Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>CN(C=O)C.C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[S:32]([CH3:31])(=[O:34])=[O:33])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1S(C)(=O)=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N2, the suspension was cooled down to −15° C. and a solution of methanesulfonyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 min at −15° C. then for 6 h at room temperature. Water (0.5 mL) was added at 0° C., solvent was removed, and the residue was diluted with MeOH, filtrated and purified by preparative HPLC to give 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(methylsulfonyl)-1H-indol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO) δ 11.6 (s, 1H), 8.7 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.33 (dd, J1=1.9 Hz, J2=8.7 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.95 (dd, J1=1.7 Hz, J2=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.02 (s, 2H), 3.07 (s, 3H), 1.56-1.40 (m, 9H), 1.41 (dd, J1=4.0 Hz, J2=6.7 Hz, 2H), 1.03 (dd, J1=4.0 Hz, J2=6.7 Hz, 2H). MS (ESI) m/e (M+H+) 455.5.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15]Cl.O>CC(C)CC(=O)C>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: c1cn[nH]c1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(Cn1cccn1)c1ccc(F)cc1F
Yield: 77.9 %

Procedure:
A mixture of 1H-pyrazole (1.3 mol) in 4-methyl-2-pentanone (500 ml) was stirred and refluxed. 1-(2,4-difluorophenyl)-2-chloroethanone (0.26 mol) dissolved in 4-methyl-2-pentanone (500 ml) was added dropwise and the mixture was stirred and refluxed for 3 h. The mixture was cooled, poured into water and separated. The organic layer was evaporated. The residue was stirred up in HCl/water, filtered off and washed with water. The precipitate was stirred up in hexane, filtered off and dried in vacuo at 45° C., yielding 45 g (78%) of 1-(2,4-difluorophenyl)-2-(1H-pyrazol-1-yl)ethanone; mp. 76.4° C. (interm. 12).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([CH3:41])[CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[C:39]([CH3:41])[CH:40]=[C:35]([CH3:34])[CH:36]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)cc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg (0.36 mmol) in dichloromethane (6 ml) was added 3,5-dimethylbenzene-1-sulfonyl chloride (0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 25 mg (33.33%); 1H NMR (CDCl3, 300 MHz): δ 9.58 (s, 1H), 7.957-7.987 (d, 1H, J=9 Hz), 7.79 (s, 2H), 7.699-7.727 (d, 2H, J=8.4 Hz), 7.605-7.642 (dd, 1H, J=9 Hz, 2.1 Hz), 7.425-7.453 (d, 2H, J=8.4 Hz), 7.29 (s, 1H), 6.96 (d, 1H, J=1.8 Hz), 2.36 (s, 6H), 1.79 (s, 6H); MS: m/z 575 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][O:6][C@:7]12[C@@H:20]3[N:21]([CH3:24])[CH2:22][CH2:23][C@:12]41[C:13]1[C:14]([O:26][C@H:11]4[C:10](=[O:27])[CH2:9][CH2:8]2)=[C:15]([OH:25])[CH:16]=[CH:17][C:18]=1[CH2:19]3.C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[C:38]#[CH:39]>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][O:6][C@:7]12[C@@H:20]3[N:21]([CH3:24])[CH2:22][CH2:23][C@:12]41[C:13]1[C:14]([O:26][C@H:11]4[C:10](=[O:27])[CH2:9][CH2:8]2)=[C:15]([O:25][CH2:39][C:38]#[CH:37])[CH:16]=[CH:17][C:18]=1[CH2:19]3
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCc2cccc(Cl)c2)[C@H]1C5
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCc5cccc(Cl)c5)[C@@H](C2)N(C)CC[C@]314
Product: Cl

Procedure:
A mixture of unpurified 14β-[(3-chlorobenzyl)oxy]-4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one (500 mg of brown foamy resin), K2CO3 (485 mg, 3.51 mmol) and propargylbromide (0.26 ml, 3.51 mmol) and 40 ml acetone (with 0.5% H2O) was reflux heated under N2 for 3 h. After cooling the inorganic material was filtered off, washed with CH2Cl2 and the filtrate evaporated down. The evaporation residue (538 mg of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH (250:2:0.5)). The evaporation residue (337 mg of yellow oil) was dissolved in ether and 18.HCl was precipitated as a pure substance by the addition of etherial HCl. Yield: 347 mg (74%). Fp. 145-150° C.; IR (KBr): 1717 (CO), 2118 (C═C) cm−1; 1H-NMR (DMSO-d6): δ 9.21 (s, wide, +NH), 7.71-7.32 (m, 4 arom. H), 6.96 (d, 1 arom. H, J=8.4 Hz), 6.82 (d, 1 arom. H, J=8.4 Hz), 5.20 (s, C5—H), 4.89 (d, 1H, C14OCH2, J=12.1 Hz), 4.69 (d, 1H, C14OCH2, J=12.1 Hz), 4.84 (d, 2H, C3OCH2, J=2.2 Hz), 3.58 (t, 1H, C═CH, J=2.2 Hz), 2.94 (d, +NCH3, J=4.4 Hz); MS (CI): m/z 465 (M++1).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8][CH2:9]C2C=CC=CC=2)[CH:6](OCC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33].[CH2:34]([N:37]=C=S)[CH2:35][CH3:36].CI.C([O-])(O)=[O:43].[Na+]>C1COCC1>[OH:25][CH2:24][CH:5]1[CH:4]([OH:43])[CH:3]([OH:33])[CH:2]2[N:1]=[C:9]([NH:37][CH2:34][CH2:35][CH3:36])[O:8][CH:7]2[CH2:6]1
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCCN=C=S
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCNC1=NC2C(CC(CO)C(O)C2O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of Intermediate B (151 mg, 0.338 mmol) in dry THF (4 mL) was added a solution of propyl isothiocyanate (42.6 mg, 0.422 mmol) in dry THF (1 mL). The mixture was stirred at room temperature for 16 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (96 mg, 0.676 mmol) was added. The mixture was stirred at room temperature for 5 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give the aminooxazoline (112 mg, 64%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.38-7.24 (m, 15H), 4.84 (d, J=11.5 Hz, 1H), 4.79-4.75 (m, 1H), 4.77 (d, J=11.2 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.45 (d, J=11.2 Hz, 1H), 4.45 (s, 2H), 4.05 (dd, J=7.9, 5.4 Hz, 1H), 3.64 (t, J=5.9 Hz, 1H), 3.56 (dd, J=9.0, 5.2 Hz, 1H), 3.52-3.46 (m, 2H), 3.21-3.08 (m, 2H), 2.17 (dt, J=14.9, 3.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.87 (ddd, J=15.4, 12.1, 3.7 Hz, 1H), 1.54 (sextuplet, J=7.3 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([P:8]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:11])[O:9]C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CCCCCC>[F:7][C:2]([P:8]([C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])[O-:11])([F:1])[C:3]([F:6])([F:5])[F:4].[CH3:19][N+:20]1[CH:24]=[CH:23][N:22]([CH3:2])[CH:21]=1
Reactant: Cn1ccnc1
Reactant: COP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CCCCCC
Product: Cn1cc[n+](C)c1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (1.870 g; 5.9 mmol) is slowly added dropwise to cooled (0° C.) N-methylimidazole (0.424 g; 5.2 mmol) (exothermic) in a 25 ml glass flask. A white solid forms. The reaction mixture is diluted with 3.5 ml of n-hexane, warmed to room temperature and stirred for 30 min. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature. 1,3-Dimethylimidazolium bis(pentafluoroethyl)phosphinate, [MMIM][(C2F5)2P(O)O], (1.982 g; 5.0 mmol) is isolated as white solid in a yield of 96% and a purity of 97%. The isolated product is characterised by means of 1H, 19F and 31P NMR spectra in CD3CN.
Reaction SMILES: [Na].[OH:2][CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].CN1CCN(C)C1=O.[CH:17]1([N:20]2[C:25]3[CH:26]=[C:27]([F:31])[C:28]([F:30])=[CH:29][C:24]=3C(=O)O[C:21]2=O)[CH2:19][CH2:18]1>CN(C=O)C.O>[CH:17]1([N:20]2[C:25]3[C:24](=[CH:29][C:28]([F:30])=[C:27]([F:31])[CH:26]=3)[C:3](=[O:2])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:21]2)[CH2:18][CH2:19]1
Reactant: O=c1oc(=O)n(C2CC2)c2cc(F)c(F)cc12
Reactant: COC(=O)C=CO
Agent: [Na]
Solvent: CN1CCN(C)C1=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 15 ml single neck round-bottom flask equipped with magnetic stirrer and under nitrogen atmosphere was added 60 mg (0.484 mmol) of the sodium salt of methyl 3-hydroxyacrylate in 1.5 ml of DMF. The resulting solution was stirred in the presence of 4A molecular sieves overnight and then filtered into another reaction vessel fitted with condenser, nitrogen line and a magnetic stirrer. To the mixture was charged 52 μl (0.467 mmol) N,N'-dimethylimidazolidinone and the solution was heated to 55° C. To this reactor was added a solution of 93 mg (0.388 mmol) of N-cyclopropyl-6,7-difluoro-2H-3, 1-benzoxazine-2,4(1H) dione in 1.5 ml of DMF. The reaction mixture was stirred at 55° C. for 1 hour. The system was allowed to cool to room temperature and was then added to 30 ml of water at pH 4.0. The pH of the resulting suspension was adjusted to 5.5 and the mixture was cooled to 0° C. and filtered. After drying there was obtained 50 mg (46%) of methyl 1-cyclopropyl-6,7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate, m.p.: 223° -224° C. The filtrate was extracted with methylene chloride and after drying and evaporation there was obtained an additional 47 mg (43.5%, total yield: 89.5%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>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.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][NH:35][CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCNC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and N-methylpropargylamine (0.055 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 2% to 10% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, methanol-ether, toluene, and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.09 g of the title compound as an off-white solid.
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][N:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:20][CH2:19]1.Cl.[OH-].[Na+]>C(O)C.C(N(CC)CC)C.CCOCC>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][S:1][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:5]3=[N:4][N:3]=2)[CH2:23][CH2:22]1
Reactant: Fc1ccc(N2CCN(CCCl)CC2)c(F)c1
Reactant: FC(F)(F)c1cccn2c(S)nnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(CCSc3nnc4c(C(F)(F)F)cccn34)CC2)c(F)c1
Yield: 58.9 %

Procedure:
A solution of 13 g of 3-mercapto-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine, prepared in Example 18, and 15.5 g of 1-chloro-2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethane as the base, freed from its hydrochloride, prepared in Example 7, by the addition of sodium hydroxide and extraction with ether, in 75 ml of ethanol containing 10 ml of triethylamine is heated under reflux for 6 hours. The reaction mixture is then concentrated in vacuo and the residue is taken up with methylene chloride, which is washed carefully with water, dried and then evaporated. The residue crystallizes when taken up in a mixture of ethyl ether and isopropyl ether. The crystals obtained are filtered off, washed with isopropyl ether and then dried to give 15.5 g of 3-[2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethylmercapto]-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine in the form of crystals melting at 119°-120° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=O)(C)(C)C.[CH3:23][CH:24]([S:26]([C:29]1[CH:30]=[C:31]([C:35]2[N:43]3[C:38]([CH:39]=[N:40][C:41](O)=[N:42]3)=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:25]>>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([NH:21][C:41]2[N:40]=[CH:39][C:38]3=[CH:37][CH:36]=[C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH:24]([CH3:25])[CH3:23])(=[O:28])=[O:27])[CH:30]=4)[N:43]3[N:42]=2)=[CH:20][C:15]=1[O:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(N)ccc1Cl
Product: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(Cl)c(OC[C@H]5CCCN5)c4)nn23)c1

Procedure:
This example was prepared by using (R)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-[3-(Propane-2-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.5 (brs, 1H), 9 (s, 1H), 8.9 (brs, 1H), 8.5 (s, 1H), 8.4 (d, (d, J=7.5 Hz, 1H), 7.8 (m, 2H), 7.5 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.8 Hz, 1H), 7 (d, J=4.8 Hz, 1H), 4.1 (m, 1H), 4.0 (m, 1H), 3.0 (brs, 1H), 3.5 (m, 2H), 3.2 (m, 2H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.1 (d, J=6.5 Hz, 6H); LC/MS (ESI+): 526 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][CH:5]=[N:4][CH2:3]1.S(Cl)([Cl:10])=O.[C:12](O)(=[O:14])[CH3:13]>>[ClH:10].[C:12]([O:1][CH:2]1[CH2:7][NH:6][CH:5]=[N:4][CH2:3]1)(=[O:14])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: OC1CN=CNC1
Reactant: CC(=O)O
Product: CC(=O)OC1CN=CNC1
Product: Cl
Yield: 7 %

Procedure:
5-Hydroxy-1,4,5,6-tetrahydropyrimidine (JOC, 1966, 31, 3838; 1 g, 10 mmol) was dissolved in glacial acetic acid (25 ml) with stirring, and thionylchloride (0.73 ml, 10 mmol) was added dropwise. The resulting solution was refluxed 19 hours, then evaporated to dryness in vacuo. The residue was taken up in water (5 ml), the pH adjusted to 12 (sat. Na2CO3), and extracted with chloroform. The chloroform was dried (MgSO4) and evaporated in vacuo to 440 mg (25%) product as a clear oil identified by 400 MHz nmr. The oil was converted to its HCl salt in anhydrous ethanol with addition of IM HCl in ether. After evaporation of solvents the resulting crude HCl salt was recrystallized from ethanol to yield 128 mg (7%) white crystals, mp 287°-289° C. 400 MHz nmr and ir confirmed product. Calculated: C 40.34, H 6.2, N 15.69; found: C 40.45, H 6.19, N 15.53.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].O.O[N:9]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[Cl:17].S(OC)(OC)(=O)=O>O1CCOCC1>[CH:19]1([N:9]([O:4][CH3:1])[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[Cl:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cccnc1Cl)N(O)C1CCCCC1
Agent: [K+]
Solvent: C1COCCO1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CON(C(=O)c1cccnc1Cl)C1CCCCC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
20 parts of potassium carbonate in 25 parts of water is added to a solution of 16.9 parts of 2-chloronicotinic acid-N-hydroxy-N-cyclohexylamide in 50 parts of dioxane. At 45° C, 12.6 parts of dimethyl sulfate is dripped into the reaction solution and the whole stirred for 30 minutes at 45° C. The reaction product is precipitated by the addition of water. Crystallization from a mixture of benzene and ligroin yields 14.8 parts of 2-chloronicotinic acid-N-cyclohexyl-N-methoxyamide, m.p.: 96° to 98° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:12][CH2:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH2:5]1.C[O-].[Na+].CO.C(N(CC)CC)C.[CH:25]1([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([Cl:37])=[O:36])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[ClH:37].[NH:8]1[C:7]2[CH2:11][CH2:12][CH:4]([NH:3][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:5][C:6]=2[N:10]=[CH:9]1
Reactant: NC1CCc2[nH]cnc2C1
Reactant: O=C(Cl)CCCCC1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCCCC1CCCCC1)NC1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a mixture of 5-amino-4,5,6,7-tetrahydro-1H-benzimidazole, dihydrochloride (420 mg, 2.0 mmol) and DMA (10 ml), 5.4 M NaOMe in MeOH (0.74 ml, 4.0 mmol) was added. triethylamine (0.276 ml, 2 mmol) was added followed by dropwise addition of 5-cyclohexylpentanoic acid chloride (609 mg, 3.0 mmol). When addition was complete the mixture was stirred at ambient temperature for 30 min and then heated at 80° C. for 1 hour and finally allowed to cool to ambient temperature within 1 hour. The volatiles were evaporated and the residue was stirred vigorously with a mixture of H2O (100 ml), 1 N hydrochloric acid (10 ml) and diethyl ether (50 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×50 ml) and then made alkaline to pH 10-11 with 4 N sodium hydroxide. The alkaline mixture was extracted with ethyl acetate (2×50 ml) and the organic extracts were evaporated in vacuo. The residue was dissolved in 1 N hydrochloric acid and evaporated to dryness. The residue was re-evaporated with acetone to give 260 mg (38%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:30])[N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[BrH:31].C(O)(=O)C>C(O)C>[BrH:31].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:30])[N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(O)ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1

Procedure:
A mixture of 7-methoxy-3-[4-[4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.2 g), 47% hydrobromic acid (2.6 ml) and acetic acid (6 ml) was refluxed for 28 hours. After cooling, the reaction mixture was diluted with ethanol and the precipitated crystals were collected. Recrystallization from ethanol afforded 7-hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione hydrobromide (0.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])=[CH:24][CH:25]=2)([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)c1ccc(CBr)cc1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(Cc2ccc(Br)cc2)(C(=O)OC)C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl 2-(4-bromobenzyl)malonate (4.2 g), 1-(bromomethyl)-4-(diethoxymethyl)benzene (4 g) in DMF (50 mL) was treated with NaH (0.8 g, 60% in mineral oil). The mixture was stirred for 2 h at 60° C., and then quenched with 100 mL of 50% saturated NH4Cl. The product was extracted with 200 mL of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated, and dried under vacuum to give the title compound which was used without further purification.