Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.[C:38](Cl)(Cl)=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:38](=[O:39])[NH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:29])([CH3:30])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=O)NN)cc3Cl)nc2O1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4n[nH]c(=O)o4)cc3Cl)nc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step C (22 mmol) in 10 mL of CH2Cl2 at −78° C. was added 300 μL of phosgene (20% in toluene). After stirring at −78° C. for 15 min and at 0° C. for 30 min, the reaction mixture was concentrated. Chromatography on a Biotage 40+S cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.86 (t, J=12.2, 1H), 2.27 (m, 1H), 5.50 (m, 1H), 5.87 (m, 1H), 6.99 (d, J=8.0, 2H), 7.17 (d, J=8.0, 2H), 7.39 (m, 1H), 7.58-7.72 (m, 3H), 9.87 (br. s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:50](SC)(=[NH:52])[CH3:51]>O>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:50](=[NH:52])[CH3:51])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CSC(C)=N
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=N)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of DMF were added 58 mg of sodium carbonate and 119 mg of methyl ethanimidothioate hydrochloride, followed by stirring at 60° C. for 1 hour. Thereafter, while stirring at 60° C., 233 mg of sodium carbonate and 478 mg of methyl ethanimidothioate hydrochloride were further added in four divided portions every 1 hour. After cooling the reaction solution, water was added thereto, followed by extraction with chloroform-isopropyl alcohol (5:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-aqueous ammonia) and then crystallized with ethyl acetate to obtain 113 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(ethanimidoylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1.[Br:22]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:22][C:17]1[S:16][C:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH:2]([CH3:1])[O:3][C:4]=2[C:18]=1[CH:19]([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C(C)C)c2O1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC1CN(C(=O)OC(C)(C)C)Cc2sc(Br)c(C(C)C)c2O1
Yield: 83.3 %

Procedure:
A solution of tert-butyl 2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (763 mg) obtained in Example 10, steps 1 and 2, N-bromosuccinimide (458 mg) and acetonitrile (6 mL) was stirred at room temperature for 2 hr, 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (797 mg, 83%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH4+:14].[OH-]>C(Cl)Cl>[OH:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:14])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)cc(Cl)c1O
Yield: 71 %

Procedure:
A solution of 39.16 g of the product from Example 3 in 100 ml CH2Cl2 was contacted with 250 ml of 28% NH4OH at 5°-8° C. Following removal of CH2Cl2 by a N2 sparge the mixture was acidified to pH 3. Filtration afforded 42.7 g of 61% pure 2-hydroxy-3,5-dichlorobenzenesulfonamide (D) (71% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Li]CCCC.[C:18](=[O:20])=[O:19]>CCOCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500 mL three-neck flask fitted with magnetic stirrer, nitrogen lines and a 125 mL addition funnel was charged with 200 mL of dry ether (newly opened can) and 6-bromo-2-naphthol (15.6 g, 70 mmol). The atmosphere was replaced with nitrogen and a solution of 15 mL of 10M n-BuLi in 100 mL of ether (150 mmol) was added via the addition funnel over a 30 minute period. The solution became pale yellow with a precipitate. After stirring for 20 minutes more, dry ice was added until the solution became quite cold (<-25° C.) and green in color. The solution was warmed to room temperature and quenched by the addition of 200 mL of water. The two-phase system was transferred to a separatory funnel, the layers separated and the ether solution extracted with 100 mL of saturated NaHCO3 solution. The combined aqueous layers were washed with 100 mL of ether and neutralized by careful addition of 12N HCl. The pale blue solid was filtered and dried in the air to give 10.3 g (76%): mp 238-241° C. (dec.); lit. mp 240°-241° C.; reference: S. V. Sunthankar and H. Gilman, J. Org. Chem., 16, 8 (1951). ##STR26##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH:12]1([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:12]1([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:7]3[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=3[F:1])=[CH:22][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3CCCCC3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.4 %

Procedure:
Following procedure A, 3,4-difluoronitrobenzene (509 mg, 3.20 mmol, 1.00 eq) and 4-cyclohexylphenol (691 mg, 3.93 mmol, 1.23 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (664 mg, 4.81 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 23 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as pale yellow solid (1002 mg, 3.18 mmol, 99% yield). Rf=0.51 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C18H19FNO3+ [M+H]+ 316.1343. found: 316.1348. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=10.3, 2.7 Hz, 1H, aromatic H), 7.97 (ddd, J=9.1, 2.7, 1.4 Hz, 1H, aromatic H), 7.33-7.22 (m, 2H, aromatic H), 7.08-6.99 (m, 2H, aromatic H), 6.96 (dd, J=9.1, 8.0 Hz, 1H, aromatic H), 2.58-251 (m, 1H, cyclohexyl H), 1.98-1.73 (m, 5H, cyclohexyl H), 1.52-1.20 (m, 5H, cyclohexyl H). 13C NMR (101 MHz, CDCl3) δ 153.35, 152.51, 152.01, 151.90, 150.84, 145.68, 142.39, 142.32, 128.67, 120.70, 120.66, 119.73, 117.70, 117.68, 113.30, 113.08, 44.09, 34.69, 26.97, 26.21.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CNCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a mixture of 4-(4-(trifluoromethyl)phenoxy)benzaldehyde (1.4 g, 5.2 mmol) in anhydrous dichloroethane (10 mL), at room temperature under nitrogen, was added (4-fluorophenyl)methanamine (0.6 mL, 52 mmol). The mixture was stirred for 3 minutes before acetic acid (0.42 mL, 7.3 mmol) was added dropwise via syringe. After an additional 30 minutes, sodium triacetoxyborohydride (1.6 g, 7.3 mmol) was added to the reaction mixture. After 20 h, the reaction was quenched with 1 N aqueous NaOH (30 mL) then extracted with chloroform. The organic extracts were combined, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCO system, eluting with 0-5% MeOH in CHCl3) to afford the desired compound (0.51 g, 24%) as a colorless oil. MS (ESI): 376.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[CH:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:12][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[CH:16]=[C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a mixture of 4-methoxyphenylboronic acid (1.57 g, 10.36 mmole) and tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (2.5 g, 8.6 mmole) in dichloromethane (75 mL) were added copper acetate (1.63 g, 8.6 mmole), triethyl amine (5.219 g, 51.6 mmol) and molecular sieves. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite pad. The filtrate was evaporated and purified by column chromatography to give the title compound (1.1 g, 32%). 1H NMR (500 MHz, CDCl3): δ ppm 7.26 (t, 1H), 6.99 (d, 2H), 6.89 (t, 3H), 6.79 (t, 2H), 6.29 (s, 1H), 3.80 (s, 3H), 3.48 (s, 2H), 3.38 (s, 2H), 2.42 (s, 2H), 2.29 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccccc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
A mixture of ethyl 7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (141 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give 5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield: 9%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.34 (s, 3H), 4.65 (d, J=8.0 Hz, 1H), 4.94 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.88-7.02 (m, 2H), 7.18 (dd, 1H), 7.28-7.29 (m, 3H), 7.34-7.36 (m, 2H); 19F-NMR (400 MHz, CD3OD) δ: −105.70 (s); LC-MS (ESI) m/z: 362 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([I:13])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]([I:13])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:1]
Reactant: COC(=O)c1cc(I)cc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(I)cc(C=O)c1
Yield: 55.8 %

Procedure:
The mixture of methyl 5-hydroxymethyl-3-iodobenzoate (5.0 g) and manganese dioxide (30.0 g) in ethyl acetate (50.0 ml) was heated under reflux for 4 hours. The magnganese dioxide was removed by filtration and the filtrate was evaporated in vacuo to give methyl 5-formyl-3-iodobenzoate (2.77 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:23])[C:20]=1[O:21][CH3:22])[C:15](O)=[O:16].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[C:19]([Cl:23])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1c(Cl)cc(C(=O)O)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CCOc3ccncc32)cc1Cl
Reaction time: 12 h
Yield: 54.4 %

Procedure:
To a mixture of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (80 mg, 0.58 mmol) and 3,5-dichloro-4-methoxy-benzoic acid (141 mg, 0.64 mmol), phosphorus oxychloride (4 ml) was added and then stirred at 100□ for 12 hours. The reaction mixture was cooled to 0□ and adjusted to pH of 8-9 by using saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=4:1. The fractions containing the product were collected and evaporated to obtain white solid (107 mg, 54%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:19]1[C:26](Cl)=[N:25][C:23]([Cl:24])=[N:22][C:20]=1[Cl:21]>O1CCCC1>[Cl:21][C:20]1[N:22]=[C:23]([Cl:24])[N:25]=[C:26]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])[N:19]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1nc(Cl)nc(Cl)n1
Temperature: 65 °C

Procedure:
2.7 g of magnesium was added to 200 ml of tetrahydrofuran and stirred until the magnesium was completely dissolved. To the solution was added dropwise a solution of bromohexadecane (31.1 g) in tetrahydrofuran (200 ml). Thereafter, the resulting solution was heated to 65° C. and reacted for 6 hours with stirring. The reaction solution was slowly added dropwise to a solution of cyanuric chloride (15 g) in tetrahydrofuran (250 ml), and reacted for 12 hours. After completion of the reaction, the resulting solution was evaporated under reduced pressure to obtain a concentrate and then the concentrate was purified by distillation in vacuo to yield pure 2,4-dichloro-6-hexadecyl-1,3,5-triazine.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:15]2([CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16]2)[C:14](=[O:22])[NH:13][CH:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[C:15]2([CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16]2)[C:14](=[O:22])[N:13]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:12]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(F)cc2)NC(=O)C12COCCOC2
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28 mg (0.66 mmol) sodium hydride were added to 0.23 g (0.6 mmol) tert-butyl-3-(4-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml DMF. After 5 min at RT 64 μl (0.91 mmol) methyl bromoacetate were added dropwise and then the reaction mixture was stirred for 1 h at RT. The reaction was poured onto ice water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[F:42][C:43]([F:48])([F:47])[CH2:44][CH2:45]I>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:45][CH2:44][C:43]([F:48])([F:47])[F:42])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: FC(F)(F)CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 26.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 1,1,1-trifluoro-3-iodopropane (0.117 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.061 g (25%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:9]=[N:10][C:11]=4[CH3:27])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CC3)cn2)cn1
Yield: 38 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (65 mg, 0.178 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (27 mg, 38%) which was obtained as an off white solid. MS: m/e=404.2 [M+H]+.
Reaction SMILES: CO[C:3]1[S:4][CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[N:7]=1.C(=O)(O)[O-].[Na+].O=P(Cl)(Cl)[Cl:23]>O>[Cl:23][C:3]1[S:4][CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[N:7]=1
Reactant: COc1nc(-c2sccc2[N+](=O)[O-])cs1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccsc1-c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-4-(3-nitrothiophen-2-yl)thiazole (403 mg, 1.66 mmol) in POCl3 (2 mL) was heated at 60° C. for 1 h then to 100° C. for a further 2 h. The resulting solution was cooled to room temperature and diluted with cold H2O then saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to give 2-chloro-4-(3-nitrothiophen-2-yl)thiazole. Retention time (min)=2.550, method [1], MS(ESI) 246.9 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
p-Hydroxytoluene (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.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:1][C:2]1[CH:3]=[C:4]2[C:10]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3cc(Br)cnc32)cc1
Yield: 111.5 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.147 mmol), 4-fluorophenylboronic acid (25 mg, 0.176 mmol) and dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.015 mmol) were combined in CH3CN (2 ml) and 1 M Na2CO3 (2 ml) and stirred at 60° C. for 3 hrs. EtOAc was added and the mixture was washed with water, dried and evaporated to yield 73 mg (112%) of the title compound. MS ESI (m/z): 445.1/447.2 (M+1)+, calc. 444/446.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9][CH2:8]1.[N+:18]([O-])([OH:20])=[O:19]>>[CH3:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)[NH:10][CH2:9][CH2:8]1
Reactant: CC1(C)CCNc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
To 13 ml of H2SO4 (96%) cooled in a salt ice bath was added dropwise 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (5.80 g, 36.0 mmol). The resulting slurry was stirred for 30 min, upon when concomitant addition of HNO3 (90%, 1.70 ml, 36.0 mmol) and H2SO4 (96%, 7 ml) was started, the addition was finished in 20 min, the mixture was stirred at 0° C. to 15° C. for 2 h, poured into ice, and extracted with EtOAc. The organic portion was washed with brine, condensed, and purified by flash column chromatography (0 to 10% of EtOAc in hexanes). The titled compound was obtained as a yellow oil. MS (ES+): 206.9 (M+H)+. Calc'd for C11H14N2O2—206.24.