Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: c1ccc2scnc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2nc3ccccc3s2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To benzothiazole (3.46 g, 25.6 mmol) dissolved in dry THF under a nitrogen atmosphere at −78° C. was added butyl lithium (17.1 mL of 1.5M solution, 1 equiv.) dropwise. The reaction mixture was stirred for 1 h then 1,4-cyclohexanedione mono-ethylene ketal dissolved in dry THF (15 mL) in one portion. The reaction mixture was stirred at −78° C. for a further 3 h then water (10 mL) was added. The mixture was warmed to room temperature and the white precipitate was collected on a filter, washed with water (2×20 mL) then dried under vacuum to give 4-(benzothiazol-2-yl)-1,1-ethylenedioxy-4-hydroxycyclohexane. The yield was 4.403 g (59%); mp 165° C.; 1H NMR (CDCl3) δ 8.05 (1H, m, benzothiazole H-4/7), 7.89 (1H, m, benzothiazole H-4/7), 7.47 (1H, m, benzothiazole H-5/6), 7.39 (1H, m, benzothiazole H-5/6), 4.02 (4H, s, ethylene 2×CH2), 3.16 (1H, s, OH), 2.41–2.31 (4H, m, cyclohexanone 2×CH2), 1.82–1.72 (4H, m, cyclohexanone 2×CH2); IR (KBr disc) 2897, 1501, 1437, 1368, 1038, 997, 764 cm−1; MS (AP+) 292 (M++1), 274 (M++1-H2O); Anal. (C15H17NO3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C@H:14]4[CH2:15][CH2:16][C@H:17]([O:20][CH3:21])[CH2:18][CH2:19]4)[C:10]3=[O:22])=[C:6]([Cl:23])[CH:5]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)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: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](OC)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Mix trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (2.134 g, 4.24 mmol), (4-methoxycarbonylphenyl)boronic acid (0.926 g, 5.09 mmol), tetrakis(triphenylphosphine)palladium(0) (0.490 g, 0.42 mmol) and 6.36 ml of 2M solution of K2CO3 in DME (10 mL). Stir for 12 hours at 80° C. Quench the reaction with water and extract with ethyl acetate. Wash the extract with brine and dry over magnesium sulfate. Purify by flash chromatography to recover 1.68 g (81%) of the title compound: MS (m/z): 490 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1.[C:49]([CH2:51][CH2:52][O:53][C:54](ON1C(=O)CCC1=O)=[O:55])#[N:50]>CC#N.CCOC(C)=O>[C:49]([CH2:51][CH2:52][O:53][C:54]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1)=[O:55])#[N:50]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCN)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOC(=O)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 96.3 %

Procedure:
To a solution of 2′-O-(5-aminopentyl)-5′-O-(4,4′-dimethoxytrityl)-adenosine (1.0 g, 1.52 mmol) in anhydrous CH3CN (8.0 mL) was added with stirring, under argon, N-(2-Cyanoethoxycarbonyl)oxy succinimide (0.43 g, 2.02 mmol) After stirring for 5 h at room temperature the reaction mixture was diluted with EtOAc (50 mL) and washed with aq saturated bicarbonate (3×20 mL) and water (20 mL), dried (Na2SO4) and evaporated to give 53 as a light yellow foam (1.1 g, 98% yield). This compound was used without further purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:26]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])=[N:8][C:6]=2[N:7]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NCCCC)nc2n1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g 2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 15 mL of n-butyl isocyanate is refluxed for 2 hours. The reaction mixture is allowed to cool to room temperature and the insoluble material filtered. The solid is recrystallized several times from ethanol to give the title compound; mp 200-202° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N+:12]([O-])=O.[ClH:15].O>C(O)C.[Pd]>[ClH:15].[ClH:15].[NH2:12][C:3]1[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1nc(C(C)(C)C)c([N+](=O)[O-])c1N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1nc(C(C)(C)C)c(N)c1N
Reaction time: 3 h

Procedure:
A suspension of 8.5 g (0.035 mol) of 5-amino-1-methyl-4-nitro-3-tert-butylpyrazole and 1.5 g of 5% by weight palladium-on-charcoal containing 50% water in 200 cm3 of ethanol was placed in a hydrogenator. After stirring for 3 hours under a hydrogen pressure of 10 bar, at a temperature of 75° C., the reaction medium was poured into a solution, precooled to 0° C., of 60 cm3 of ethanol and 20 cm3 of 12N hydrochloric acid. The solution was clarified by filtration on a sinter funnel and then evaporated to dryness under reduced pressure. The brown solid obtained was taken up, at reflux, in 35 cm3 of 5N hydrochloric ethanol and 11 cm3 of water and then cooled to room temperature. The white crystals obtained were filtered off on a sinter funnel and then dried under vacuum at room temperature. 4.9 g of the expected product were obtained in the form of white crystals, the melting point of which was 260° C. The elemental analysis for C8H10N4.2HCl was:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:27][N:28]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[CH3:29]>>[CH3:27][N:28]([CH3:29])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([O:13][CH:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[N:10]=3)=[CH:21][CH:22]=2)=[O:38])=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)Nc2ccc(-c3nc(OC4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1

Procedure:
1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 4-(N,N-dimethylamino)phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 519.61.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])=[O:27]>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:14](=[O:16])[NH:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
90 g of carbobenzoxy-L-alanine are dissolved in 500 ml of absolute methylene chloride, the solution is cooled to -40° C and treated with 95 g of phosphorus pentachloride. The mixture is stirred at -30° C for 20 minutes and subsequently added to a shaken solution of 52 g of 2-amino-5-nitro-2'-fluorobenzophenone in 250 ml of absolute methylene chloride. The solution is concentrated on a rotary evaporator at 50°-60° C, treated twice with toluene and evaporated each time. By crystallisation of the residue from ether, there is obtained (-)-benzyl-[1-[{2-(o-fluorobenzoyl)-4-nitrophenyl}-carbamoyl]ethyl]carbamate which melts at 158°-160° C and exhibits a rotation of [α]25D =-23.4° (in methylene chloride, 1%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[O:29]1CCC[CH2:30]1>>[F:28][C:26]1[CH:27]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH2:11][CH2:10]3)[C:30](=[O:29])[NH:1]2)=[CH:24][CH:25]=1
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C1CCOC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cc(F)ccc3c2=O)CC1
Yield: 30 %

Procedure:
A mixture of 2.2 parts of 2-amino-4-fluoro-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 1.2 parts of 1,1'-bis[1H-imidazol-1-yl]methanone and 45 parts of tetrahydrofuran is stirred and refluxed for 3 hours. The reaction mixture is cooled and the solvent is evaporated. The residue is boiled in 4-methyl-2-pentanone. The solid product is filtered off and crystallized from N,N-dimethylformamide, yielding 0.8 parts (30%) of 7-fluoro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 248° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=O>C(O)C>[CH3:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=[N:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cc1ccsc1C=O
Solvent: CCO
Product: Cc1ccsc1C=Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 4-nitro-o-aminophenol (15.4 g, 0.1 mole) in 200 ml of ethanol, 3-methyl-2-thiophene carboxaldehyde (12.6 g, 0.1 mole) is added at room temperature. The mixture is allowed to stir for 1 hour and the precipitated yellow Schiff's Base is collected. Crystallization from acetonitrile yields 24.1 g of product, melting point 169°-171°C.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:54]=[CH:53][C:34]([NH:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:43])[CH2:38][CH2:37]3)=[CH:33][CH:32]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:45]([NH:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:34]2[CH:53]=[CH:54][C:31]([O:30][CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:32][CH:33]=2)[CH2:37][CH2:38]1)=[O:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 54.6 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethoxy)anilino]-N-octyl-1-piperidinecarboxamide (0.30 g, 0.377 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.115 g, 0.206 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]C3)=[N:8][CH:9]=1)([O-:3])=[O:2].C1(C2C[S:37]C3C=C(O)C=CC=3O2)C=CC=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[O:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][S:37][C:13]=3[CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Oc1ccc2c(c1)SCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)SCC(c2ccccc2)O3)nc1

Procedure:
5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 269 mg 2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol. The product was recrystallised from ethanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.43 (m, 4H), 7.37-7.41 (m, 1H), 7.02 (d, 1H, J 9.1 Hz), 6.99 (d, 1H, J 8.9 Hz), 6.95 (d, 1H, J 2.8 Hz), 6.82 (dd, 1H, J 8.9, 2.8 Hz), 5.21 (dd, 1H, J 9.7, 1.9 Hz), 3.31 (dd, 1H, 13.2, 9.7 Hz), 3.11 (dd, 1H, 13.2, 1.9 Hz).
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[C:4]#[N:5].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:20]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[C:4]#[N:5])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(NCCCc2ccccc2)ccnc1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(NCCCc2ccccc2)ccnc1N=[N+]=[N-]
Yield: 91.1 %

Procedure:
Prepared according to the methods above using 2-bromo-4-((3-phenylpropyl)amino)nicotinonitrile (43.6 mg, 0.138 mmol), sodium azide (17.93 mg, 0.276 mmol) and ammonium chloride (14.75 mg, 0.276 mmol) in DMF (0.5 mL) at 100° C. for 18 hours to give the desired product as a yellow oil (35 mg). LC/MS (277, [M−H]−). This material was used as is.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:21]=[C:20]([C:22]2[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([Cl:28])=[N:26][CH:27]=2)[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:12][C:13]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][C:25]([Cl:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=3)[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccc(CCl)n1
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and DMF (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. N-{5-[4-amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulphonamide (600 mg, 1.255 mmol) was dissolved in DCM (5 ml) and pyridine (0.122 mL, 1.506 mmol) was added followed by 6-(chloromethyl)-2-pyridinecarbonyl chloride (281 mg, 1.255 mmol) in DCM (5 ml). The reaction was stirred at 0° C. for 1 hr. A further portion of 6-(chloromethyl)-2-pyridinecarbonyl chloride (281 mg, 1.255 mmol) was added and the mixture stirred at 0° C. for 30 mins. The crude mixture was partitioned between saturated aqueous sodium bicarbonate solution (10 ml) and DCM (10 ml). The organic layer was separated using a hydrophobic frit, washed with water (10 ml) and concentrated in vacuo to give an orange solid which was purified by column chromatography (80 g silica RediSep column) eluting with 0-10% MeOH/DCM over 20 column volumes. Separation was incomplete, so all fractions were combined and the solvent was removed in vacuo. The resultant orange solid was re-purified by column chromatography on silica (80 g silica RediSep column) eluting with 50-100% EtOAc/cyclohexane over 40 mins on the ISCO Companion. Fractions containing desired material were combined to afford the title compound as a pale yellow solid (141 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:20])[O:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[N:22]1([C:32](N2C=C[N+](C)=C2)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:8]1[C:9](=[O:20])[O:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([O:19][C:32]([N:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]1)=[O:33])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-benzyl-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=426 (M+1), Rt: 5.34 min.
Reaction SMILES: Br[C:2]1[C:3]([Cl:29])=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([NH:8][CH2:9][CH:10]2[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]3)[CH2:11]2)[CH:7]=1.[Cu][C:31]#[N:32]>CN(C=O)C.[Cl-].[Na+].O>[Cl:29][C:3]1[CH:4]=[C:5]([N+:26]([O-:28])=[O:27])[C:6]([NH:8][CH2:9][CH:10]2[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:13]3)[CH2:11]2)=[CH:7][C:2]=1[C:31]#[N:32]
Reactant: CC(C)(C)CN1CC2(CCCC(CNc3cc(Br)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CN1CC2(CCCC(CNc3cc(C#N)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
A suspension containing 7-(((5-bromo-4-chloro-2-nitrophenyl)amino)methyl)-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.260 g, 0.532 mmol) and copper (I) cyanide (0.333 g, 3.72 mmol) in DMF (2 mL) was subject to microwave heating at 180° C. for 1.5 h. The reaction was cooled to rt, diluted with brine solution, and stirred for 20 min. The mixture was filtered through a pad of celite, and the celite was washed with EtOAc. The combined filtrates were washed with EtOAc. The combined organics were washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified on a 24 g silica gel column (0-75% EtOAc/hexanes, 15 min gradient; 75% EtOAc/hexanes, 10 min; 35 mL/min elution; 254 nm detection) to afford the title compound as an orange solid. MS (m/z) 435.2 (M+H+).
Reaction SMILES: Cl.[C:2]([CH:7]1[CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:17])[N:11]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:20]=[C:10]3[C:9]=2[CH2:8]1)([O:4][CH2:5][CH3:6])=[O:3].[CH3:28]C(O)C>>[C:2]([CH:7]1[CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:17])[N:11]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:20]=[C:10]3[C:9]=2[CH2:8]1)([O:4][CH:5]([CH3:28])[CH3:6])=[O:3]
Reactant: CC(C)O
Reactant: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Agent: Cl
Product: CC(C)OC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 150 °C

Procedure:
To 10 mL of 2-propanol saturated with HCl gas was added 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (100 mg) and the mixture was heated in a sealed tube at 150° C. for 1 h. The reaction was cooled and the solvent was evaporated in vacuo. To the reaction mixture was added 10 mL of H2O and the mixture was then brought to pH 7 with ammonium hydroxide. The solid was collected and dried to yield 9-Carboisopropoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydroimidazo[1,2-c]-quinazolin-5(6H)-one (Compound 14), m.p. 282°-285° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:26])=[O:25]
Reactant: CCCCCCCC(=O)NCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCOS(C)(=O)=O
Yield: 105.7 %

Procedure:
To a solution of 2.00 g (8.22 mmol) of N-(4-hydroxybutyl)caprylamide and 1.37 ml (9.86 mmol) of triethylamine in 50 ml of methylene chloride was added 0.76 ml (9.86 mmol) of methanesulfonyl chloride under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.55 g of the desired compound (96.5%, colorless powder), mp: 59.0°-60.0° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:4]2[CH:3]=[C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C)CC1
Product: COC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C)CC1
Temperature: 70 °C
Yield: 92.5 %

Procedure:
The methyl 4-fluoro-2-(1-methylpiperidin-4-yloxy)benzoate (10.6 g, 40 mmol) was mixed with pyrrolidine (14 g, 200 mmol) and heated at 70° C. for 3 hours, then heated at 100° C. for 1 hour before concentrating under vacuum. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (100 mL). The combined organic layer was dried over MgSO4 and concentrated to 12.5 g of an oil which was purified by flash chromatography, using THF/Hex/Et3 N 20/75/5 then 40/55/5 and finally 60/35/5, to give 11.9 g (37 mmol, 93%) of the desired product as an oil.