Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNCCNC.[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(O[Na])(C)(C)C>[Cu].C1(C)C(C)=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:27][CH:26]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: CC(C)(C)O[Na]
Agent: CNCCNC
Solvent: Cc1ccccc1C
Product: Brc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Yield: 68.1 %

Procedure:
Adding 17.6 g of N,N′-dimethylethylenediamine into a solution prepared by mixing 21.9 g of N-phenyl-1-naphthylamine, 28.2 g of 4-bromoiodobenzene, 14.4 g of t-butoxysodium, 3.81 g of copper powder and 100 milliliter of xylene, the resultant solution was refluxed with heating under ambient atmosphere of argon gas for 24 hours. After cooling the resultant solution down to a room temperature, the solution was filtered and insolubles were removed followed by concentrating the filtrate. Refining the residue by means of a silicagel column chromatography, 25.4 g of N-(4-bromophenyl)-N-phenyl-1-naphthylamine was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](OCC)=[O:26]>>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:24][CH:25]=[O:26])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: NCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Product: O=CNCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 67.5 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
A mixture of 2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethylamine (0.0714 g, 0.226 mmol) and ethyl formate (3 mL) is stirred at 65-70° C. for 45 min. After cooling, excess ethyl formate is removed in vacuo and the residue is partitioned between CH2Cl2 and aq. sodium sulfate. The organic layers are dried over sodium sulfate and concentrated; the residue is crystallized from CH2Cl2-EtOAc-hexane to give 0.0585 g (75%) of the title compound as a white, crystalline solid; mp 161-162° C.; MS (ESI+) for m/z 345 (M+H)+, 367 (M+Na); 1H NMR (CDCl3) δ3.95, 4.38, 5.52, 6.13, 6.68, 7.03, 7.10, 7.2-7.4, 8.27, 8.29; IR (drift) 3297, 1659, 1459, 1385, 1341, 1332, 1269, 1255, 1145, 1116, 780, 747, 737, 717, 700 cm−1. Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C, 76.53; H, 5.99; N, 8.09.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]#[N:18])[N:3]=1.S(=O)(=O)(O)[OH:20]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17](=[O:20])[NH2:18])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl
Product: NC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 61 by reaction with concentrated sulphuric acid at room temperature, mp. 298°-299° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[N:4]=1.O.[SH:25][C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[NH:28][CH:29]=[N:30]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][S:25][C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][NH:30]2
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 73.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2o (216 mg, 0.617 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 212 mg of a yellow crystalline solid (74%), mp 218.0-218.3° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.49 (s, 1H); 8.42 (s, 1H); 8.38-8.45 (m, 2H); 8.31 (d, J=8.4 Hz, 1H); 7.81 (d, J=6.5 Hz, 1H); 7.68 (d, J=6.7 Hz, 1H); 7.43-7.58 (m, 2H); 4.53 (s, 2H). 13C NMR (DMSO-d6) ppm: 157.7, 154.4, 153.3, 149.8, 149.3, 147.6, 145.2, 141.4, 131.5, 129.8, 129.7, 129.2, 128.4, 127.1, 126.7, 122.7, 120.3, 119.4, 29.9. MS (ES): m/z 466.0 (M+). Anal. calcd. for C20H12ClN7O3S.0.4C2H6O.0.5KCl: C, 51.19; H, 2.97; Cl, 7.63; N, 20.09; S, 6.57. Found: C, 51.27; H, 2.88; Cl, 7.40; N, 20.04; S, 6.52.
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:16][C:15]=4[N:14]=[C:13]([NH2:28])[C:12]=3[N:11]=[C:10]2[CH2:29][O:30][CH2:31][CH3:32])[CH2:5][O:4]1>C1COCC1>[NH2:28][C:13]1[C:12]2[N:11]=[C:10]([CH2:29][O:30][CH2:31][CH3:32])[N:9]([CH2:8][CH:6]([OH:7])[CH2:5][OH:4])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][C:15]=2[N:14]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1COC(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Hydrochloric acid (12 mL of 1 N) was added to a solution of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 1.73 mmol) in THF, and the reaction was stirred overnight at ambient temperature. The THF was removed under reduced pressure, and 1% aqueous sodium hydroxide was added to the remaining solution to adjust to pH 9. A precipitate formed, was isolated by filtration, washed with water, and dried in an oven at 60° C. to provide 0.61 g of 3-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol as a white solid, mp 218-220° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:13]=3)[C:8](=[O:34])[C:7]=2[CH:6]=1.CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O.O>C(OCC)C>[CH2:32]([O:31][C:29]([C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[CH:16]=[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:5]([CH2:4][CH2:3][C:2]([OH:37])=[O:1])=[CH:6][C:7]=3[C:8]2=[O:34])=[CH:13][CH:12]=1)=[O:30])[CH3:33]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCOc1cc2c(cc1CCCO)C(=O)c1cc(C(=O)OCC)ccc1-2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCOc1cc2c(cc1CCC(=O)O)C(=O)c1cc(C(=O)OCC)ccc1-2
Reaction time: 8 h

Procedure:
A solution of 170 mg of 2-(3-hydroxypropyl)-3-decyloxy-7-ethoxycarbonyl-9-oxo-9H-fluorene in diethyl ether were treated with 0.75 ml of Jones reagent (chromic acid solution). The reaction mixture was stirred overnight, poured into water and the layer separated. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo providing 90 mg of material which was taken directly to hydrolysis. NMR.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:9]([C:17]#[N:18])=[N:10][C:11]([CH2:15][CH3:16])=[C:12]([CH3:14])[N:13]=1.ClC1C(C#N)=NC(C)=C(CC)N=1.[C:31]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:15]([C:11]1[N:10]=[C:9]([C:17]#[N:18])[C:8]([N:40]2[CH2:41][CH2:42][N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:38][CH2:39]2)=[N:13][C:12]=1[CH3:14])[CH3:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCc1nc(C#N)c(Cl)nc1C
Agent: CCc1nc(Cl)c(C#N)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc(C#N)c(N2CCN(c3ccccc3)CC2)nc1C
Temperature: 0 °C
Yield: 21.8 %

Procedure:
0.416 mg (3.0 mmol) of potassium carbonate were added to a solution of 0.182 g (1.0 mmol) of the 1:1 mixture of the 3-chloro-6-ethyl-5-methyl-pyrazine-2-carbonitrile and the 3-chloro-5-ethyl-6-methyl-pyrazine-2-carbonitrile and of 0.199 g (1.2 mmol) of 1-phenylpiperazine in 10.0 ml of N,N-dimethylformamide and the reaction mixture was stirred at room temperature for 16 hours. It was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 4:1 to 0:100 v/v gradient of hexane and dichloromethane as the eluent giving 0.067 g (0.218 mmol, 21.8% of theory) of the 5′-ethyl-6′-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as orange oil; MS: 308 (M+H)+; and 0.043 g (0.14 mmol, 14% of theory) of the 6′-ethyl-5′-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as yellow solid; m.p. 99-101° C.; MS: 308 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1OC
Yield: 78 %

Procedure:
To a solution of 3-ethoxy-4-methoxybenzaldehyde (6.0 g, 33.3 mmol, 1.0 equiv; commercially available) in diethyl ether (50 mL) was added dropwise nitric acid 65% (4.12 mL, 5.81 g, 59.9 mmol, 1.8 equiv) over a period of 30 min at rt. After the addition was completed the reaction mixture was heated to reflux for 4 h. The reaction product precipitated out of solution, was filtered off, washed with cold diethyl ether (3×20 mL) and dried yielding 5.85 g (78%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.53 (t, J=7.0 Hz, 3H), 4.04 (s, 3H), 4.26 (q, J=7.0 Hz, 2H), 7.37 (s, 1H), 7.61 (s, 1H), 10.40 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.34, 56.68, 65.35, 107.31, 110.48, 125.52, 143.56, 152.54, 152.70, 187.60. MS (ISP): 225.9 [M+H]+.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#C)=[O:14])[CH2:7][CH2:6]1)=[O:4].O=S(Cl)Cl.[C:34]([O-:37])(O)=O.[Na+].N1C=CC=C[CH:40]=1>>[C:34]([O:4][CH2:3][C:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:14])[CH2:7][CH:6]=1)(=[O:37])[CH3:40]
Reactant: c1ccncc1
Reactant: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)OC)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CC=C(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-hydroxy-1-acetoxymethyl)-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (Example 171, isomer #1, 19.5 mg, 0.047 mmol) in 2 mL of pyridine was added SOCl2 (0.2 mL, 2.7 mmol) at 0° C. and the mixture was stirred at rt for 1 h. It was then poured into NaHCO3, extracted with CH2Cl2 (2×), dried over MgSO4 filtered and concentrated. The residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 7.75/6.0 mL/min) to give the title compound. 1H NMR (CDCl3) δ 8.18 (d, 1H, J=7.8 Hz), 7.60 (bs, 1H), 7.26-7.41 (m, 6H), 7.03 (t, 1H, J=7.6 Hz), 6.83 (d, 1H, J=8.3 Hz), 5.81 (s, 1H), 4.39-4.45 (m, 2H), 3.80 (d of d, 1H, J=6.4, 13.2 Hz), 3.75 (d of d, 1H, J=6.4, 13.2 Hz), 3.15 (s, 3H), 2.61 (d, 1H, J=17.7 Hz), 2.38 (d, 1H, J=17.7), 2.04 (s, 3H), 1.77-2.16 (m, 4H); Mass Spectrum (CI) m/e 394 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:41])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19](COCC[Si](C)(C)C)[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:41])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:29])([F:28])[F:30])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 15 %

Procedure:
To a solution of 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.085 g, 0.142 mmol) in THF (5 mL) was added a solution of TBAF in THF (1M, 0.709 mL, 0.709 mmol). The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 9) to give 3-methyl-3-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.010 g, 15%). LC/MS (Table 1, Method 5) Rt=1.207 min; MS m/z: 492 [M+23]+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:36]=[CH:35][C:22]4[N:23]([CH2:27][O:28]CC[Si](C)(C)C)[C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)=[CH:13][N:12]=2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:28][CH2:27][N:23]1[C:22]2[CH:35]=[CH:36][C:19]([O:18][CH2:17][C:14]3[CH:13]=[N:12][C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:38])([F:1])[F:37])=[CH:5][CH:6]=4)=[N:16][CH:15]=3)=[CH:20][C:21]=2[O:25][C:24]1=[O:26]
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2cc(OCc3cnc(Nc4ccc(OC(F)(F)F)cc4)nc3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1oc2cc(OCc3cnc(Nc4ccc(OC(F)(F)F)cc4)nc3)ccc2n1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a solution of 6-((2-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (0.05 g, 0.091 mmol) in DCM (3 mL) at 0° C., TFA (0.035 mL, 0.456 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum and the residue was washed with diethyl ether. The crude product was purified by preparative HPLC on an Inertsil ODS column (19×250 mm, 5μ) using 0 to 65% mobile phase B (ACN) in mobile phase A (0.1% TFA) over 6 min to give 3-(hydroxymethyl)-6-((2-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)benzo[d]oxazol-2(3H)-one as a white solid (0.025 g, 61%). 1H-NMR: 400 MHz, DMSO-d6 δ ppm 5.03 (s, 2H), 5.19 (s, 2H), 6.92-6.95 (m, 1H), 7.21-7.32 (m, 4H), 7.86-7.88 (m, 1H), 8.62 (s, 2H), 9.96 (s, 1H). LCMS: R.T. 2.303 min; 449 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:10][C:3]=12.[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCC1>O.C(OCC)(=O)C>[CH:11]1([C:9]2[NH:8][C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:20]4[CH:19]=[C:18]([F:17])[CH:23]=[CH:22][C:21]=4[O:27][CH3:28])=[C:3]3[CH:10]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ccnc2[nH]c(C3CCCCC3)cc12
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCCC3)cc12
Temperature: 60 °C

Procedure:
A solution of Example 98B (200 mg, 0.852 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (188 mg, 1.108 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (50 mg, 0.077 mmol) and potassium phosphate (543 mg, 2.56 mmol) in 8 mL 3:1 tetrahydrofuran:water was purged with nitrogen and heated under nitrogen at 60° C. for 4 hours. The cooled mixture was diluted with water and ethyl acetate and filtered through diatomaceous earth. The mixture was extracted into ethyl acetate (twice) and the combined extracts were rinsed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (1:1 ethyl acetate:hexanes) provided only a small amount of material. The column was washed with 10% methanol/dichloromethane and the remainder of the material eluted. The combined residue was suspended in diethyl ether and the solids were collected and rinsed with diethyl ether to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.48 (m, 5H) 1.64-1.76 (m, 3H) 1.99-2.02 (m, 2H) 2.70-2.73 (m, 1H) 3.72 (s, 3H) 5.92 (s, 1H) 6.99 (d, J=5.08 Hz, 1H) 7.15-7.27 (m, 3H) 8.12 (d, J=4.75 Hz, 1H) 11.50 (s, 1H). MS (DCI) m/e 325 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:10]([OH:30])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[OH:30][CH:10]1[CH2:9][NH:8][CH2:29][CH2:28][C:11]21[C:15](=[O:16])[N:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=1)[CH2:13][CH2:12]2
Reactant: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2O
Agent: [Pd+2]
Agent: [OH-]
Product: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCNCC2O

Procedure:
The title compound was prepared in analogy to example 2 step A from a mixture of (5SR,6RS)-8-benzyl-6-hydroxy-2-[4-(2,2,2-trifluoro-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one and Pearlman's catalyst under an atmosphere of hydrogen. White solid. MS (ESI): 329.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[OH:29])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:34][CH:35](Br)[CH3:36])(=[O:33])[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[OH:29])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\C4CC4)CS[C@H]23)cs1
Reactant: CC(=O)OC(C)Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)C1=C(/C=C\C2CC2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (318 mg) of Example 57 was dissolved in dimethylformamide (4.4 ml), to which a solution of 1-acetoxyethyl bromide (120 mg) in dimethylformamide (2 ml) was added dropwise under ice cooling. The resulting mixture was stirred for one and a half hours. The reaction mixture was diluted with ethyl acetate and the resulting precipitate was filtered off. After the filtrate was washed with water and then saturated saline, anhydrous magnesium sulfate was added to dry the solution. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel, whereby the title compound (18 mg) was obtained.
Reaction SMILES: [CH2:1]([C:7]1[C:8]([C:21]([OH:23])=[O:22])=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][N:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:7]1[C:8]([C:21]([O:23][C:25]2[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])=[CH:27][N:26]=2)=[O:22])=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:17])([CH3:18])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCc1cc2c(cc1C(=O)Oc1ccc(C(=O)OCc3ccccc3)cn1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
6 g of 3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carboxylic acid were dissolved in 180 ml of methylene chloride. After the addition of a solution of 4.8 g of benzyl 6-hydroxy-nicotinate in 160 ml of methylene chloride and of 2.3 g of 4-dimethylaminopyridine, the solution was cooled to 0° C. and treated with 4.4 g of dicyclohexylcarbodiimide. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours, thereafter poured into ice-cold aqueous ammonium chloride solution, extracted several times with ether, washed with water, dried over sodium sulfate and evaporated. The crude product, for the most part crystalline, was filtered over silica gel (eluent hexane/ethyl acetate=9:1) and recrystallized from hexane. After repeated crystallization of the mother liquor there were obtained all together 5.7 g of benzyl 6-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinate in colorless crystals, m.p. 94°-95° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH:21]1([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH2:24][CH2:23][CH2:22]1.F[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[C:42]#[N:43]>O1CCCC1>[C:42]([C:41]1[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=1[C:21]1([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH2:22][CH2:23][CH2:24]1)#[N:43]
Reactant: COc1cc2c(cc1OC)C(C1CCC1)=NCC2
Reactant: N#Cc1ccccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(C1(c3ccccc3C#N)CCC1)=NCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (24.5 ml, 2M solution in hexane) was added to a solution of diisopropylamine (6.85 ml) in tetrahydrofuran (50 ml) at 0° C. The resulting solution of lithium diisopropylamide was stirred at 0° C. for 20 minutes. A solution of 1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (10 g) in tetrahydrofuran (100 ml) was added. The mixture was stirred at 0° C. for 1 hour, then cooled to -70° C. and treated dropwise with 2-fluorobenzonitrile (4.42 ml). The mixture was stirred at -70° C. for 50 minutes, then allowed to warm slowly to ambient temperature. The mixture was poured onto hydrochloric acid and washed with ether. The aqueous phase was basified with ammonia solution and the product was extracted with ethyl acetate. The resulting solid (0.6 g) was collected by filtration. The filtrate was washed with brine, dried over magnesium sulphate and the solvent removed in vacuo to give further solid. The combined solids were recrystallised from acetonitrile yielding a solid which was dried in vacuo to give 1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-3,4-dihydroisoquinoline (5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:11].[Br:12]Br.C([O-])(O)=O.[Na+]>CC(O)=O>[Br:12][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[NH2:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(F)cc([N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH (50 mL) was added Br2 (3.9 mL, 77 mmol) dropwise at 0° C. The mixture was stirred at 20° C. for 3 h. The reaction mixture was basified with sat. aq. NaHCO3, and extracted with EtOAc (100 mL×3). The combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.22 (m, 1H), 7.90 (dd, J=2.4, 10.8 Hz, 1H), 4.88 (brs, 2H).