Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH3:35])[CH2:5][P:6]([C@@H:9]([NH:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:33])[N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[CH:20]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:8])=[O:7].O[Li].O>CO.O>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C@H:9]([P:6]([OH:8])([CH2:5][CH:4]([CH3:35])[C:3]([OH:36])=[O:2])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:34])=[O:33])[CH2:31][CH3:32]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)P(=O)(O)CC(C)C(=O)OC)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)P(=O)(O)CC(C)C(=O)O)c1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A solution of 2.11 g of 3-{[(R)-1-(3-dipropylcarbamoyl-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoyl}-2-methyl-propionic acid methyl ester in 8 ml of MeOH was treated with a solution of 865 mg of LiOH.H2O in 2 ml of H2O and the turbid solution was stirred at 20° C. for 1.5 h. The mixture was evaporated and the residue partitioned between aqueous HCl (pH=2) and AcOEt. The organic layer was washed with brine, dried and evaporated to give 1.54 g of the title compound. MS: 501.4 (M−H)—.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=S)=[C:4]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:3]=1[S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28].CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:4]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[C:3]=1[S:27]([N:30]([CH3:32])[CH3:31])(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.3 %

Procedure:
To a solution of N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-bromophenyl)thiourea (240 mg, 0.42 mmol) in dichloromethane (10 mL) at 0° C., methanesulfonyl chloride (0.065 mL, 0.84 mmol) and triethylamine (0.12 mL, 0.84 mmol) were added. 4-Dimethylaminopyridine was added as a catalyst. The reaction mixture was stirred at 0° C. for 1 hour, then it was partitioned between dichloromethane and water. The combined organic phase was dried and concentrated to give the desired product (266.2 mg, crude). 1H NMR (CDCl3) δ 0.4 (s, 6H), 1.09 (s, 9H), 2.86 (s, 6H), 7.06 (d, 2H), 7.1-7.37 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].BrC1C=C2C(=CC=1)N(CC1C=CC(C(C)(C)C)=CC=1)C=C2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]3)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: OCc1cc2cc(Br)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2ccc3[nH]c(CO)cc3c2)c1
Temperature: 70 °C
Yield: 63.5 %

Procedure:
A mixture of (5-bromo-1H-indol-2-yl) methanol (9 g, 39.8 mmol), 3-methylbenzeneboronic acid (6.14 g, 43.78 mmol), potassium carbonate (13.75 g, 99.5 mmol), palladium(II) acetate (0.045 g) and tetrabutylammonium bromide (12.84 g, 39.8 mmol) in 10% dioxane in water (degassed, 0.38 L) was stirred at 70° C. The reaction was monitored by TLC. Additional 3-methylbenzeneboronic acid (5.6 g, 39.8 mmol) was added. After no 5-bromo-1-(4-tert-butylbenzyl)-1H-indole was detected by TLC, the reaction was cooled to room temperature and the solvent was decanted. The residual thick oil was stirred with hexane. The hexane was decanted and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water filtered and concentrated. The residue was purified by flash column chromatography using hexane/ethyl acetate (55:45) as an eluant to give [5-(3-Methylphenyl)-1H-indol-2-yl]methanol as a brown solid (6.0 g). Reaction of [5-(3-Methylphenyl)-1H-indol-2-yl]methanol with acetyl chloride according to the procedure described in step 4 of Example 1 afforded the title compound as an oil (3.94 g); Mass spectrum (ESI, [M−H]−) m/z 278. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.46 (s, 1H), 7.42-7.36 (m, 3H), 7.30 (s, 1H), 7.10 (d, 1H, J=7.48 Hz), 6.50 (s, 1H), 2.37 (s, 3H), and 2.07 ppm (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:14]([CH2:13][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:15](=[O:16])[N:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: O=C(NCC1CCCCC1)NCC1CCCCC1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
Cyanoacetic acid (Aldrich, 21.0 g, 0.247 mole) was dissolved in acetic anhydride (260 mL). This solution was added to 1,3-bis(cyclohexylmethyl)urea (from step (a), 54.5 g, 0.216 mole) and the solution maintained at 80° C. for 2 h under nitrogen. Volatiles were removed in vacuo and the residual oil dried by evaporation of portions of 10% water-ethanol (3×400 mL). The residual solids were dissolved in ethanol (600 mL)-water(300 mL) at 80° C. with adjustment of the pH to 10 by addition of 10% aqueous sodium carbonate. The hot solution was diluted with water (75 mL) and cooled to ambient temperature. The colorless crystals which formed were filtered off, washed with water (3×500 mL) and dried at 0.5 Torr to give 6-amino-1,3-bis(cyclohexylmethyl)uracil (64.98 g, 94%), m.p. 138°-141° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CCNCC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M−H)−=444/446/448 (chlorine isotope).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CN(C)[CH:32]=[O:33]>O1CCCC1.CCCCCC>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][C:23]=1[CH:32]=[O:33]
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
A solution of 68 ml (0.4 mol) of 2,2,6,6-tetramethyl- piperidine in 1 l of tetrahydrofuran is cooled under argon to -10° and at this temperature there are added dropwise thereto while stirring 250 ml of a 1.6M solution of n-butyllithium in hexane. Subsequently, 62 ml (0.4 mol) of 1,3-bis(trifluoromethyl)-benzene are added dropwise thereto at -10° within 5 minutes. The resulting wine-red solution is stirred at -10° for a further 5 minutes and then 62 ml (0.8 mol) of N,N-dimethylformamide are allowed to flow in rapidly. The internal temperature rises by 15° as a consequence of the exothermic reaction. The dark brown solution obtained is then added slowly and under a slight argon pressure to 1.2 l of stirred, ice-cold 1M hydrochloric acid. The internal temperature rises to 10° as a consequence of the stongly exothermic reaction in spite of constant cooling. The resulting emulsion is diluted with 750 ml of hexane, the aqueous phase (1.5 l) is separated and stored for the recovery of 2,2,6,6-tetra- methylpiperidine. The organic phase (1.9 l) is extracted twice with 1 l of water each time, dried over sodium sulphate, filtered and the organic solvent is distilled off at 40° under a vacuum (20 kPa). The residue (about 100 ml) is distilled over a column having a length of 20 cm, firstly at 50° bath temperature under a vacuum of 20 kPa in order to remove the residual solvent, then the bath temperature is increased to 80° and the vacuum is increased to 1.4 kPa. A forerun is removed until the constant internal temperature of 57° has been reached and then the residue distils over as a fraction at 57°/1.4 kPa. There are obtained 68 g (70%) of 2,4-bis(trifluoromethyl)benzaldehyde with a purity (GC) of 96-98%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:6]2[C:7](=[O:9])[CH:8]=1.[Br:15]N1C(=O)CCC1=O.C(O)(=O)C.O>C(Cl)Cl>[Br:15][C:8]1[C:7](=[O:9])[N:6]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: Cc1cccc2nc(CCl)cc(=O)n12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2nc(CCl)c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-(chloromethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.5648 g, 17.09 mmol), N-bromosuccinimide (3.35 g, 18.79 mmol), and acetic acid (48.2 mL, 843 mmol) was stirred at rt. After 4.5 h, the mixture was poured into water (200 mL) and the resulting precipitate was collected by filtration, washed with water (200 mL), and dried to give an orange solid. The orange solid was dissolved in DCM (100 mL), dried over Na2SO4, filtered, and concd under reduced pressure to give 3-bromo-2-(chloromethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (1 H, dd, J=9.0, 7.0 Hz), 7.47-7.52 (1 H, m), 7.04-7.09 (1 H, m), 4.71 (2 H, s), 2.95 (3 H, s); Mass Spectrum (ESI) m/e=288.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].[Br:18]Br.C1(C)C=CC=CC=1>CC(O)=O>[Br:18][C:15]1[C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]([OH:17])=[C:2]([Br:1])[CH:16]=1
Reactant: BrBr
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCNC(=O)Nc1nc2c(Br)cc(Br)c(O)c2s1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea (50 mg, 0.158 mmol) in AcOH (2 mL) at about 20° C. was added Br2 (9 μl, 0.174 mmol). The reaction mixture was stirred at about 20° C. for about 15 minutes. Toluene (10 mL) was added and the solvents evaporated. The crude material was purified by preparative LC/MS to give 19 mg (30%) pure 18. 1H NMR (DMSO) δ 1.09 (t, 3H, J=6 Hz CH3), 3.19 (m, 2H, CH2), 6.55 (br s, 1H, NH), 7.68 (s, 1H, ArH), 10.51 (br s, 1H, NH or OH), 11.20 (br s, 1H, NH or OH). HPLC retention timer 2.90 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCOc1cccnc1
Product: c1ccc(CNCCCCCCOCCOc2cccnc2)cc1

Procedure:
A solution of 3-[[2-[(6-bromohexyl)oxy]ethyl]oxy]pyridine (2 g) and benzylamine (10 ml) was stirred at 140° under nitrogen for 3 h. The solution was partitioned between 8% sodium bicarbonate (100 ml) and ethylacetate (100 ml). The organic extract was dried and distilled to give the title compound (1.8 g) as an oil. T.l.c. (System B 80:20:1) Rf 0.54
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[O:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([OH:17])[CH2:16][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: c1ccc(COc2ccc(C3CO3)nc2)cc1
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)cn1

Procedure:
To a solution of 20.7 g. (0.091 mole) of 5-benzyloxy-2-(1,2-epoxyethyl)pyridine in 250 ml. of methanol, 25 ml. of tert-butylamine was added and the resulting solution was heated at the reflux temperature for 2.5 hours. The solvent and the excess tert-butylamine were evaporated in vacuo to give after recrystallization from hexanes, 17.3 g. (61%) of 5-benzyloxy-2-(1-hydroxy-2-tert-butylaminoethyl)pyridine; m.p. 69°-73° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[H][H].C.CC.C=C.[C]=O.C(=O)=O>O>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[NH:5][CH:11]=[CH:10]2)[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: [H][H]
Agent: C
Agent: C=C
Agent: CC
Solvent: O
Product: CCc1cccc2cc[nH]c12
Temperature: 660 °C

Procedure:
The reactor for the dehydrocyclization contained 0.5 liter of Cu-chromite/BaO catalyst in table form (4×4 mm). The reactor was heated to 660° C. and was fed 68 g of 2,6-diethylaniline and 81 g of water per hour. After cooling, a mixture of a heavily organic phase and of a lighter water phase, as well as a waste (discharge) gas, was obtained in the recipient vessel. The waste gas had the following typical composition (vol. percent): 80.0 percent of hydrogen; 2.9 percent of methane; 2.0 percent of ethane; 0.4 percent of ethylene; 2.0 percent of carbon monoxide; and 10.7 percent of carbon dioxide. Obtained per hour were 38 l of waste gas, 59 g of organic raw product and 76 g of water which can be used again. The organic raw product had the following composition:
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O.[BH4-].[Na+]>O>[Cl:12][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: OCc1ccc(Cl)nc1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
69.5 g (0.5 mol) of 6-hydroxynicotinic acid are introduced into a mixture of 200 g (1 mol) of phosphorus pentachloride and 233 g (1.5 mol) of phosphorus oxychloride at room temperature, the mixture is stirred at 95° C. for 5 hours and excess phosphorus chlorides are then removed in vacuo. The crystalline residue is introduced into a solution of 75 g (1.98 mol) of sodium borohydride in 1,000 ml of water, the temperature being maintained at 30° C. at most. The mixture is then stirred at room temperature until the completion of gas evolution and is filtered with suction from solid material, and the filtrate is extracted using ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[F:40])=[O:31])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:16])[S:14][C:7]=12.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[F:40])=[O:31])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[S:14][C:7]=12
Reactant: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCC(=O)O)sc34)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate (110 mg, 0.19 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 60° C. for 2 hours, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid as white solid. Yield: 95 mg, 90%.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C>[C:7]1(=[O:9])[O:11][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: O=C1CCCCCC(=O)O1

Procedure:
A solution of 32 g. pimelic acid in 300 g. dry diethyl ether was added portionwise, while stirring, to 40 g. dicyclohexyl carbodiimide in 100 ml. dry diethyl ether. The mixture was stirred for 24 hours and filtered. The filtrate was evaporated to give pimelic anhydride in the form of a thick oil. This was taken up in 150 ml. dry pyridine and treated with 12 g. 2-hydroxymethyl-18α-glycyrrhetinic acid. The solution was stirred and left for 5 days, whereafter it was poured into dilute hydrochloric acid and ice. After stirring the mixture for 1 hour, the gummy precipitate was separated off, dissolved in diethyl ether, washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulphate and treated with charcoal. After filtration and evaporation of the filtrate, there was obtained 2-carboxyhexanoyloxymethyl-18α-glycyrrhetinic acid in the form of a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH2:13])=[S:12].BrBr>C(Cl)(Cl)Cl>[NH2:13][C:11]1[S:12][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:10]=1
Reactant: COc1ccc(Cl)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)c2sc(N)nc12
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmole) in chloroform (10 mL) was cooled to 10° C. and treated with bromine (2.2 mmole) in chloroform (10 mL). The reaction was stirred at 10° C. for 20 mm and at room temperature for 0.5 h. The resulting suspension was heated at reflux for 0.5 h. The precipitate was collected via filtration (washed with CH2Cl2) to give 2-amino-4-methoxy-7-chlorobenzothiazole which was subjected to Steps A, B, C and D of Example 34 to give 2-amino-4-phosphonomethoxy-6-bromo-7-chloro benzothiazole (35.1). mp >220° C. (dec.). Anal. Calcd. for C8H7N2O4PSCIBr: C:25.72; H: 1.89; N:7.50. Found: C:25.66; H:1.67; N:7.23.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][CH2:24][C:25]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.ClCCl.[C:45](Cl)(=[O:47])[CH3:46]>C(OCC)(=O)C.O>[C:45]([N:28]1[CH2:29][CH2:30][C:25]([CH2:24][NH:23][C:21]([C:17]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[C:12]3=[N:19][C:18]=2[CH3:20])=[O:22])([C:31]([O:33][CH3:34])=[O:32])[CH2:26][CH2:27]1)(=[O:47])[CH3:46]
Reactant: COC(=O)C1(CNC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1(CNC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 150 mg of methyl 4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]piperidine-4-carboxylate dihydrochloride, 150 μl of triethylamine, and 5 ml of dichloromethane was added 25 μl of acetyl chloride under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 135 mg of methyl 1-acetyl-4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]piperidine-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17].[S:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[S:30].C1(C)C=CC=CC=1>CCOC(C)=O>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:34]2[S:28][C:29](=[S:30])[NH:31][C:32]2=[O:33])[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C(C)=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(C)=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reaction time: 8 h
Yield: 62 %

Procedure:
To a flask with a stir bar and attached to a condenser, was added 1-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-ethanone from Step A (244 mg, 622 μmol), rhodanine (133 ng, 1.0 mmol), NH4OAc (77 mg, 1.0 mmol) and toluene (5 mL). The reaction mixture was heated to reflux and stirred for 8 h at reflux. Additional NH4OAc (50 mg) and toluene (2 mL) was added to the mixture and allowed to reflux for an additional 24 hours. The reaction solution was then diluted with EtOAc (75 mL), washed with NH4Cl (50 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (TLC, DCM/EtOAc 100:0 to 85:15) to provide the intermediate compound. (195 mg, 62% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.Cl.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][O:18][CH2:17]2.CCN(CC)CC>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:23]2[CH:16]3[CH2:22][CH2:21][CH:20]2[CH2:19][O:18][CH2:17]3)[N:7]=1
Reactant: C1CC2COCC1N2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)nc(N2C3CCC2COC3)n1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in CH2Cl2 (100 mL) were added 3-oxa-8-azabicyclo[3,2,1]octane hydrochloride (1.645 g, 11 mmol) and Et3N (4.2 mL, 30 mmol). The mixture was stirred at room temperature over night. The reaction mixture was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white solid (3.0 g, 96% yield). MS (ESI) m/z 312.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)(=[O:16])=[O:15])([O-])=O.O.O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:7]=[CH:6][C:5]=1[S:14]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)(=[O:15])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 70.7 %

Procedure:
In a similar fashion using route 15 general procedure 29, 2-nitro-N-quinolin-8-yl-4-trifluoromethyl-benzenesulfonamide (Example Compound 32) (1.22 g, 3.07 mmol) and tin (II) chloride dihydrate (3.46 g, 15.4 mmol) gave the title compound (797 mg, 71%).