzene, 12 g (0.078 mol) of ethyl 2-methylimidazole-4-carboxylate and 500 ml of toluene, and the mixture was refluxed for 18 hours. The solvent was then distilled off under reduced pressure and the residue was chromatographed using pentane/ethyl acetate as mobile phase.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:27])[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:20])[O:17]2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:19]1[C:10]([OH:9])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16]([CH3:20])=[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]2=[O:27]
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc2c(Br)c(O)ccc2c(=O)c1-c1ccccc1
Reaction time: 24 h
Yield: 58.9 %

Procedure:
N-Bromosuccinimide (2.0 g, 11.2 mmol) was added to a solution of 7-hydroxy-2-methyl-3-phenyl-chromen-4-one (2.5 g, 10 mmol) in DMF (20 ml) and the solution stirred for ˜24 hrs. to give an orange suspension. The suspension was poured into water (200 ml) to give a pale pink precipitate, solids were removed by filtation and washed with water. Solids were recrystallised from ethanol, to give the 8-bromo-7-hydroxy-2-methyl-3-phenyl-chromen-4-one as an off-white solid (1.95 g)
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:16][CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]2=3)=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: O=C(O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (0.1 g, 0.41 mmol), 4-fluoro benzoic acid (57 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated by rotary evaporation to obtain 19.22 mg of 4-fluoro-N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)benzamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.98 (bs, 1H), 8.72 (t, 1H), 7.80-7.84 (m, 2H), 7.45 (d, 1H), 7.25-7.30 (m, 2H), 7.20 (s, 1H), 7.0 (d, 1H), 4.50-4.59 (m, 1H), 4.17-4.30 (m, 2H), 3.73-3.80 (m, 2H), (3.50-3.59 (m, 3H), 3.05-3.15 (m, 2H), 2.92 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC(C)CC3)c(F)c2)c1
Yield: 17.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.7 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:13]I)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:39]1[C:48]([CH2:49][P:50]([O:55][CH2:56][CH3:57])([O:52][CH2:53][CH3:54])=[O:51])=[CH:47][C:46]2[C:41](=[CH:42][C:43]([Cl:59])=[C:44]([CH3:58])[CH:45]=2)[N:40]=1>C1(C)C=CC=CC=1.CC(N(C)C)=O.C(OCC)(=O)C.[Cu].Cl[Pd]Cl>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:13][C:39]1[C:48]([CH2:49][P:50]([O:52][CH2:53][CH3:54])([O:55][CH2:56][CH3:57])=[O:51])=[CH:47][C:46]2[C:41](=[CH:42][C:43]([Cl:59])=[C:44]([CH3:58])[CH:45]=2)[N:40]=1)[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOP(=O)(Cc1cc2cc(C)c(Cl)cc2nc1Br)OCC
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc2cc(C)c(Cl)cc2nc1C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.81 g, 2.46 mmol) in dry toluene (12 ml) and dry dimethylacetamide (0.8 ml) was added to a nitrogen purged flask charged with zink-copper couple (0.32 g, 4.92 mmol). The mixture was treated in an ultrasonic bath for 1 h until no starting material remained (as judged by TLC). A mixture of PdCl2 (23 mg, 0.13 mmol) and tri-o-tolylphosphine (79 mg, 0.26 mmol) was added followed by 2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline (0.5 g, 1.23 mmol) and sonication was continued for 3 hours at 50°-60° C. After cooling the reaction mixture was diluted with ethyl acetate, extracted with saturated sodium hydrogen carbonate solution, dried over MgSO4 and evaporated. The crude product was subjected to chromatography on silica gel with ethyl acetate as eluant to yield 0.49 g of methyl (R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-6-methyl-2-quinolinepropionate.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: CC(C)(N)CO
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: CC(C)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and 2-amino-2-methylpropanol.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:29][C:30]1[CH:31]=[C:32]([C:36](=O)[CH3:37])[CH:33]=[N:34][CH:35]=1>C1COCC1>[Br:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32]([C:36]([CH3:37])=[CH:2][O:3][CH3:4])[CH:31]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C(C)c1cncc(Br)c1
Temperature: -78 °C
Yield: 54.8 %

Procedure:
To a solution of methoxymethyltriphenylphosphonium chloride (20.57 g, 60 mmol) in THF at −78° C. was added slowly butyl lithium (1.6 M in hexanes, 37.5 mL). The resulting mixture was further stirred for 45 min to room temperature. After the reaction was cooled down to −78° C., 1-(5-bromopyridin-3-yl)ethanone (Aldich) (8 g, 40 mmol) in THF was added to the reaction mixture. The resulting solution was stirred from −78° C. to room temperature for overnight, then quenched with saturated aqueous NH4Cl solution, and extracted with diethyl ether three times. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and concentrated to a residue which was purified by flash column to give 3-bromo-5-(1-methoxyprop-1-en-2-yl)pyridine (E/Z mixture, 5 g). 1H NMR (300 MHz, CDCl3), d: 8.769 (m, 0.5H), 8.491 (m, 1.5H), 8.143 (m, 0.4H), 7.737 (m, 0.6H), 6.517 (m, 0.6H), 6.271 (m, 0.4H), 3.804, 3.773 (ss, 3H), 1.949 (m, 3H). The aldehyde was synthesized using the methods described herein.
Reaction SMILES: N1CCCC1.C1(NC(N2C3C(=CC(OC4C=CN=C(N(C(OC5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)C=4)=CC=3)C=C2)=O)CC1.[CH:47]1([NH:50][C:51]([N:53]2[C:61]3[C:56](=[CH:57][C:58]([O:62][C:63]4[CH:68]=[CH:67][N:66]=[C:65]([NH:69][C:70]([N:72]5[CH2:77][CH2:76][CH:75](N6CCCC6)[CH2:74]C5)=[O:71])[CH:64]=4)=[CH:59][CH:60]=3)[CH:55]=[CH:54]2)=[O:52])[CH2:49][CH2:48]1>CN(C)C=O>[CH:47]1([NH:50][C:51]([N:53]2[C:61]3[C:56](=[CH:57][C:58]([O:62][C:63]4[CH:68]=[CH:67][N:66]=[C:65]([NH:69][C:70]([N:72]5[CH2:77][CH2:76][CH2:75][CH2:74]5)=[O:71])[CH:64]=4)=[CH:59][CH:60]=3)[CH:55]=[CH:54]2)=[O:52])[CH2:49][CH2:48]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Agent: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCCC1
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and pyrrolidine (0.35 ml, 4.2 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (200 mg, 0.49 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To 150 g (735 mmol) (S)-1-(4-bromophenyl)ethylamine in 2 L DCM are added 459 mL (918 mmol) of an aq. Na2CO3 solution (c=2 mol/L). To this mixture a solution of 164 g (749 mmol) BOC2O in 350 mL THF is added dropwise at r.t. and stirring is continued for 1 h. After that the mixture is poured onto water and stirred for additional 20 min. The layers are separated, the org. layer is washed with water (2×), dried over Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Na+].[I-].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A 250 mL round bottom flask was charged with 4-bromoacetophenone (1.99 g, 10.0 mmol), TBSCl (6.03 g, 40.0 mmol) and NaI (6.00, 40 mmol). The flask was capped with a rubber septum and placed under an atmosphere of Argon. After the addition of 200 mL MeCN, NEt3 (6.13 mL, 44.0 mmol) was introduced and the reaction mixture was stirred for 16 h at rt until TLC monitoring indicated complete conversion. The reaction mixture was poured onto sat. NaHCO3 solution and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated to yield a brown slurry. Hexanes was added and the obtained heterogeneous mixture was filtered through a short plug of silica using hexanes to afford the title compound as a colorless oil (3.02 g, 96% yield). Rf=0.49 (1% EtOc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 4.88 (s, 1H), 4.44 (s, 1H), 1.00 (s, 9H), 0.21 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.2, 137.0, 131.4, 127.1, 122.4, 91.6, 26.0, 18.5, −4.4; HR-MS(ESI): calcd. For C14H21ObrSi (M+): 312.0545; found: 312.0542.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[NH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH2:8][N:10]1[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:4]
Reactant: NC1CCOCC1
Reactant: COC(=O)C(Br)CCBr
Product: COC(=O)C1CCN1C1CCOCC1
Yield: 27 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 4-aminotetrahydropyran 18E yielded 1-(tetrahydro-pyran-4-yl)-azetidine-2-carboxylic acid methyl ester as a light yellow oil (27%). MS ISP (m/e): 200.2 (100) [(M+H)]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH2:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:56][CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C.O>CN(C)C=O>[F:48][C:45]1[CH:46]=[CH:47][C:42]([NH:41][C:40]([C:37]2([C:35]([NH:34][C:33]3[CH:32]=[CH:31][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:61]5[CH2:62][CH2:63][CH:58]([CH2:57][N:52]6[CH2:56][CH2:55][CH2:54][CH2:53]6)[CH2:59][CH2:60]5)=[O:14])[CH:7]=4)=[CH:3][C:2]=3[F:1])=[O:36])[CH2:39][CH2:38]2)=[O:49])=[CH:43][CH:44]=1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 27.5 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (41.0 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (74.2 mg), triethylamine (0.0857 ml) and water (0.20 ml), followed by stirring at room temperature for 13 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue were added diethyl ether and hexane, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (10.5 mg, 28%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:5]([CH3:7])=O.[CH3:19][N:20]1[C:24]([NH2:25])=[CH:23][C:22]([CH3:26])=[N:21]1>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:23]2[C:22]([CH3:26])=[N:21][N:20]([CH3:19])[C:24]=2[NH:25][C:5]=1[CH3:7])=[O:18]
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: Cc1cc(N)n(C)n1
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2c(c(C)nn2C)C1c1ccccc1[N+](=O)[O-]

Procedure:
Methyl-2-(2-nitrobenzyliden)acetoacetate (10 g; 0.040 mol) is added to 1,3-dimethyl-5-pyrazolamine (4.89 g; 0.044 mol) in ethanol (40 ml) The mixture is refluxed for about 5 hours, then the solvent is evaporated under reduced pressure and the residue is taken up in ethyl ether and recovered by filtration. M.p. 216°-220° C.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH:13]([CH:16]1[CH:20]2[C:21]3[C:26]([CH:17]1[CH2:18][CH2:19]2)=[CH:25][CH:24]=[CH:23][C:22]=3[NH2:27])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([CH:16]1[CH:20]2[C:21]3[C:26]([CH:17]1[CH2:18][CH2:19]2)=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])([CH3:15])[CH3:14]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CC(C)C1C2CCC1c1c(N)cccc12
Solvent: Cc1ccccc1
Product: CC(C)C1C2CCC1c1c(NC(=O)c3cn(C)nc3C(F)F)cccc12
Temperature: 85 °C
Reaction time: 1 h

Procedure:
15.1 g (0.0752 mol, 96.5% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 100 ml of toluene. The solution was evacuated to 350 mbar and heated to 85° C. Subsequently, within 60 min, 20 g (0.074 mol, 75%; 65:10 syn/anti isomer mixture) of 9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ylamine, dissolved in 100 ml of toluene, were metered in and the reaction mixture was stirred for another 1 hour. After venting and cooling to 25° C., the mixture was stirred overnight. Subsequently, the mixture was concentrated under reduced pressure and dried. The yield was 31.3 g; according to 1H NMR 70% pure (82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:17]=1[CH2:16][CH2:15][NH:14][C:13]2=[O:12]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C
Yield: 66 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-indol-2-one (23 mg, 0.11 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-1-carbaldehyde (29.7 mg, 0.18 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 26 mg (67%) of the title compound.
Reaction SMILES: CI.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(O)cccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1CCC2=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Methyl iodide (69 ml) is added dropwise over a period of 15 minutes to a stirred mixture of 4-hydroxy-1-indanone (150 g) and anhydrous potassium carbonate (154 g) dissolved in DMF (1.5 liter) cooled to 0° C. under nitrogen. The reaction mixture is stirred at RT for 24 hours and partitioned between methylene chloride and water. The methylene chloride fraction is washed with water and 2% aqueous NaOH and dried over Na2SO4. The dried extract is filtered, concentrated in vacuo and the residue dissolved in hot methanol which upon cooling forms a precipitate. The precipitate is filtered and recrystallized from methanol yielding the methoxy product as a solid, M.P. 104°-106° C.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.I[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].N>[Cu]I.O.C1(C)C=CC=CC=1>[NH2:27][CH2:26][C:25]1[CH:24]=[C:23]([N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:7])[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCCCN1
Reactant: NCc1cccc(I)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: NCc1cccc(N2CCCCC2=O)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), δ-valerolactam (120 mg, 1.21 mmol), K3PO4 (430 mg, 2.03 mmol), briefly evacuated and backfilled with argon. N,N′-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol %), 3-iodobenzylamine (134 μL, 1.01 mmol), and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 100° C. for 18 h. The resulting pale yellow suspension was allowed to reach room temperature, and then 30% aq ammonia (1 mL) and water (10 mL) were added. The biphasic mixture was extracted with CH2Cl2 (3×15 mL). The combined organic phases were dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm; CH2Cl2(saturated with 30% aq ammonia)-CH2Cl2-MeOH 10:10:1; 15 mL fractions). Fractions 14-19 provided 199 mg (96% yield) of the product as a pale yellow oil.