Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11]
Reactant: COC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C(C)=O
Temperature: 100 °C

Procedure:
Methyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.84 g, 2.51 mmol) was dissolved in 24 mL of a solvent mixture of acetone/water (v/v=5/1), and p-toluenesulfonic acid monohydrate (about 0.19 g) was then added to the obtained solution. The resulting mixture was refluxed at 100° C. for 2 days. After the reaction was completed, the reaction mixture was concentrated under a reduced pressure and then extracted with dichloromethane. The desired product was obtained (0.55 mg, 75%) by performing column chromatography (eluent: n-hexane/ethyl acetate=2/1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N(OC)C)=[O:9])=[CH:6][C:5]([Cl:14])=[N:4][CH:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9])=[CH:6][C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: CON(C)C(=O)c1cc(Cl)ncc1N
Reactant: Br[Mg]c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cnc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-Amino-2-chloro-N-methoxy-N-methyl-isonicotinamide (1.50 g, 6.608 mmol) in THF (25 mL) under argon is added phenylmagnesium bromide in diethyl ether (6.00 mL, 2M, 18 mmol) at 0° C. The mixture is stirred for 30 minutes at 0° C. Aqueous citric acid solution (1 M, 25 mL) is added to the reaction and the mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate. The drying agent is removed by filtration and the solvent is concentrated to dryness. This provides the desired compound which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:39])=[CH:17][N:16]=1>>[Cl:39][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a gray solid (142 mg, 77%). m.p.=281-283° C.; LCMS (m/e) 535 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.52 (bs, 1H), 9.47-9.38 (m, 2H), 8.60-8.54 (m, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.71-7.63 (m, 2H), 7.25 (d, 1H, J=8.4 Hz), 7.09 (bs, 1H), 6.93 (d, 1H, J=8.1 Hz), 3.90 (s, 3H), 2.74 (d, 3H, J=4.0 Hz), 2.58-2.47 (m, 2H), 2.08-1.93 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:16]([C:15]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Reactant: NNC(=O)c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2nnc(-c3c(F)cccc3F)n2nc1Cl
Yield: 13.3 %

Procedure:
A mixture of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (2 g, 9.75 mmol), 2,6-difluorobenzoic acid hydrazide (2.52 g, 14.6 mmol) (WO 95/24403) and triethylamine hydrochloride (2.01 g, 14.6 mmol) in 1,4-dioxane (10 ml) was stirred and heated at reflux for 3.5 days. Upon cooling, the volatiles were removed in vacuo and the residue was triturated with dichloromethane. Any undissolved solid was removed by filtration. The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate in dichloromethane to give the required product (0.42 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.57 (9H, s), 7.09-7.16 (2H, m), 7.51-7.63 (1H, m), 8.19 (1H, s); MS (ES30) m/e 323 (MH+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(=O)CC>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCCCCI
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 30 °C

Procedure:
Anhydrous K2CO3 (416g, 3 mol) was added to a mixture of 4-bromo-4′-hydroxybiphenyl (300 g, 1.2 mol), 1-iodopentane (234 ml, 1.79 mol) and 2-butanone (600 ml). The reaction mixture was refluxed for 44 h until TLC (85:15 hexanes/EtOAc) showed complete consumption of the bromo alcohol. The mixture was cooled to about 30° C., diluted with CH2C12 (600 ml) and then filtered. The filtrate was washed twice with H2O and twice with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and then dried at reduced pressure to provide a solid. This solid was isolated by filtration, washed repeatedly with a total of 2 L of ice-cold heptane to remove all traces of iodopentane and then dried overnight under high vacuum. Yield: 340 g (88%) of a white powder.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH:2]=[CH2:3]
Reactant: COc1cccc(CBr)c1
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCn1c(SCc2cccc(OC)c2)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.075 g, 0.222 mmol), 3-methoxybenzyl bromide (0.034 ml, 0.244 mmol), potassium hydroxide (0.019 g, 0.332 mmol) in Ethanol (1.303 ml) was refluxed overnight. To the cooled solution, water (1 ml) was added and the product was extracted with 10% MeOH in EtOAc, dried over sodium sulfate, and concentrated. The title compound was purified by flash column chromatography, eluting with 0 to 5% EtOAc in hexane. 1H NMR (500 MHz, CDCl3) δ ppm 8.15, 7.38-7.23, 7.06-7.02, 6.86-6.84, 5.945.32, 5.32-5.27, 4.69, 4.59, 3.77, 3.06, 2.60, 1.75-1.72, 1.60-1.54, 1.43-1.37; MS (EI) m/z 459 (M+1)
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)O)co1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(N)n1
Yield: 35.7 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-amino-1,3-oxazole-4-carboxylic acid (0.037 g, 0.288 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.05 g, 0.192 mmol). Yield 35.7%. 1H-NMR (400 MHz; MeOD): δ 1.23 (d, 3H), 4.30 (dd, 1H), 4.37 (dd, 1H), 4.46-4.54 (m, 1H), 6.77 (d, 1H), 7.65 (s, 1H), 7.69 (d, 1H), 7.79 (dd, 1H), 7.91 (dd, 1H), 8.05 (dd, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NCc2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1CCC(C)(C)c2cc(CNc3ccc(C(=O)O)cc3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)methylamino]benzoate (Compound 9, 43 mg, 0.11 mmol) was dissolved in ethanol (4.0 mL) and the solution treated with 2.3 M KOH (1.0 mL). The solution was heated to 40° C. and stirred for 16 hours. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30% ethyl acetate in hexanes) give the title compound (29 mg, 73%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[C:40]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:39][N:38]([CH2:45][CH3:46])[N:37]=1>CN(C)C1C=CN=CC=1.C(OCC)C.CCCCCC.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:44][S:41]([C:40]3[C:36]([Cl:35])=[N:37][N:38]([CH2:45][CH3:46])[CH:39]=3)(=[O:43])=[O:42])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCn1cc(S(N)(=O)=O)c(Cl)n1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: CCn1cc(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c(Cl)n1
Reaction time: 8 h

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (110 mg, 0.42 mmol, prepared as described in Example 1 Step C) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL) was added 4-(dimethylamino)pyridine (152 mg, 1.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol). The reaction mixture was stirred for 15 min after which time 3-chloro-1-ethyl-1H-pyrazole-4-sulfonamide (81 mg, 0.38 mmol, the product of Step D) was added and stirring was continued at room temperature overnight. Dichloromethane (100 mL) was then added and the mixture was extracted with 1 N hydrochloric acid (3×50 mL). The separated organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was suspended in a mixture of diethyl ether and hexane and filtered to afford 85 mg of the title compound, a compound of the present invention, as a solid, m.p. 184-185° C. 1H NMR (CDCl3) δ 9.96 (br s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.54 (s, 1H), 4.17 (q, 2H), 1.54 (t, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[CH2:10][CH2:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([P:35](=[O:40])([O:38]C)[O:36]C)[CH:30]=2)=[CH:25][CH:24]=1)(C(C)(C)C)(C)C.Br[Si](C)(C)C>ClCCl>[F:47][C:44]1[CH:45]=[CH:46][C:41]([C@@H:9]([OH:8])[CH2:10][CH2:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]2[C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([P:35](=[O:36])([OH:40])[OH:38])[CH:30]=3)=[CH:25][CH:24]=2)=[CH:42][CH:43]=1
Reactant: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(P(=O)(O)O)c3)cc2)N1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of dimethyl (4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate (0.32 g, 0.47 mmol) in dry dichloromethane (15 mL) under nitrogen was cooled in an ice bath and bromotrimethylsilane (0.30 mL, 2.27 mmol) was dripped in over 5 min. The reaction mixture was stirred at room temperature for 3 h, then poured into ice water (20 m]L) and extracted with ethyl acetate. The organic solution was washed successively with water (2×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 20% to 70% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid (0.25 g, 99%) as a white powder; 1H NMR (300 MHz, CD3OD) δ 8.04 (br d, J=14.2 Hz, 1H) 7.68 (d, J=8.5 Hz, 2H), 7.50(d, J=8.5 Hz, 2H), 7.0-7.8 (m, 12H), 4.93 (d, J=2.2 Hz, 1H), 4.63 (t, J=5.2 Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H]− 531, [2M-H]− 1061.
Reaction SMILES: [Na][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[I-].[Na+].Cl[CH2:14][C:15](=[O:17])[CH3:16]>CC(C)=O>[C:5]([CH:4]([CH2:14][C:15](=[O:17])[CH3:16])[C:3](=[O:10])[CH3:2])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CC(=O)C[Na]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(C)=O)C(C)=O

Procedure:
To a stirred and refluxing solution of ethyl sodioacetoacetate (0.5 mole, 78g.) and sodium iodide (1g.) in dry acetone (250 ml.) was added chloroactone (0.54 mol. 50g.) over a period of ten minutes. After one hour the acetone was distilled from the reaction mixture and the residue was diluted with 400 ml. water. The preciptated oil was extracted with ether and the ether removed to yield the intermediate 3-carbethoxy-2,5-hexanedione (75g.). The intermediate (26.4g.) was cyclized by heating under reflux over 5 g. anhydrous oxalic acid for 11/4 hours. The crude ester was saponified by heating under reflux for 45 minutes with potassium hydroxide (26g.) in methanol (200 ml.). The methanol was removed, the residue dissolved in water and the solution acidified to yield 2,5-dimethyl-3-furoic acid (18g.), m.p. 130°-133°.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:10]2[CH:9]=[C:8]3[N:11](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:32])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([N:14]([CH3:15])[C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC)n3S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N(C)C(=O)c4ccccc4)nc3cc21
Temperature: 130 °C
Yield: 35.6 %

Procedure:
To a solution of 7,7-dimethyl-2-methylamino-5-pentyl-1-(toluene-4-sulfonyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (120 mg) in pyridine (5 ml) is added drop-wise benzoyl chloride (0.1 ml; 0.79 mmol) at 0° C. After addition the mixture is heated at 130° C. for 5 h. An aqueous work-up and purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (40:1) yield the desired compound (38 mg).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[F:47][C:48]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:49]=1/[CH:50]=[CH:51]/[C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1>CN(C=O)C.O>[F:47][C:48]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:49]=1/[CH:50]=[CH:51]/[C:52]1[CH:53]=[CH:54][C:55]([NH:56][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]2[CH:16]3[CH:11]([NH:12][C:13](=[O:14])[NH:15]3)[CH2:10][S:9]2)=[CH:57][CH:58]=1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: Nc1ccc(/C=C/c2c(F)cccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(/C=C/c2c(F)cccc2F)cc1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a suspension of 100 mg (0.41 mmol 1 equiv) of biotin in 3 mL of anhydrous DMF was added 66 mg (0.49 mmol, 1.2 equiv) of 1-hydroxybenzotriazole hydrate, 94 mg (0.49 mmol, 1.2 equiv) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and 79 mg (0.78 mmol, 1.9 equiv) of Et3N. The mixture was stirred for 10 min, and 95 mg (0.41 mmol) of 9 was added. The mixture was stirred for 24 h at 25° C. and poured into water. The precipitate was collected by filtration and chromatographed using 1:1 EtOAc-MeOH to give 120 mg (66%) of 11 as white crystals: mp 278-280° C. 1H NMR (DMSO-d6): δ 9.99 (s, 1H), 7.64 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.37-7.29 (m, 2H), 7.19-7.12 (m, 2H), 7.02 (d, 1H, J=16.4 Hz), 6.44 (s, 1H), 6.36 (s, 1H), 4.33-4.29 (m, 1H), 4.16-4.13 (m, 1H), 3.15-3.10 (m, 1H), 2.83 (dd, 1H, J1=12.8 Hz, J2=4.8 Hz), 2.58 (d, 1H, J=12.0 Hz), 2.33 (t, 2H, J=7.2 Hz), 1.70-1.33 (m, 6H). 13C NMR (DMSO-d6): δ 171.70, 163.13, 160.53 (dd, J1=247.8 Hz, J2=7.7 Hz, two C), 140.09, 135.28 (t, J=7.9 Hz), 131.77, 129.18 (t, J=10.7 Hz), 127.69 (two C), 119.54 (two C), 114.61 (t, J=15.5 Hz), 113.25, 112.45 (dd, J1=19.1 Hz, J2=6.3 Hz, two C), 61.48, 59.63, 55.82, 40.28, 36.70, 28.67, 28.53, 25.50. HRMS (EI) Calcd for C24H25F2N3O2S: 457.1636. Found: 457.1650. Anal. Calcd for C24H25F2N3O2S: C, 63.00; H, 5.51. Found: C, 62.82; H, 5.47.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:29])[C@H:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:28][O:27][C:25]([NH:24][C@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:29])=[O:26]
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Yield: 38.8 %

Procedure:
1.5 g of 1-[(R)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester were dissolved in a mixture of 15 mL of methanol and 15 ML of tetrahydrofuran and hydrogenated for 3 h at room temperature using 0.4 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.45 g (100%) of the title compound as a white solid. (+)-APCI-MS: 307 (MH+).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:23]=[CH:22][C:7]2=[C:8]3[C:17](=[CH:18][CH:19]=[C:6]2[CH:5]=1)[C:16](=[O:20])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]3=[O:21].CCCC[O:28][N:29]=O>O.C(O)CCC>[OH:3][C:4]1[CH:23]=[CH:22][C:7]2=[C:8]3[C:17](=[CH:18][CH:19]=[C:6]2[C:5]=1[N:29]=[O:28])[C:16](=[O:20])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]3=[O:21]
Reactant: CCCCON=O
Reactant: O=C1c2ccccc2C(=O)c2c1ccc1cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: O=Nc1c(O)ccc2c3c(ccc12)C(=O)c1ccccc1C3=O
Temperature: 60 °C

Procedure:
A solution of sodium hydroxide (0.72 g) in water (0.72 g) is added under stirring at ambient temperature to a suspension of 3-hydroxy-benzo[a]anthracene-7,12-dione, prepared as described in Journal Organic Chemistry (1986) 51 page 3502, (5 g; 18 mmoles) in butanol (25 ml). N-butylnitrite (2 g; 19.4 mmoles) is added over a period of 1 hour to the mixture, which is maintained at 60° C. The reaction mixture is maintained at 60° C. for 4 hours, cooled to ambient temperature and filtered. The solid is washed with toluene (2×10 ml), dried under vacuum and suspended in water (25 ml). Acetic acid (2 ml) is added to the suspension over a period of 30 minutes, operating at ambient temperature under stirring.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([I:21])[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].IC1C=CC=C2C=1N=C(SC)N(C[CH2:36][O:37][CH2:38]COC)C2=O>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:36][O:37][CH3:38])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([I:21])[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCCn1c(SC)nc2c(I)cccc2c1=O
Reactant: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Product: COCCOCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O

Procedure:
This compound (0.33 g, 0.74 mmol) was prepared according to the procedures described for Intermediate 715, starting from 8-iodo-3-(2-(2-methoxyethoxyl)ethyl)-2-(methylthio)quinazolin-4(3H)-one (716b; 0.79 g, 1.87 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (ddd, J=14.43, 7.68, 1.56 Hz, 2H), 6.84 (t, J=7.73 Hz, 1H), 6.20 (s, 1H), 4.19-4.25 (m, 2H), 3.81-3.86 (m, 2H), 3.60-3.65 (m, 2H), 3.51-3.56 (m, 2H), 3.35 (s, 3H), 1.61 (s, 9H). m/z (ESI, +ve ion) 446.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:36])=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:24]3[C:23]([CH3:36])=[N:22][N:21]([CH3:20])[C:25]=3[CH3:26])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)c(C)c1-c1cc(Nc2ccc(OC(F)(F)F)cc2)ncn1
Temperature: 95 °C
Reaction time: 5 h
Yield: 105.2 %

Procedure:
6-Chloro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine intermediate (5.2 mg, 0.17 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.17 mmol), Pd(PPh3)4 (10 mg, 0.085 mmol) and sodium carbonate (73 mg, 0.69 mmol) were dissolved in acetonitrile:water (v/v 1:1, 10 ml). The flask was stirred at 95° C. for 5 hr. The solvent was removed and directly subjected to prep-HPLC to afford 65 mg (80% Yield) of the title compound as TFA salt. 1H NMR 400 MHz (DMSO-d6) δ 10.32 (s, 1H), 8.75 (s, 1H), 8.39 (s, 2H), 7.84 (d, 2H, J=9.2 Hz), 7.45 (d, 2H, J=9.2 Hz), 3.84 (s, 3H), 2.89 (s, 3H), 2.24 (s, 3H). MS m/z 364.11 (M+1).