Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](=[O:25])[N:6]([C:8]([CH3:24])([CH3:23])[CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CC(O)(C)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][C:8]([N:6]3[C:5](=[O:25])[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:7]3)([CH3:23])[CH3:24])=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCC(C)(C)n3cc(N)ccc3=O)ccnc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccc2c(OCC(C)(C)n3cc(NC(=O)c4ccccc4)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-amino-1-(1-(7-methoxyquinolin-4-yloxy)-2-methylpropan-2-yl)pyridin-2(1 H)-one (33 mg, 97 μmol) in CH2Cl2 (3 mL) and tBuOH (1 mL) at 0° C. under nitrogen was added DIEA (17 μl, 97 μmol) followed by a solution of benzoyl chloride (11 μl, 97 μmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 24 h at 23° C. and partitioned between CH2Cl2 (10 mL) and 5% NaHCO3 (5 mL). The organic was dried over MgSO4, concentrated onto dry silica, and purified on silica (12 g) eluting with 0-5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 444. Calc'd exact mass for C26H25N3O4: 443. 1H NMR (400 MHz, Chloroform-d) 8 ppm 1.77 (s, 6 H) 3.89 (s, 3 H) 4.97 (s, 2 H) 6.15 (d, J=5.67 Hz, 1 H) 6.60 (d, J=9.59 Hz, 1H) 7.08 (dd, J=9.19, 2.54 Hz, 1 H) 7.29-7.58 (m, 8H) 7.66 (d, J=2.74 Hz, 1 H) 7.85-7.92 (m, 3 H) 8.02-8.18 (m, 2 H).
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:32][C@H:29]1[CH2:30][CH2:31][N:27]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[CH:12][N:4]3[CH:1]([CH3:3])[CH3:2])=[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)[CH2:28]1
Reactant: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(N3CC[C@H](N)C3)nc21
Reaction time: 3 h
Yield: 110.8 %

Procedure:
To a solution of (S)-tert-butyl (1-(9-isopropyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamate (1.40 g, 2.61 mmol) in DCM (30 mL) was added TFA (2.11 mL, 21 mmol). The reaction vial was capped and stirred for 3 hr. The volatiles were then removed and methanol (50 mL) and aqueous LiOH (2 M, 20 mL) were added and the mixture stirred for 16 hr. The volatiles were removed to give a white solid residue. Water (30 mL) was added and the mixture was sonicated to give a white suspension. The solid was collected by filtration and dried to give the title product as a white solid (1.26 g, 111% yield, ˜90% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (br. s., 1 H) 7.76-7.94 (m, 3 H) 6.87 (d, J=8.80 Hz, 2 H) 4.60 (dt, J=13.33, 6.66 Hz, 1 H) 3.58-3.72 (m, 2 H) 3.51 (dd, J=10.64, 5.99 Hz, 2 H) 3.06 (br. s., 4 H) 2.45 (br. s., 4 H) 2.22 (s, 3 H) 1.95-2.10 (m, 2 H) 1.58-1.73 (m, 3 H) 1.50 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C23H33N9 436.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[CH3:20][N:21](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C#N)cc2C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 73) (2.67 g, 8.14 mmol), zinc cyanide (1.715 g, 16.27 mmol) and tetakis(triphenylphosphine)palladium(0) (1.410 g, 1.220 mmol) in DMF (30 ml) was heated at 80° C. overnight. Additional tetakis(triphenylphosphine)palladium(0) (700 mg) was added and the yellow suspension heated at 80° C. for a further 5 hrs. The cooled reaction mixture was diluted with EtOAc/water, separated, and organics dried over anhydrous magnesium sulphate and evaporated. The crude was purified by flash chromatography eluting with EtOAc/iso-hexane 1:9. The combined fractions were evaporated to give the title compound (2.01 g) as a yellow solid. 6H (CDCl3, 400 MHz): 1.42 (9H, br.s), 3.81 (2H, t), 4.09 (2H, m), 4.43 (1H, s), 4.51 (1H, s), 7.09 (1H, m), 7.47-7.59 (2H, m).
Reaction SMILES: [CH:1]1[C:6]([N:7]=[C:8]=[S:9])=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH2:45])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1.O>N1C=CC=CC=1>[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH:45][C:8]([NH:7][C:6]3[CH:1]=[CH:2][C:3]([C:13]4[C:14]5[C:15]([O:21][C:22]6[C:23]=4[CH:24]=[CH:25][C:26](=[O:28])[CH:27]=6)=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=5)=[C:4]([CH:5]=3)[C:10]([OH:12])=[O:11])=[S:9])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=S)Nc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Yield: 56.5 %

Procedure:
A solution of fluorescein-5-isothiocyanate (778 mg, 2.0 mmol) in pyridine (5 mL) was added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine (566 mg, 2.0 mmol) in pyridine (5 mL). The reaction mixture was heated at reflux for 30 minutes and then poured into water (50 mL). The resulting orange solid was isolated by filtration, dried under high vacuum and then recrystallized from pyridine to provide 0.76 g of the desired product as an orange solid, m.p. >245°. Analysis by high performance liquid chromatography indicated pure product. Analysis: Calculated for C37H32N6O5S: % C, 66.06; % H, 4.79; % N, 12.49; Found: % C, 63.03; % H, 4.89; % N, 12.59. High resolution mass spectroscopy: TM=673.2233 Da., MM=673.2251 Da.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:34])([CH3:33])[CH2:14][C:15]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[CH:19]=[CH:18]2)[CH:10]=[CH:11][CH:12]=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[F:31][C:28]([F:29])([F:30])[C:15]([OH:32])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:14][C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:2]=[O:1])([CH3:33])[CH3:34]
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-(3-[1,3]dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.99 g, 2.09 mmol), ethanol (66 mL), water (13.2 mL), and pyridinium p-toluenesulfonic acid (262 mg, 1.04 mmol) was heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo to remove ethanol. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Removal of the volatile in vacuo afforded 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde. Yield: 77 mg (89%).
Reaction SMILES: C[C@H]1O[C@H]([O:8][C@@H:9]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@@H](N)C[C@@H]1NC(C(O)=O)=N.FC(F)(F)C(O)=O>>[CH:9]1([OH:8])[CH:10]([OH:19])[CH:11]([OH:18])[CH:12]([OH:17])[CH:13]([OH:16])[CH:14]1[OH:15]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](N)C[C@@H]1NC(=N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: OC1C(O)C(O)C(O)C(O)C1O

Procedure:
The need for investigational and commercial quantities of D-chiro-inositol has led to the development of several methods for the isolation (by extraction from plant tissues), partial synthesis or complete synthesis of that compound. Especially promising is hydrolysis of the aminoglycoside kasugamycin (produced by fermentation of Streptomyces kasugaspinus) as described in U.S. Pat. No. 5,091,596 issued to Kennington et al. According to that patent, kasugamycin is treated with trifluoroacetic acid for 3 hours at 100° C., after which the resulting D-chiro-inositol is isolated by resin and gel chromatography and purified by recrystallization from 90% ethanol. Alternatively, kasugamycin may be treated with hydrochloric acid for 8 hours at 90° C., followed by isolation of the D-chiro-inositol by resin chromatography and subsequent purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.Cl[CH:19](Cl)[O:20]C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[C:10]([CH:19]=[O:20])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(-c3ccccc3)ccc2O1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(-c3ccccc3)cc(C=O)c2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran (544) (2.24 g, 10.0 mmol) in dichloromethane (15 mL) was added slowly titanium tetrachloride (2 mL, 18 mmol). After stirring of 5 minutes, dichloro(methoxy)methane (1 mL, 11 mol) was added slowly. The resulting mixture was stirred at 0° C. for 3 hours, quenched slowly with ice water. The product was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran-7-carbaldehyde (545).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.Br[C:20]1[CH2:24][O:23][C:22](=[O:25])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:20]1[CH2:24][O:23][C:22](=[O:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: O=C1C=C(Br)CO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.83 g, 7.20 mmol), commercially available 4-bromofuran-2(5H)-one (1.41 g, 8.63 mmol), Xantphos (0.416 g, 0.720 mmol), water (0.389 mL, 21.6 mmol), and potassium carbonate (1.989 g, 14.39 mmol) in toluene (50 mL) was degassed with nitrogen followed by addition of palladium acetate (0.081 g, 0.36 mmol). The resulting mixture was heated at 65° C. for 16 h. After filtration through CELITE®, the filtrate was concentrated and the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 337.18.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH3:54][NH:55][O:56][CH3:57]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:55]([O:56][CH3:57])[CH3:54])=[O:6]
Reactant: CNOC
Reactant: COc1cccc(C(=O)O)c1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N(C)OC)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 2-fluoro-3-methoxy-benzoic acid (5.0 g, 29.4 mmol) and PyBOP (13.7 g, 29.4 mmol) in 7:1 CH2Cl2:THF was added triethylamine (4.10 mL, 29.4 mmol) over a 10 min period. N,O-Dimethylhydroxylamine hydrochloride (2.87 g, 29.4 mL) was then added and the reaction was allowed to stir at rt for 3 h. The reaction was then partitioned between dichloromethane and water. The organic phase was separated and the aqueous phase was extracted with 2×100 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was taken up in ethyl acetate and was washed successively with 1N HCl, saturated aqueous NaHCO3, and brine. The organic phase was again dried (MgSO4) and concentrated in vacuo to yield the title compound (2.30 g, 37%).
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:31][O:32]C(Cl)Cl.C(O)(=O)C(C(C(O)=O)O)O.N>ClCCl.O>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[C:13]([CH:31]=[O:32])[CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:25])[CH2:7][N:6]1[CH3:26]
Reactant: COC(Cl)Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C=O)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
838 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (2 mmol) is dissolved in 100 ml of dichloromethane, 1.2 g of anhydrous aluminum chloride (9 mmol) and 1.8 ml of dichloromethyl methyl ether (20 mmol) are added and stirred for 15 minutes at room temperature. The reaction mixture is mixed with ice and, after 15 minutes, with a solution of 1.5 g of tartaric acid in 50 ml of water and made alkaline with 5 ml of conc. ammonia solution. It is extracted with dichloromethane, the organic phases are dried with sodium sulfate and the solvent is distilled off. The residue is chromatographed on silica gel with dichloromethane/methanol, 406 mg (45% of theory) is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: COc1cc(CSC)ccc1C(=O)O
Product: COc1cc(CSC)ccc1-c1nc2cnccc2[nH]1

Procedure:
Prepared analogously to Example 14 from 3,4-diaminopyridine and 2-methoxy-4-methylthiomethyl-benzoic acid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:26]([O:30][C:31]([C:33]1([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CCO>[C:26]([O:30][C:31]([C:33]1([CH2:37][NH:38][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:34][CH2:35][CH2:36]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C1(CN)CCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3c(=O)n(Cc4ccccc4)ccc3c2O)CCC1
Temperature: 140 °C
Yield: 87.3 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (55 mg, 0.30 mmol) in EtOH (2 mL) was heated at 140° C. in a microwave reactor for 2 h. Solvent was evaporated in vacuo, and the residue was purified by chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a viscous oil. MS: (+) m/z 489.33 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:13](Br)[N:14]2[CH2:17][C:18]([N:20]([CH2:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2Br)[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:19])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].N#N>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[C:13]3[C:28]4[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=4[CH2:26][N:20]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:18](=[O:19])[CH2:17][N:14]3[C:15]=2[CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)CCN(Cc1cc(Cl)ccc1Br)C(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCN1Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2CC1=O

Procedure:
To a Smith PROCESS VIAL™ (2-5 ml) charged with a magnetic stirring bar, tert-butyl-2-bromo-1-(2-{(2-bromo-5-chlorobenzyl)[2-(dimethylamino)ethyl]amino}-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (from Step 8, 1 eq) in DMF dry (0.02 M), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.1 eq), PdCl2(dppf) (0.03 eq) and potassium acetate (3 eq) were added. The vial was closed with its cap and filled with N2 and microwaved in a Smith PERSONAL SYNTHESIZER at 150° C. for 6 min. The solution was then diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude that was filtered through a plug of silica (EtOAc:PE:Et3N) (5:5:0.1%) and used in the next step without further purification; MS (ES+) m/z 550 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH:42]([CH3:43])[CH3:44])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (193 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (260 mg, 67%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][O:47][CH3:48])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][O:47][CH3:48])[CH:43]=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCOC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCOC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-(2-methoxyethyl)imidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.49 g) was dissolved in methylene chloride (14.7 ml), and a solution of metachloroperbenzoic acid (0.25 g) in methylene chloride (9.8 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-(2-methoxyethyl)imidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 308) (0.26 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=[C:48]3[C:43]([O:44]CC[O:47]3)=CC=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[C:24]5[C:23]([O:44][CH2:43][CH2:48][O:47]5)=[CH:22][C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc3c(cc12)OCCO3
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc5c(cc4c3=O)OCCO5)cc2)CCC1
Yield: 55 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-6-phenyl-2,3-dihydro-1,4,5-trioxa-anthracen-8-one (91 mg, 0.225 mmol) was reacted to give the title compound (65 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.43-7.14 (m, 9H), 7.00 (s, 1H), 5.03 (s, 1H), 4.43-4.30 (m, 4H), 2.64-2.43 (m, 4H), 2.14-1.98 (m, 1H), 1.91-1.63 (m, 1H), 1.50-1.14 (m, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][CH:7]([NH2:14])[CH2:6]2)[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:12]([C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[CH2:1][CH3:2])[CH2:6][CH:7]([NH:14][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8]2)[CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc2c(cc1CC)CC(N)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(cc1CC)CC(NC(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-Diethyl-indan-2-ylamine (4.10 g) is dissolved in dichloromethane (DCM) (150 mL) and triethylamine (2.41 g) is added. Benzoyl chloride (3.20 g) is then added dropwise and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 1 hour. The solution is washed with 0.2M HCl (100 mL), water (100 mL) and brine (100 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. Crystallised from ethyl acetate. TLC (silica, dichloromethane/methanol 10:1 Rf=0.85).