Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[C:34](=[O:37])([O-])[O-].[K+].[K+].O.[CH3:41][N:42](C)C=O>>[OH:37][CH2:34][CH2:41][NH:42][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCNCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (compound 132) (68 mg), 4-aminoethanol (25 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (36 mg, yield 54%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.F.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: F
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
500 g of anthraquinone and 500 ml of 85 percent strength hydrogen fluoride are initially introduced into a 4 liter Venuleth vessel and stirred for 15 minutes. A mixture of 500 ml of hydrogen fluoride (85 percent strength) and 140 ml of nitric acid (98 percent strength) is added at room temperature over the course of 5 minutes. The bath temperature of the Venuleth vessel is then raised to 50°C and the mixture is stirred at this temperature for 8 hours. The hydrogen fluoride is largely stripped off in vacuo (approx. 50 mm Hg) at the same temperature. The residue is treated with water, filtered off, washed and dried. 610 g of nitro-anthraquinone of the following composition are obtained:
Reaction SMILES: [N+](C1C=CC(S(O[CH:14]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:15]2)(=O)=O)=CC=1)([O-])=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[CH3:32][N:30]1[CH:31]=[C:27]([C:25]2[CH:24]=[CH:23][C:21]3[N:22]=[C:18]([N:16]4[CH2:17][CH:14]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:15]4)[S:19][C:20]=3[CH:26]=2)[CH:28]=[N:29]1
Reactant: C1CCNCC1
Reactant: Cn1cc(-c2ccc3nc(N4CC(OS(=O)(=O)c5ccc([N+](=O)[O-])cc5)C4)sc3c2)cn1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nc(N4CC(N5CCCCC5)C4)sc3c2)cn1
Temperature: 25 °C

Procedure:
A stirred solution of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-yl 4-nitrobenzenesulfonate (Reference Example 3, 38 mg, 0.08 mmol), and piperidine (0.024 mL, 0.24 mmol) in N,N-dimethylformamide (0.5 mL) was heated at 160° C. under microwave irradiation for 15 minutes. The mixture was cooled to room temperature then purified by silica gel chromatography (60:30:10 hexane/dichloromethane/2 M NH3 in isopropanol). These product fractions were purified by silica gel chromatography again (79:20:1 to 70:25:5 hexane/dichloromethane/2 M NH3 in isopropanol). A final silica gel chromatographic purification was performed by first eluting the column with 100% dichloromethane to 80:20 dichloromethane/ethyl acetate followed by elution with 99:1 to 96:4 dichloromethane/methanol to provide 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-(piperidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.57 (m, 1H), 1.65 (pentet, J=5 Hz, 4H), 2.37-2.45 (m, 4H), 3.36-3.46 (m, 1H), 3.92 (s, 3H), 4.02-4.09 (m, 2H), 4.25 (t, J=8 Hz, 2H), 7.45 (d, J=8 Hz, 1H), 7.50 (dd, J=2, 8 Hz, 1H), 7,79 (s, 1H), 7.85 (d, J=2 Hz, 1H), 7.92 (s, 1H); MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH:23]([CH3:25])[CH3:24])[C:10]1=[O:26].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ClCCl.CO.[C:39]([OH:42])(=O)[CH3:40].O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:42][CH2:39][CH2:40][N:9]([CH2:18][CH3:17])[CH2:3][CH3:2])=[CH:30][CH:29]=3)=[N:15][CH:16]=2)[N:11]([CH:23]([CH3:25])[CH3:24])[C:10]1=[O:26]
Reactant: CC(C)N1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CC(=O)O
Reactant: Nc1ccccc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C(C)C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 22 %

Procedure:
A mixture of 70 mg (0.16 mmol) of 3-(2,6-dichlorophenyl)-1-isopropyl-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 166 mg (0.8 mmol) of 4-[2-diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution each time, dried over magnesium sulfate, filtered and evaporated to give 5 mg (22%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-isopropylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 125° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH2:16][N:15]([CH2:17][C:18](=[O:29])[NH:19][CH:20]2[CH2:24][C:23](=[O:25])[O:22][CH:21]2[O:26]CC)[C:14](=[O:30])[CH:13]([NH:31][C:32]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][N:35]=2)=[O:33])[CH2:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>CC#N.O>[CH2:1]([NH:8][CH2:9][C:10]1[CH2:16][N:15]([CH2:17][C:18](=[O:29])[NH:19][CH:20]2[CH2:24][C:23](=[O:25])[O:22][CH:21]2[OH:26])[C:14](=[O:30])[CH:13]([NH:31][C:32]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][N:35]=2)=[O:33])[CH2:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Yield: 38 %

Procedure:
Isoquinoline-1-carboxylic acid {6-(benzylamino-methyl)-1-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide, 26, prepared herein above, is treated with TFA in CH3CN/H2O. The solution is then concentrated in vacuo and the resulting residue it purified by preparative reverse phase HPLC to afford 30 mg (38% yield) of the desired product. 1H NMR (CD3OD) δ 9.20–9.17 (d, J=8.7 Hz, 1H), 8.57–8.56 (d, J=5.7 Hz, 1H), 8.06–8.02 (m, 2H), 7.88–7.83 (d, d, d, J=8.1, 6.6, 0.9 Hz, 1H), 7.79–7.73 (d, d, d, J=6.9, 6.9, 0.9 Hz, 1H), 7.64–7.60 (m, 2H), 7.55–7.47 (m, 3H), 6.14 (bs, 1H), 5.56–5.50 (d, d, J=12.3, 3.9 Hz, 1H), 4.85–4.79 (d, d, J=16.2, 1.8 Hz, 1H), 4.66–4.62 (d, d, J=9.0, 3.6 Hz, 1H), 4.39–4.25 (m, 4H), 3.89–3.68 (m, 4H), 2.99–2.93 (m, 1H), 2.74–2.45 (m, 4H), MS 557 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:68][N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1>CN(C=O)C>[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([C:32]([C:29]2[CH:30]=[CH:31][C:19]3[C:18]4[C:23](=[N:24][CH:25]=[CH:26][C:17]=4[NH:16][C:13]4[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:15][CH:14]=4)[NH:22][C:21](=[O:27])[C:20]=3[CH:28]=2)=[O:33])[CH2:71][CH2:70]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
268 (30 mg, 0.07 mmol), DIEA (25 mg, 0.2 mmol), HATU (31 mg, 0.08 mmol), and 1-methylpiperazine (20 mg, 0.2 mmol) were dissolved in DMF (1 mL), and stirred for 3 h at room temperature. The crude product was purified directlyl via HPLC to provide 269 (27 mg, 63% yield) as a solid. LC-MS (M+H=533, obsd.=533).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[N:9]2)=[CH:5][CH:4]=1.C[O-].[Na+].[Cl-].[NH4+:25].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17](=[NH:25])[NH2:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Cn2nc(C#N)c3ccccc32)cc1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cn2nc(C(=N)N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9.25 g of 1-(4-methoxybenzyl)-1H-indazole-3-carbonitrile (1-1-1, 35.1 mmol, 1 eq.) were suspended in 128 ml of dry methanol under a nitrogen atmosphere. 0.949 g (17.6 mmol, 0.5 eq.) of sodium methanolate were added. The reaction mixture was stirred for 18 hours at room temperature. To the resulting mixture were added 2.82 g (52.7 mmol, 1.5 eq.) of ammonium chloride and 1.0 ml (17.6 mmol, 0.5 eq.) of 100% acetic acid and stirred for 5 hours at 50° C. After cooling down at room temperature the mixture was concentrated in vacuo. The residue was partitioned between aq. half saturated sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The aqueous layer was extracted three times with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to yield 6.45 g (23 mmol, 65.5%) of the analytically pure target compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:18]([NH:31]C(=O)OC(C)(C)C)[C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH3:20])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.FC1C=C(C2SC(NC(=O)[O:63][C:64](C)(C)[CH3:65])=NN=2)C=CC=1[N+]([O-])=O.[F:69][C:70]([F:92])([F:91])[C:71]1[CH:76]=[CH:75][C:74]([C@@H:77]([C@H:79]2[CH2:83][O:82][S:81][N:80]2[C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH3:78])=[CH:73][CH:72]=1>>[NH2:31][C@@H:18]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH3:20])[CH2:17][NH:16][C:14]1[S:15][C:11]([C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[NH:8][C:64](=[O:63])[CH2:65]3)=[N:12][N:13]=1.[F:92][C:70]([F:69])([F:91])[C:71]1[CH:76]=[CH:75][C:74]([C@@H:77]([C@H:79]2[CH2:83][O:82][S:81][N:80]2[C:84]([O:86][C:87]([CH3:89])([CH3:88])[CH3:90])=[O:85])[CH3:78])=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)NC(=O)OC(C)(C)C
Agent: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]1COSN1C(=O)OC(C)(C)C
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1

Procedure:
LCMS (API-ES) m/z (%): 448.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.41 (d, J=7.03 Hz, 3H) 2.93-3.02 (m, 1H) 3.26-3.31 (m, 4H) 3.58-3.69 (m, 1H) 6.97 (d, J=8.53 Hz, 1H) 7.51 (d, J=8.03 Hz, 2H) 7.64 (t, J=7.28 Hz, 3H) 7.70 (s, 1H). The title compound was synthesized in a similar manner as Example 2 starting with tert-butyl (2S,3S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-Boc-amino)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate, which was synthesized in a similar manner to described for Example 1 using tert-butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate to react with (S)-tert-butyl 4-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3-oxathiazolidine-3-carboxylate, 2,2-dioxide. (S)-tert-Butyl 4-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3-oxathiazolidine-3-carboxylate, 2,2-dioxide was synthesized as shown in Scheme 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([NH:24]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:1]([O:5][C:6]([N:8]([CH3:16])[C@@H:9]([CH:13]([CH3:14])[CH3:15])[C:10]([O:12][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)[C@@H](C(=O)[O-])N(C)C(=O)OC(C)(C)C
Product: CC(C)[C@@H](C(=O)ONC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate is prepared from (25)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compound exists as rotomers and is reported as such. (1.18 g, 42%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.50-8.11 (1H, m), 4.02-4.94 (1H, m), 3.49-3.50 (3H, m), 2.07-2.41 (1H, m), 1.37-1.55 (18H, m), 0.83-1.17 (6H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([O:24][CH3:25])[CH2:21][CH2:20][CH:19]2[C:26](O)=[O:27])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:40]([O:43][NH2:44])[CH:41]=[CH2:42].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH2:40]([O:43][NH:44][C:26]([CH:19]1[CH2:20][CH2:21][CH:22]([O:24][CH3:25])[CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:17])=[O:27])[CH:41]=[CH2:42]
Reactant: C=CCON
Reactant: COC1CCC(C(=O)O)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCONC(=O)C1CCC(OC)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.9 %

Procedure:
A solution of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid (0.077 g, 0.19 mmol), HOBT (0.044 g, 0.29 mmol), O-allylhydroxylamine hydrochloride (0.043 g, 0.29 mmol), di-isopropylethylamine (0.066 mL, 0.38 mmol) and CH2Cl2 (2 mL) was treated with EDCl (0.056 g, 0.29 mmol). After stirring for 24 h at room temperature, the mixture was diluted with ethyl acetate, washed with 1M HCl, saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo, affording 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid allyloxy-amide (0.090 g, 100%) as a colorless syrup:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH2:11]([Mg]Br)[CH3:12].C1COCC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:11][CH3:12])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(O)c1c(Cl)ncnc1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Charge 4,6-dichloro-pyrimidine-5-carbaldehyde (2.5 g, 1.0 eq) and toluene (50 mL) in a round bottom flask. Cool the reaction mass to −10° C. Add ethyl magnesium bromide (3M) in THF solution (5.1 mL, 1.1 eq) drop wise at −10° C. Slowly allow the reaction mass to come to RT in 1 h. Charge chilled ammonium chloride solution to the reaction mass and extract with diethyl ether. Wash ether layer with saturated aq. sodium chloride solution. Dry the ether layer over anhydrous sodium sulfate and concentrated it under reduced pressure to get the desired product (2.3 g, 79.3%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[O:28].[BH3-]C#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: NCCC(=O)NS(=O)(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(=O)(=O)c4ccccc4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(Trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(phenylsulfonyl)propanamide (1.19 mmol, 1.5 equiv) were dissolved in anhydrous ethanol. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by preparative thin layer chromatography (mobile phase was methanol:dichloromethane 1:10) to give 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamideas a white solid. 284 mg, white solid, 62%. ESI-MS: 523.0 (M+H)+. HPLC: 99.42%. 1H NMR (400 MHz, DMSO-d6) δ: 7.91 (s, 1H), 7.85˜7.82 (m, 2H), 7.74˜7.72 (m, 2H), 7.53˜7.51 (m, 1H), 7.41˜7.35 (m, 4H), 7.20˜7.15 (m, 1H), 4.45˜4.40 (m, 1H), 4.23 (s, 2H), 2.99 (t, 2H), 2.33 (t, 2H), 2.28˜2.16 (m, 2H), 1.89˜1.78 (m, 2H), 1.41˜1.31 (m, 2H), 1.27˜1.17 (m, 2H), 1.13˜1.06 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](CC(N2CCOCC2)=S)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:24]([OH:26])[CH3:25].[OH-:27].[K+].Cl>C(OCC)(=O)C.O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:25][C:24]([OH:27])=[O:26])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCO
Reactant: CCCCCCCCc1ccc(CC(=S)N2CCOCC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
117 g of the 4[2-(4-octylphenyl)-1-thioxoethyl]morpholine was added to 250 ml of ethanol and dissolved therein. 50 ml of water and 46.3 g of potassium hydroxide were added to the obtained solution and the mixture was refluxed for three hours and then allowed to cool to room temperature. Then 10% hydrochloric acid was added thereto by portions until the mixture became acidic. After adding 500 ml of ethyl acetate, the organic layer was washed with water until the aqueous layer became neutral. The organic layer was separated and the solvent was distilled off. To the residue, were added 500 ml of triethylene glycol, 70 ml of water and 77.2 g of potassium hydroxide and the resulting mixture was refluxed for four hours. After allowing to cool to room temperature, 10% hydrochloric acid was added thereto by portions until it became acidic. After adding 500 ml of ethyl acetate, the organic layer was washed with water until the aqueous layer became neutral. The organic layer was separated and dehydrated over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from hexane. Thus 65.5 g of p-octylphenylacetic acid was obtained. Yield: 74%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]=[C:14]=[O:15])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(N=C=O)c(F)cc1Cl

Procedure:
A solution of 4-chloro-2-fluoro-5-isopropoxy-aniline (30 g) in toluene (100 ml) was added to a 1 M phosgene/toluene solution (500 ml) at room temperature (ca. 20° C.), followed by heating under reflux. The mixture was concentrated under reduced pressure, and the residue was distilled to give 26 g of 4-chloro-2-fluoro-5-isopropoxy-phenyl isocyanate as pale yellow crystals. M.P., 36°-37° C. B.P., 90°-91° C./3 mmHg.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[C:14](=[CH:23]/[C:24](/[NH:27][OH:28])=[N:25]\[H])[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:35](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3/[C:14](=[CH:23]/[C:24]4[N:25]=[CH:35][O:28][N:27]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: [H]/N=C(\C=C1c2ccccc2CCc2cc(Cn3c(CCC)nc4ccccc43)ccc21)NO
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1ncon1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
[step 2] To (E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]-N-hydroxyacetamidine (65 mg, 0.149 mmol) obtained in step 1 was added triethyl orthoformate (1 mL), and the mixture was stirred at 80° C. for 2 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 0/100) to give the title compound (compound 9) (28 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][CH2:11][O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC#Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A solution of 2,5-dibromo-pyridine (41, 4.64 g, 19.6 mmol), 3-methoxy-propyne (30, 1.66 mL, 19.7 mmol), and copper(I) iodide (0.084 g, 0.44 mmol) in 61.6 mL of triethylamine was purged with nitrogen, and bis(triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water and brine. The organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (42, 2.64 g).