Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]([F:27])([F:26])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.C(N(CC)CC)C.O1CCOCC1>O>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]([F:27])([F:16])[F:26])[CH2:20][CH2:21]1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC2CCN(CC(F)(F)F)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
4-chloro-3-nitrobenzenesulfonamide (1.300 g), 1-(2,2,2-trifluoro ethyl)piperidin-4-amine hydrochloride (1.201 g), and triethylamine (2.30 mL) were added to 1,4-dioxane (50 mL) and water (5 mL) and heated at 90° C. for 16 hours. The solution was concentrated on vacuum and purified by flash column chromatography on silica gel with ethyl acetate increasing to 5% methanol in ethyl acetate.
Reaction SMILES: CS(O[C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:9][O:8][CH2:7]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([C@H:6]1[C@@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:9][O:8][CH2:7]1)=[N+:20]=[N-:21]
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1
Temperature: 110 °C

Procedure:
To a solution of trans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate (133.2 g, 0.395 mol) in dimethylformamide (3 L) was added sodium azide (192.6 g, 2.96 mol) and the reaction was heated at 110° C. for 66 hours. The reaction was cooled to room temperature and water (12 L) was added. This reaction was carried out a total of three times on the same scale, and the combined batches were extracted with tert-butyl methyl ether. The organic layers were then dried over sodium sulfate and concentrated in vacuo to afford product as a red-brown oil, contaminated with 18% dimethylformamide. Corrected yield: 286.7 g, 1.01 mol, 85%. 1H NMR (400 MHz, CDCl3) δ 3.93-3.97 (m, 2H), 4.00 (m, 1H), 4.09 (dd, J=8.7, 5.8 Hz, 1H), 4.17 (dd, J=10.0, 5.6 Hz, 1H), 4.90 (ddd, J=5.4, 5.4, 4.4 Hz, 1H), 6.83 (d, J=9.1 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 71 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methyl phenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 71%). 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.18-3.21 (m, 4H), 3.75-3.79 (m, 4H), 4.14 (s, 3H), 6.75-6.78 (m, 4H), 7.32 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:17][C:18]([O:21][C:22]([N:24]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:25]([C:33]1[C:38]([F:39])=[C:37](Cl)[N:36]=[C:35]([Cl:41])[N:34]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:20][C:18]([O:21][C:22]([N:24]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:25]([C:33]1[C:38]([F:39])=[C:37]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:36]=[C:35]([Cl:41])[N:34]=1)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[O:23])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: NC1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCOCC2)c1F
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of commercially available tetrahydro-2H-pyran-4-amine (0.122 g, 1.21 mmol) in DMF (6 mL) was cooled to 0° C. Then diisopropylethylamine (0.24 mL, 1.33 mmol) and tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.600 g, 1.21 mmol) were added. The resulting solution was left to reach room temperature and stir overnight. The mixture was extracted with ether and washed with water, and the resulting aqueous layer was extracted once with ether. The combined ether layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was purified by silica gel chromatography with (5-60% ethyl acetate in hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate as a white solid (0.602 g, 89%). LCMS: (M+H−2Boc)+=362.1.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][CH3:15])[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O>[C:1]([NH:4][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][CH3:15])[CH:8]=1)[C:16]([O:18][CH2:27][CH:26]=[CH2:25])=[O:17])(=[O:3])[CH3:2]
Reactant: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(Cc1ccc(N)c(CC)c1)NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A mixture of N-acetyl-4-amino-3-ethylphenylalanine (2.0 g, 8.0 mmol), Cs2CO3 (2.61 g, 8.0 mmol) and allyl bromide (692 μL, 8.0 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 3 hours, concentrated under reduce pressure and partitioned between ethyl acetate and water (100 mL, 1:1). The organic phase was washed with brine (1×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by on silica gel with ethyl acetate/hexane (5:3) to provide titled compound (1.44 g). MS (ESI(+)) m/e 291 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, 1H), 6.77-6.70 (m, 2H), 6.50 (d, 1H), 5.90-5.76 (m, 1H), 5.30-5.15 (m, 2H), 4.67 (s, 2H), 4.54-4.50 (m, 2H), 4.38-4.30 (m, 1H), 2.77(dddd, 2H), 2.39 (q, 2H), 1.80 (s, 3H), 1.10 (t, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](N)[CH2:9][NH2:10].C=O>C(Cl)Cl>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:8][CH2:9][NH:10]1
Reactant: Oc1ccccc1
Reactant: NCCN
Agent: C=O
Solvent: ClCCl
Product: c1ccc2c(c1)CCNO2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts methylene chloride and 144 parts of ethylene diamine. The temperature of the reaction mixture is adjusted to 25° C. and 595 parts of 50% formalin is added while maintaining the temperature below 30° C. The reaction mixture is stirred for 2 hours at 30° C. after formaldehyde addition is complete. It is then heated to atmospheric reflux, refluxed for 3 hours and allowed to cool and separate into two layers. The upper water layer is withdrawn and discarded. The lower organic layer is reheated to atmospheric reflux and distilled to remove solvent. Heating is continued with the gradual reduction of pressure until a temperature of 70° C. at about 5.0 kPa pressure is reached. Cellosolve (460 parts) is added to the resin slowly, keeping the temperature near 70° C. A uniform yellow solution forms which is cooled and filtered. The product has 66% closed dihydroxybenzoxazine ring and a calculated equivalent wt. of 224. The solution has a solids content of 60.2%.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O.CN1CCN(C)C1=O.O1CCCC1.[ClH:36]>CO>[ClH:36].[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][NH:5][CH2:3][C@@H:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:1])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=C(NCCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: O=[N+]([O-])c1ccc(CCNC[C@H](O)c2ccccc2)cc1
Temperature: -18 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
A mixture of 7.51 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, 23 liters of 1,3-dimethyl-2-imidazolidinone and 23 liters of tetrahydrofuran was cooled at −18° C. and 49.4 kg of 1 M boran-tetrahydrofuran solution was dropped thereinto at not higher than −7° C. After that, temperature of the mixture was raised to 70° C. followed by stirring for 5 hours. The reaction mixture was cooled at −12° C. and 2.9 kg of methanol and 5.9 kg of concentrated hydrochloric acid were added thereto at not higher than 5° C. After stirring at 68° C. for 1 hour, the mixture was concentrated in vacuo until the amount became 50 liters. A 30% aqueous solution (60 kg) of K2CO3 and 6 liters of water were added thereto followed by extracting with 75 liters of ethyl acetate. The organic layer was washed with 75 liters of water and concentrated in vacuo. Isopropanol (75 liters) was added to the residue, the mixture was dissolved at 40° C. and 2.46 kg of concentrated hydrochloric acid was added to crystallize followed by stirring at 23° C. throughout one night. The crystals were filtered and washed with 38 liters of isopropanol. They were dried in vacuo to give 7.29 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccn1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 49 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine (100 mg, 0.24 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.74 mmol, 0.74 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.26 mmol, 38 mg). After 16 h, filtration of the precipitate, washing with cold water (1 mL) and trituration with Et2O gave the product (61 mg, 49%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.58 (br s, 3H, CHCH3), 2.44-2.58 (2 m, 4H, piperazine N(CH2)2), 3.01 (s, 6H, N(CH3)2), 3.72-3.90 (br s, 5H, piperazine N(CH2)2 & CHCH3), 6.83 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 7.43 (br, 1H, pyridine H-5 or H-3), 7.52 (s, br, 1H, pyridine H-3 or H-5), 7.91-7.98 (m, 1H, pyridine H-4), 8.00 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.70 (br, 1H, pyridine H-6), 13.20 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH2:3][CH2:4][OH:5].[H-].[Na+].BrO.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.CN(C)[CH:25]=[O:26]>CO>[CH3:1][CH:2]([CH2:6][CH3:7])[CH2:3][CH2:4][O:5][CH2:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:25][OH:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(C)CCO
Reactant: CN(C)C=O
Agent: OBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)CCOCCCCCCCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.67 gms of 3-methyl pentanol in 40 ml of dimethylformamide, 0.62 gms of sodium hydride are added; and the reaction mixture is stirred at room temperature for 1 hour. To this solution is added 4.0 gms of the protected bromo-alcohol and the reaction mixture is stirred at room temperature for 17 hours. The reaction mixture is then partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give a yellow liquid. To a solution of 4.0 gms of this liquid in 240 ml of methanol is added 0.40 gms of p-toluenesulfonic acid and the reaction is stirred at room temperature for 16 hours. The methanol is removed under reduced pressure, and the residue is partitioned between ethyl acetate and water. The organic layer is washed with aqueous NaHCO3 and brine, then dried over Na2SO4, filtered, and concentrated under vacuum to give 8-(3-methylpentyloxy)octanol.
Reaction SMILES: [CH2:1](C1(N2C=CC=N2)C=C(C)C=CC1)CC#C.C(C1(N2C=CC=N2)C=CC=C(C)C1)CC#C.C[C:34]1[N:38]([CH2:39][CH2:40][C:41]#[C:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:37]=[CH:36][C:35]=1[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:1][C:36]1[C:35]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[CH:34][N:38]([CH2:39][CH2:40][C:41]#[C:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:37]=1
Reactant: Cc1c(-c2ccccc2)cnn1CCC#Cc1ccccn1
Reactant: C#CCCC1(n2cccn2)C=C(C)C=CC1
Agent: C#CCCC1(n2cccn2)C=CC=C(C)C1
Product: Cc1nn(CCC#Cc2ccccn2)cc1-c1ccccc1
Yield: 10 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 1, from 255 mg (1.21 mmol) of 1-but-3-ynyl-5-methylphenyl-1H-pyrazole and 1-but-3-ynyl-3-methylphenyl-1H-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 33 mg (0.11 mmol, 10%) of 2-(4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine and 2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a orange oil.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1>C(Cl)Cl>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38]([NH:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1)=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: NC1(CO)CC1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl) methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCc1ccc(F)cc1
Product: O=C(NCCc1ccc(F)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 4-fluorophenethylamine (68 mg, 0.49 mmol). The title compound was obtained as a solid (50 mg, 26% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, s), 8.93 (1H, m), 8.39 (1H, s), 37.23 (2H, dd), 7.10 (2H, dd), 3.41 (2H, m), 2.77 (2H, m). MS m/z: 470.04, 472.03 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.Cl>O.C(OCC)(=O)C.CN(C)C=O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrCC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnc2ccccc2n1CC1OCCO1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To 20 mL of an N,N-dimethylformamide suspension containing 2.0 g of quinoxalin-2(1H)-one, 0.82 g of 60% sodium hydride was dividedly added at room temperature, and the mixture was stirred at 40° C. for 15 minutes. Thereto was added 2.1 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 60° C. for 30 minutes, and stirred at 110 to 120° C. for 1 hour. Thereto was added 2.1 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 110 to 120° C. for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the resultant solution was adjusted to pH 2.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 1:2] to obtain 1.5 g of a light brown oily substance, 1-(1,3-dioxolan-2-ylmethyl)quinoxalin-2(1H)-one.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:7][C:6]1[CH:8]=[CH:2][C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)=[CH:4][C:5]=1[F:9]
Reactant: Nc1cc(Cl)c(CC2CCNCC2)cc1F
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 99.6 %

Procedure:
5-Chloro-2-fluoro-4-(piperidin-4-ylmethyl)aniline (1.730 mmol, 420 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.730 mmol, 583 mg) and potassium carbonate (3.46 mmol, 478 mg) were combined and stirred at room temperature in acetonitrile (20 mL) for 2 hours. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by SCX chromatography to afford the title compound (800 mg). MS (ESI) m/z 499.5 [M+H]+
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C([Sn](=O)CCCC)CCC.[F:18][C:19]1[CH:20]=[C:21]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:22]=[CH:23][C:24]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]#[N:32])[CH2:27][CH:26]=1.CO>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:22]=[CH:23][C:24]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]2[NH:32][N:3]=[N:2][N:1]=2)[CH2:27][CH:26]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C#N)CC3)c(F)c2)C(=O)O1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4nnn[nH]4)CC3)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Azidotrimethylsilane (154 mg) and dibutyltin oxide (97 mg) were added to a stirred suspension of Example 24 (240 mg) in dry toluene (10 ml), and the mixture stirred at 70° C. for 18 hours. On cooling, methanol (5 ml) was added and after stirring for 10 minutes the solvent was evaporated. The title compound was isolated by MPLC (20% MeOH/CH2Cl2. Merck 9385 silica) and crystallised on evaporating the fractions to a small volume. The title product was filtered off washed with a little cold methanol (150 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1.Cl.N1C=CC=CC=1.[K+].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH:20][C:19]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COc1ccnc(C=O)c1
Reactant: COC(=O)CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cc(OC)ccn1
Temperature: 120 °C

Procedure:
A mixture of 45 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem.Pharm.Bull. 38, 2446-2458 (1990)), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are slowly heated, with stirring, to 120° C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120° C. for a further 2.5 hours, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2:1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m.p. of 80-82° C. The mass spectrum shows the molecular peak MH+ at 194 Da.
Reaction SMILES: Cl[CH2:2]CCC(Cl)=O.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([F:39])[CH:33]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([NH:36][C:35]1[CH:37]=[CH:38][C:32]([O:31][C:22]2[C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)[N:25]=[CH:24][CH:2]=2)=[CH:33][C:34]=1[F:39])=[S:16])=[O:13]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(Cl)CCCCl
Agent: O=C(CCCCl)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCCCl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
4-Chlorobutanoyl isothiocyanate was prepared using commercially available 4-chlorobutanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Chlorobutanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 67%).